Andrew Huberman (4:19)

I'd love to learn more from you about ocd. Could you perhaps just tell us what is ocd? 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?

Dr. Casey Halpern (4:37)

My perspective on OCD may be a little bit different than a psychiatrist who lives and breathes OCD and sees patients every single day with ocd? 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, I'm very focused on trying to improve outcomes of deep brain stimulation for ocd. So I do feel I have expertise and a perspective to share. 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 better than we're actually doing it. I've been leading an endeavor with a number of collaborators around the country to try to better understand these circuits in the brain. Study them in humans, both invasively and non invasively. That would be with an electrode based surgery, 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 at a broader level as well. I consider OCD to be a, a spectrum disorder in a way, and I apologize to those 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 criteria for ocd. As a neurosurgeon, I'm really obsessive about safety and compulsive about my surgical procedures. So I think that some aspect of ocd, which we often joke about, but we should consider seriously because people do suffer from this, some aspect of it helps us. There are famous CEOs that probably have some level of OCD, surgeons and scientists alike. So perhaps if it can be controlled, it's an asset. But if it goes awry and is uncontrollable, then it becomes obsessive compulsive disorder. And 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.

Andrew Huberman (6:59)

Which neurotransmitter systems do they tend to poke at?

Dr. Casey Halpern (7:02)

Well, SSRIs are sort of the first line for OCD, but also tricyclics can be helpful. So this is still the serotonin system, but as we know, the serotonin system interacts with the noradrenergic system and the dopamine system. So it's hard to be specific to one of these things. And, and I think that's also why it's hard for us to predict how these medications are going 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, response, prevention, is 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 whole clinic at my institution focused. It was started by Ed Nafoa at Penn, who. This is what they do for these patients 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 compulsions to help these patients live in every day and function. These are all fabulously helpful 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. Our therapies for those patients right now I would say are worth pursuing, but not optimal. And so 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. Others would say it's safer to modulate. I have seen patients do very well with these ablations. And so, you know, you asked me earlier 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 traverse parts of the brain without having any adverse effects on patients. Function, at least that you can test. 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. But nonetheless, despite how safe they might be, 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 can generally achieve a responder rate of about 50% and responders still have symptomatic OCD. So I'm really sort of inspired to really find a way to deliver these therapies in a more disease specific or symptom specific way.

Andrew Huberman (10:11)

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Andrew Huberman (11:51)

Come into your clinic for this sort of work of ablations or stimulation. Where would you first start to probe? In the brain?

Dr. Casey Halpern (12:01)

Yeah. This is a disorder of both cortex and the subcortex. We find that areas in the cortex like the prefrontal and orbital frontal cortex are not functioning the way they would in a non ocd patient. They are often hyper functioning and we need to find a way to try to normalize their function. And then there are projections to the subcortex. This is the basal ganglia, caudape, putamen or the dorsal striatum. And these are interconnected with the ventral striatum. This is an area of the brain that I focus A lot of my energy in this is the ventral stratum, which is not limited to, but includes the nucleus accumbens. This is an area of the brain that 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 foot shock, for example. And that can be similar to an OCD patient. They will check their home for safety until 3am in the morning and not sleep that night. Doing something because of the urge. But despite the risk, when our judgment is consistently sort of puts us at risk, that's where we have something like OCD contamination behavior where if they feel contaminated, they will wash their hands for hours repeatedly, or if they drop their toothbrush on the floor, they. This will lead to a compulsive behavior of cleaning a toothbrush or brushing your teeth consistently. Very, very common symptoms that we see or signs that patients report to us or that we observe. But patients with eating disorders, they tend to, if they have binge eating disorder, they'll overeat. If they have bulimia, they might purge. Despite the risk of these things. And so addiction is similar. We tend to drug seek. If we're addicted to, we'll pay off a dealer in order to get our fix, despite the risk. And that type of urge, despite the risk is something that I've always been really interested in. 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 today. And I think the nucleus accumbens and the cortical areas that we've been discussing that sort of send projections to these areas are probably at least one of the main circuits involved in these kinds of things.

Andrew Huberman (14:12)

What is nucleus accumbens? What roles does it play in healthy brain behavior and in pathology?

