Essentials: Compulsive Behaviors & Deep Brain Stimulation | Dr. Casey Halpern

[00:01] [music] where we revisit past episodes for the most potent and actionable science-based tools for mental health, physical health, and performance. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at

[00:15] Stanford School of Medicine. And now for my discussion with Dr. Casey Halpern. welcome. >> Thank you. >> You're a neurosurgeon, which I consider the astronauts of neuroscience. For

[00:28] differences between neurosurgery, neurology, psychiatry, could you just educate us a bit? What does a neurosurgeon do and how do you think >> Yeah, yeah, the scope of neurosurgery is quite broad. We take out brain tumors,

[00:43] we clip aneurysms in the brain, we take care of patients that have had traumatic brain injury, um concussion, uh spine surgeries. 90% of what neurosurgeons do around the country, uh you know, taking care of herniated discs and lumbar

[00:57] fusions. So, you know, the the scope is includ- including the peripheral nervous system. We take care of patients with carpal tunnel syndrome and nerve disorders. Historically, neurosurgeons

[01:10] did everything in that domain, but now we subspecialize and I I'm lucky to be at Penn Medicine where we can focus on one of these areas. So, I'm uh chief of stereotactic functional neurosurgery.

[01:26] All I do is deep brain stimulation surgery and a complement to that is 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

[01:40] moment. Deep brain stimulation is a procedure where we have to place a uh 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

[01:55] 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 wire. They're very small. It's a bit more like I have to implant a a tool to

[02:10] to deliver you a medication, uh but that medication is going to be in the form of delivered into a very small region of the brain. I'm very privileged to be able to interact with the human brain in this way. It's always in the

[02:23] it with the goal of trying to provide somebody with a meaningful therapy. But 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

[02:36] 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 off. But often, these side effects

[02:49] that's how we have discovered ways to use deep brain stimulation um not just disease, but for example, patients with Parkinson's disease that have a

[03:02] uh comorbidity like depression or obsessive-compulsive disorder, a lot of these patients are highly compulsive uh and impulsive. Um Sometimes, these problems actually melt

[03:16] tremor, but the patients also tell us that their gambling issue has gotten why is that? Well, reason. You know, you can help somebody's mood by making their tremor

[03:29] go away, of course. But we see laughter in the clinic sometimes. And And why is stimulating parts of the brain that are not just involved in these motor circuits, but they're also involved in

[03:41] 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

[03:55] impressive and consistent effect we have when we have a patient with tremor who 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

[04:09] I've never really wanted to do anything else except help develop that type of symptom. >> I'd love to learn more from you about

[04:22] is OCD? >> Sure. >> 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

[04:36] true OCD? >> 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 a three to

[04:49] 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

[05:02] improve outcomes of deep brain stimulation for for OCD. So I I do feel I have expertise and and a perspective to share. I do feel that as a neurosurgeon, I am obligated to better understand

[05:15] where the obsessions in the brain come from and how we can interrupt them to stop the compulsion that's associated with the obsession better than we're actually doing it. I've been leading an endeavor with a number of collaborators

[05:27] around the country to try to better understand the circuits in the brain, uh study them in humans both invasively and non-invasively. That surgery, uh sort of like we do in epilepsy to understand where seizures

[05:42] where obsessions come from, but we're also working with imaging experts and geneticists to understand OCD at a broader level as well. I consider OCD to be a a spectrum disorder in a way. And I

[05:57] I I apologize to those who who might feel that I'm using that term incorrectly. I'm using it in a way to describe patients that have obsessions and even some related compulsions might not meet

[06:09] criteria for OCD. As a neurosurgeon, I'm really obsessive about safety and compulsive about my surgical procedures. So, you know, I I think that some aspect we should, you know, consider seriously cuz people do suffer from this.

[06:25] Uh some aspect of it helps us. Uh there are, you know, famous uh CEOs 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

[06:40] asset. And uh but if it goes awry and it's uncontrollable, then it becomes obsessive-compulsive disorder. And uh I tend to see the patients that are the most severe. So, they have failed

[06:53] medications that are worth trying for OCD. Some can actually be very helpful. >> Which which neurotransmitter systems do they tend to poke at? >> Well, SSRIs are sort of the the first uh line for OCD, but also tricyclics can be

[07:07] Uh 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 be specific to one of these things. And

[07:21] 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. And there's others. Exposure

[07:34] response prevention is probably the most effective option, which is kind of like are different and offered by psychologists, and this is a whole field, and there's a whole clinic at my institution

[07:48] uh focused was started by Edna Foa um uh at Penn who this is what they do for these patients uh is offer these types of cognitive therapies, exposure to the stressor, and

[08:02] whatever it is that stresses them and causes these uh compulsions to help these patients live in everyday and function. The These fabulously helpful uh therapies for a variety of patients, but there's still

[08:17] about 30% of patients that still suffer from OCD, and some of them have 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

[08:32] pursuing, but not optimal. Um and so it's it's one of those things because when you see patients like this, help them, and I think it's important to educate patients on the risk and

[08:45] stimulation surgery, but also capsulotomy, which is more of an ablation approach, a little bit like deep brain stimulation, but rather than electrode, you can actually heat the tissue and even destroy it. Some would

[08:59] 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 I find so amazing about the brain, these

[09:14] effects that we can have. Sometimes the lack of effect is what's so amazing. You 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

[09:28] of the brain. We're talking 3 or 4 mm 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

[09:40] 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

[09:53] 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

[10:08] disease-specific or symptom-specific way. Were one to come into your clinic this, you know, for this sort of a work of ablations or uh where would you first start to probe in the brain?

[10:22] Yeah, you this is a uh a disorder of both cortex and the sub- subcortex. We find that areas in the cortex like the prefrontal and orbitalfrontal cortex are are not

[10:35] non-OCD patient. They are often hyperfunctioning, and we need to find a And then there are projections to the subcortex. This is the basal ganglia, striatum. And these are interconnected with the ventral striatum. This is an

[10:49] area of the brain that 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

[11:02] 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 similar to an OCD patient. They will

[11:14] check their home for safety until 3:00 a.m. in the morning and not sleep that night. Doing something because of the urge, but despite the risk. When our judgment is consistently uh sort of puts us at risk, that's where

[11:28] we have something like OCD. Contamination behavior, where they if their hands for hours repeatedly or if they drop their toothbrush on the floor this will lead to a compulsive behavior of cleaning a toothbrush or brushing

[11:41] your teeth consistently very very common symptoms that we see or signs that the patients report to us or or that we observe. But you know patients with eating disorders you know they tend to if if they have bingeing disorder

[11:53] they'll overeat if they have bulimia they might purge despite the risk of these things. And so addiction is is similar we we tend to drug seek if we're addicted we'll we'll pay off a dealer in order to

[12:07] get our fix and despite the risk and and that type of urge despite the risk is interested in and it's a common denominator to all of these problems and these are some of the most common conditions in our society today and I

[12:22] cortical areas that we've been discussing that that sort of send projections to these areas are are probably at least one of the main >> What is nucleus accumbens? What roles

[12:36] and in pathology? >> Yeah the nucleus accumbens is a part of the brain part of our reward circuits. It has a lot of functions. Uh

[12:48] it interconnects with many parts of the brain. So when I started getting interested in reward and what a what I could do as a reward and what a what I could do as a surgeon to try to improve how we manage

[13:00] And what I mean by that specifically is if you have an urge for a reward that's not something we're trying to stop. The the issue is if you have an urge for a a reward that either puts you or somebody else at risk it's probably a

[13:16] reward we shouldn't have. If you're a drug addict and you use heroin or opiate that opiate might make you feel better cuz life is stressful but the risk of doing those things is really high. In fact, potentially lethal. If you have

[13:30] fact, potentially lethal. If you have OCD and you nervous that you didn't lock the door and you've checked 30 times. That's an urge we got to treat. Eating disorders the same. This problem can be

[13:43] ameliorated or improved upon by a better understanding and a tailored treatment to the nucleus accumbens specifically. It seems that repeated exposure to something like a drug of abuse or any type of reward that is a really strong

[13:59] In a way, it it can hijack normal functioning of the nucleus accumbens. So, the goal is to just disrupt perhaps what is kind of habitual. or or at least this kind of recurring problem that is

[14:14] binge eating disorder, at least at a severe level, they tend to binge about once a day. So, what we decided to do in the operating room was to actually try to leverage a tool that

[14:27] 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 to try to improve their movement disorder,

[14:40] uh we often can hear tremor cells. And they sound we convert their so we can actually hear it. And it sounds kind of like the tremor looks, like the frequency of the signal is the same as the hand shaking.