Dr. Casey Halpern (14:17)

Yeah, the nucleus accumbens is a part of the brain, part of our reward circuits. It has a lot of functions. It interconnects with many parts of the brain. So when I started getting interested in reward and what I could do as a surgeon to try to improve how we manage rewards, and what I mean by that specifically is if you have an urge for a reward, that's a normal phenomenon. That's not something we're trying to stop. The issue is if you have an urge for a reward that either puts you or somebody else at risk, it's probably a reward we shouldn't have. If you're a drug addict and you use heroin or opiate, that opiate might make you feel better because life is stressful, but the risk of doing those things is really high, in fact, potentially lethal. 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've checked 30 times, that's an urge we gotta treat. Eating disorder is the same. This problem can be 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 reward in a way, it can hijack normal functioning of the nucleus accumbens. So the goal is to just disrupt perhaps what is kind of habitual 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. So what we decided to do 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, 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, we often can hear tremor cells and they sound. We convert their electrical signal to an audible signal 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. Exactly.

Andrew Huberman (16:34)

And you're poking around in a dedicated, careful way, of course.

Dr. Casey Halpern (16:37)

One poke at a time.

Andrew Huberman (16:38)

One poke at a time with a very fine wire, a set of wires, listening to the electrical activity until you encounter some cells that are sending out electrical activity at a similar frequency.

Dr. Casey Halpern (16:51)

Exactly.

Andrew Huberman (16:52)

And then you can stimulate them or quiet them and see if the tremor goes away.

Dr. Casey Halpern (16:56)

So we are very confident that when we stimulate that area of, in this case, the subthalamic nucleus, we will disrupt that tremor circuit and that tremor will dissolve. And it does.

Andrew Huberman (17:06)

So what is the analog to tremor in terms of appetite and desire to binge?

Dr. Casey Halpern (17:12)

Craving. So craving is a term that, you know, there's probably other terms we could use, by the way, but 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. If you ask them if they crave, the answer will often be yes. If you ask them if they lose control or binge, they might not know what you mean. Or they might not actually feel out of control even when they are. But the word craving is relatable. And so we set out to see if we could identify craving cells in a patient with ocd, which is related. In fact, we target a very similar part of the brain. We tried to identify cells related to obsessions, and we believe we did do that. It was a single case study where we tried to optimize where our electrode was placed so we had some proof of concept that we would be able 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 procedure, but at least for these first, in human trials where we're trying, we're trying to establish where in the brain we need to be, I think this type of approach is really critical.

Andrew Huberman (18:28)

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Andrew Huberman (19:46)

What is the status of non invasive brain stimulation, ablation and blocking activity in the brain? My understanding is that transcranial magnetic stimulation is being used to treat depression and a number of other brain syndromes non invasively. So no drilling through the skull. My understanding is that the spatial precision isn't that great. Yes, ultrasound is something I hear a lot about these days. And my 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 stimulation and blockade of brain activity.

Dr. Casey Halpern (20:27)