[14:55] >> And you're poking around in a dedicated, careful way, of course. >> One poke at a time and with a very fine wire set of wires, listening to the electrical activity until you you encounter some cells that are

[15:10] >> Exactly. >> And then you can stimulate them or quiet >> So, we we are very confident that when we stimulate that area of, in this case,

[15:22] the subthalamic nucleus, we will disrupt that tremor circuit and that tremor will dissolve. And it does. >> So, what is the analog to tremor in >> Craving. So, craving is a term

[15:38] terms we could use, by the way, but that that's the term we've chosen to use for a number of reasons. One, because people relate with that term. People that have binge eating disorder or obesity, they if you ask them if they crave, the

[15:50] answer will often be yes. Um if you ask them if they lose control or binge, they might not know what you mean, or they might not actually feel Um So, uh

[16:02] but the word craving is relatable. And so, we set out to see if we could identify craving cells. Um in a patient with OCD, which is similar part of the brain, uh

[16:17] we tried to identify cells related to obsessions. And we believe we did do that. It was a single case study uh where we tried to optimize had some proof of concept that we would be able

[16:31] to elicit a sort of disease-specific symptom in the operating room, assuming the patient could tolerate being awake. Not everybody needs to be awake for this in human trials where um we're trying we're trying to

[16:45] be, uh I think this type of approach is >> What is the status of non-invasive brain stimulation, ablation, and blocking is that transcranial magnetic stimulation is being used to treat

[16:59] depression and a number of other um brain syndromes through the skull. My understanding is that the spatial precision isn't that ultrasound is something I hear a lot

[17:12] understanding is that ultrasound can allow researchers and clinicians to stimulate specific brain areas. What are your thoughts on these forms of non-invasive, meaning no no flipping open of a piece of the skull, type brain

[17:26] stimulation and blockade of brain activity? approaches. Some of them are a little fluffy in that we don't understand how We don't necessarily understand how deep brain stimulation works, by the way, so

[17:39] they work, they're not as precise as we would like them to be, so we have work to do there. And I actually think that work is doable and actually underway. TMS, transcranial magnetic stimulation, it is FDA approved for depression, by

[17:52] and for nicotine addiction. We believe we can use TMS to to define a circuit we can use TMS to to define a circuit that if modulated improves OCD, albeit it's temporary, they would be appropriate for an invasive study. So,

[18:09] I've always believed that neurosurgeons need to be part of the discussion with need to do them, um but um I think we can help make them

[18:21] more precise and to probe non-invasively with purpose. Perhaps one day there will be a TMS target for anorexia and obesity. if we are scratching the surface with

[18:34] invasive approaches to these problems, we we're even doing less with the brain stimulation. Um so, we have so much work to do there. Eating disorders and TMS have been so um sort of

[18:47] there have been such little research done in that space. Um so, it it it is an area that we need to to work on. So, ultrasound right now transcranial magnetic guide magnetic resonance guided focus

[19:01] ultrasound. So, um uh this this is an FDA approved method to deliver an ablation to the brain There are uh researchers, myself

[19:15] included, that are trying to use transcranial magnetic guided magnetic resonance guided focused ultrasound or MRI guided focused ultrasound to use it in a modulatory way, not just as an ablation, but to drive neuronal

[19:28] activity or inhibit it, perhaps. We're still learning how to do that. Um understand if you can use ultrasound to open the blood-brain barrier so you can deliver a medication to that specific area. Perhaps for a brain tumor or

[19:42] something like that. So, it's a very exciting field now. And so, I actually for patients with tremor with Parkinson's or essential tremor.

[19:56] Parkinson's or essential tremor. And so, I I love doing it. It's often no incision. I don't have to place an electrode into the brain to achieve a effective for these patients. It treats patients on one side, usually their

[20:10] it um it really speaks to the fact that well, you can deliver non-invasively an ablation to the brain in a hypothesized zone that we think is related to the problem at hand. And at least with

[20:24] tremor, it works really well. Could this be effective for psychiatric disease, obesity, eating disorders? Uh well, ideal. The problem is we don't know where to do

[20:38] the ablation. Um there is a trial that we would like to do for OCD where we would deliver an ablation to the same area of the brain for years for patients with OCD and it helps a bit. That's called a

[20:50] capsulotomy. Um but really the outcome is probably going because it's it's not invasive, but we need to find a new target for these for these conditions. And because of the common denominator of the urge despite

[21:04] the risk, sort of that compulsion, Um yeah, perhaps it could be the same target. I don't know. Um but I would argue we need to do these modulatory experiments either with a device or with invasive recordings uh to

[21:19] better understand where these problems are coming from, to define where we should do an ultrasound treatment. There has been a revolution in America. It was in Europe before it was in America where we would do stereo encephalography,

[21:31] which is basically like doing an EEG of patients with epilepsy, but with invasive electrodes. And we would place tiny little wires less than a millimeter parts of the brain that we believe are involved in seizures.

[21:45] hospital and figure out where the seizures were starting and propagating. through these electrodes to see if there was a symptom that was important and I try to identify a region that we thought we could either

[21:59] remove surgically, ablate with a laser, or put a stimulator in it, perhaps. Um that's commonplace now for epilepsy. Um and it works extremely well and it's very safe. Of course, it's still a brain

[22:12] procedure, um but the uh the complication rate is surprisingly low, electrodes that we place. And it's extremely well tolerated. Most of these surgery.

[22:25] interest in using that procedure to study to do it for patients with obsessive compul- compulsive disorder. We're awaiting an FDA decision on that. Uh but actually I credit uh

[22:39] our colleagues at Baylor and at UCSF for for studying this uh already. Bringing together the epilepsy technique and the psychiatry expertise to study how we could better target electrodes in depression.

[22:52] consistent target, perhaps there becomes an ultrasound target. Um but right now the approach is a bit more reversible cuz you can always shut that electrode off or even remove the electrode if perhaps it's not in the

[23:07] depression. Uh but actually after a large volume of uh cases perhaps, they could pool that data cases perhaps, they could pool that data to develop a a new ultrasound target for

[23:20] fabulous and probably is their long-term goal. Not to speak for them, uh but that their radar. You might ask, well, why aren't you doing this for obesity right now in uh in our in our study? And the reason is

[23:33] we've developed a target for obesity uh and binge eating disorder uh developed out of mice that we believe um is relevant for the human state because you can model this problem in a mouse a bit better than you than you can model

[23:47] depression or OCD. So, we feel like we can rely on the preclinical studies more. Whereas with these perhaps more I don't want to say more complicated, but more human mental health conditions that are

[23:59] hard to model in a mouse, you really have to study it in the human. And you patient, a patient that has electrodes and try to provoke a depressed state or study epileptics that have comorbid depression, for example.

[24:14] approach as well. But in the end, it's it's getting into the human brain that we need to do in the disease specifically. That will eventually lead to a non-invasive approach, either a lesion

[24:28] or modulatory approach. Modulatory would be like TMS or lesion approach would be with uh ultrasound. >> If people can be made to feel or make better, a little less anxious just prior to a

[24:41] craving episode or a binge episode, maybe even if people can become better at detecting their own internal states and when they're kind of veering toward a binge or veering toward using a drug or

[24:54] maybe even veering toward suicidal thinking. Seems like that awareness seems like maybe among the best tools that people could develop. I've always thought that if we can improve awareness, we can improve

[25:07] outcomes. I think that's probably true for many of these patients. The problem I think comes down to the fact that some of these patients are so resistant to treatment. And the patients that we see as a

[25:19] surgeon, for example, are the patients that they've tried cognitive behavioral therapy, and they've tried medications, they've tried behavioral management. They're as aware as they could possibly be, and they still lose control. We've

[25:32] had this studied in the lab. So, we will bring patients to the laboratory with this implanted device to to try to provoke this electrographic um that can be detected by the actual device that will stimulate them when

[25:47] But before we actually initiate stimulation, we want to to see can this stimulation, we want to to see can this device detect this craving cell signal, we saw in the operating room, because that's a single cell, but these devices,

[26:00] in diameter instead of like a tenth of a millimeter, which is what we use in the operating room. Um so, they're they're only hearing or or detecting, I should say, thousands of cells' responses. And

[26:15] we actually have a way to provoke binges. It's called a mood provocation. It's a little bit like provoking seizures in the epilepsy monitoring but uh psychiatric monitoring unit or the the

[26:30] food monitoring unit, uh we we actually have a psychiatrist and eating disorder specialist come and induce a mood that is related to each patient's sort of self-described binge episode.

[26:46] >> Yes. >> a feeling that can evoke the negative >> That's exactly right. So that we can video and synchronize the video to the

[26:58] brain signal recordings. The patients all wear an eye tracker so times and what they're looking at specifically and that allows us to

[27:10] have the best temporal resolution possible to understand what is happening right before the bite. And even under video surveillance through a one-way one-way mirror in a laboratory setting when patients are

[27:24] very well aware that they're there to be studied if they're going to They still do and we believe they do because they just it.

[27:37] most severe. So I think if we can improve awareness, I've been talking about earlier, but the patient awareness around their problem, I think that could be a powerful way to help so many of

[27:50] these patients and that's sort of the role of cognitive behavioral therapy. therapy or I should say the limitation of it, I actually don't have a any problem with it. I think it's a wonderful treatment.

[28:04] patients go back to their old behaviors. I don't want to say old habits, but it might be a habit, but the old behaviors. And so um necessarily lasting in the absence of continued cognitive behavioral therapy.

[28:17] Some people can benefit [clears throat] from it long term, but some can't. Uh but I think in in in in the less severe patients, But in these really refractory patients, this is this is kind of like this is the

[28:29] disease despite the awareness. They can't control themselves and that's what we're trying to restore is that improved ability to control their behavior. >> Do you think there's a role for machines and artificial intelligence here?

[28:44] the University of Washington that are using particular signature patterns of within voice to try and help suicidal

[28:57] people who are suicidally depressed know when they're headed towards an know. This gets right down to issues of free will and whether or not machines know, one could argue that some of the search algorithms

[29:10] actually more aware of our preferences Basically, what these are these are devices that are listening to people attention to patterns of breathing and how well people slept, etc. Integrating

[29:24] a a huge number of cues and then signaling somebody with a uh you know, a yellow light. Like, you know, you're headed into a depressive episode. The "I feel pretty good. This is kind of baseline state for me." And they're

[29:36] baseline state for me." And they're saying, "Uh-uh. This is where you were down a deep dark trench and it took months to get out of." >> Um I wonder whether or not some of these devices could help with the sorts of

[29:49] >> Yeah. I think so. Um I've always said we have to get in the brain before we get out of it. And if we get in the brain and understand what these signals look like, we'll know what

[30:01] those non-invasive signals are. I think it's possible that we are uh scientifically sophisticated enough to use machine learning and sort of this use machine learning and sort of this kind of bot technique to anticipate when

[30:16] impulsive. You know, suicide is the most dangerous impulse. It's something that dangerous impulse. It's something that is compulsion. Compulsion being, you know, going after

[30:31] a reward or or the urge despite the risk. Um different. It's It's kind of going after something um impulsivity in a in a mouse, it's, you know, related to

[30:46] you know, going after a food reward without the sort of paired tone that for. The mouse doesn't want to wait anymore. They they just go after the >> I've been that mouse. >> Yeah, we've all been.

[31:00] We can all relate with this uh to a certain extent. Again, it's a spectrum. um So, in any case, I non sequitur, but I I I certainly think that there is a way to use our own

[31:14] body's physiology to anticipate when these impulses are coming online. How best to do that, I think we're just scratching the surface, but um these are the kinds of solutions we

[31:27] need. Some of these problems are of epidemic proportions, largest public health problems in this country, in this world, obesity, opiate crisis, depression, suicidality. I mean, that's like a third of our country, maybe more.

[31:40] know, I'm I'm a neurosurgeon. I'm only going to be able to treat the most You know, how you know, we've only done about 200,000 ever. So, I mean, the problem we're talking

[31:56] about here is 50 million Americans. There's no possibility that surgeons can address that problem. But, we could help inspire an initiative to go after that kind of problem or help make it more rigorous.

[32:10] Because the last thing we need is a you know, some sort of wearable fancy tool know, some sort of wearable fancy tool that you know, we need real therapies for these things. Not that these devices that we're

[32:22] discussing are not. I think actually there's lots of promise. the time. I'm not a an electrical engineer or the type of work. I I just helped develop the hypotheses around it. But, um I help

[32:36] fundraise around it. But I I definitely think there's a future for it. I just surface on how best to do it. >> I really appreciate you sharing those I'm guessing out there might want to become neurosurgeons. I really believe

[32:51] that in hearing today's conversation that you will spark an interest in >> Um well, certainly you need to be a physician before you can become a neurosurgeon. So and neurosurgery in some cases and that would be beautiful

[33:03] will happen excuse me as a consequence to thank you for taking time out out of your not just immensely busy, but very important schedule because again, the work that you're doing is

[33:16] really out there on that cutting I don't want to say bleeding edge cuz in this context it's not going to sound right, but on that extreme cutting edge of what we understand about how the human brain works and how it can be repaired. So on

[33:28] behalf of everybody and and myself as well, thank you so so very much. >> I'm honored. Thank you so much for having me.