We need to embrace noninvasive approaches. Some of them are a little fluffy in that we don't understand how they work. We don't necessarily understand how deep brain stimulation works, by the way, but because we don't know exactly how 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 the way. It's also FDA approved for OCD and for nicotine addiction. We believe we can use TMS to define a circuit that if modulated, improves ocd, albeit temporarily. And in those patients, if it's temporary, they would be appropriate for an invasive study. So something we're actively working on. I've always believed that neurosurgeons need to be part of the discussion with these non invasive approaches. We don't need to do them, but I think we can help make them more precise and to probe noninvasively with purpose. Perhaps one day there will be a TMS target for anorexia and obesity. If we are scratching the surface with invasive approaches to these problems, we're even doing less with the brain stimulation. So we have so much work to do there. Eating disorders and TMS have been so sort of scarcely studied or there have been such little research done in that space. So it is an area that we need to work work on. So ultrasound right now, Transcranial magnetic guide, magnetic resonance guided focus ultrasound. So this, this is an FDA approved method to deliver an ablation to the brain non invasively. There are researchers, myself included, that are trying to use transcranial magnetic guided magnetic resonance guided focus ultrasound, or MRI guided focus ultrasound to use it in a modulatory way, not just as an ablation, but to drive neuronal activity or inhibit it. Perhaps we're still learning how to do that. There are trials that are trying to 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 something like that. So it's a very Exciting field. And it is FDA approved for tremor right now. And so I actually do it routinely for patients with tremor, with Parkinson's or essential tremor. And so I love doing it. It's often just kind of a miracle because there's no incision. I don't have to place an electrode into the brain to achieve a similar result. It's fabulously effective for these patients. It treats patients on one side, usually their dominant hand or their worst hand. And it really speaks to the fact that, wow, you can deliver noninvasively an ablation to the brain in a hypothesized zone that we think is related to the problem at hand. And at least with tremor, it works really well. Could this be effective for psychiatric disease? Obesity, Eating disorders? Well, perhaps. Actually, that would be the ideal. The problem is we don't know where to do the ablation. 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 that we've been delivering ablations to for years for patients with ocd. And it helps a bit. That's called a capsulotomy. But really the outcome is probably going to be about the same. It's a nice method because it's non invasive, but we need to find a new target for these conditions. And because of the common denominator of the urge, despite the risk, sort of that compulsion, perhaps it could be the same target. I don't know. But I would argue we need to do these modulatory experiments either with a device or with invasive recordings to 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 stereoencephalography, 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 in diameter all throughout the brain, into parts of the brain that we believe are involved in seizures. And we would admit the patients to the hospital and figure out where the seizures were starting and propagating. And then we could stimulate these electrodes to see if there was a symptom that was important and try to identify a region that we thought we could either remove surgically, ablate with a laser, or put a stimulator in it. Perhaps that's commonplace now for epilepsy, and it works extremely well and it's very safe. Of course, it's still a brain procedure, but the complication rate is surprisingly low, quite honestly, for the amount of electrodes that we place. And it's extremely well tolerated. Most of these patients leave the hospital and they don't even feel like they've had surgery. So there's actually a lot of interest in using that procedure to study mental health disorders. We are trying to do it for patients with obsessive compulsive disorder. We're awaiting an FDA decision on that. But actually, I credit our colleagues at Baylor and at UCSF for studying this already bringing together the epilepsy technique and the psychiatry expertise to study how we could better target electrodes in depression. And I'll tell you, if they have a consistent target, perhaps there becomes an ultrasound target. But right now the approach is a bit more reversible because you can always shut that electrode off or even remove the electrode if perhaps it's not in the optimal location to treat the depression. But actually, after a large volume of cases, perhaps they could pool that data to develop a new ultrasound target for depression. I think that would be fabulous and probably is their long term goal, not to speak for them, but that would be something that I'm sure is on their radar. You might ask, well, why aren't you doing this for obesity right now in our study, and the reason is that we've developed a target for obesity and binge eating disorder developed out of mice that we believe is relevant for the human state. Because you can model this problem in a mouse a bit better than you can model 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 hard to model in a mouse, you really have to study it in the human. And you can perhaps start in an epileptic patient, a patient that has electrodes and try to provoke a depressed state, or study epileptics that have comorbid depression, for example, and that can really validate this approach as well. But in the end, 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 or modulatory approach. Modulatory would be like TMS or lesion approach would be with ultrasound.

Andrew Huberman (27:30)

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Andrew Huberman (28:47)

can be made to feel or make themselves feel just a little bit better, a little less anxious just prior to a 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 maybe even veering towards suicidal thinking, it seems like that awareness seems like maybe among the best tools that people could develop.

Dr. Casey Halpern (29:16)

Yes. I've always thought that if we can improve awareness, we can improve 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, are so resistant to treatment. And the patients that we see as a surgeon, for example, are the patients that they've tried cognitive behavioral therapy, certainly have tried medications, they've tried behavioral management. They're as aware as they could possibly be, and they still lose control. We've had this studied in the lab. So we will bring patients to the laboratory with this implanted device to try to provoke this electrographic electrical signal that can be detected by the actual device that will stimulate them when they're at home. But before we actually initiate stimulation, we want us to see, can this device detect this craving cell signal, which is going to be different than what we saw in the operating room, because that's a single cell. But these devices, these electrodes are about a millimeter in diameter instead of like a tenth of a millimeter, which is what we use in the operating room. So they're only hearing or detecting, I should say thousands of cells responses. And we actually have a way to provoke binges. It's called a mood provocation. It's very well validated. It's a little bit like provoking seizures in the epilepsy monitoring unit. But here in the sort of psychiatric monitoring unit or the food monitoring unit, 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.

Andrew Huberman (30:58)

Does the psychiatrist comes in and provokes. Yes, a feeling that can evoke the negative behavior.

Dr. Casey Halpern (31:06)

That's exactly right. So that we can video and synchronize the video to the brain signal recordings. The patients all wear an eye tracker so we can see what they're eating at all times and what they're looking at specifically. And that allows us to have the best temporal resolution possible to understand what is happening right before the bite. And even under video surveillance through a one way mirror in a laboratory setting. When patients are very well aware that their they're to be studied if they're going to binge, they still do. And we believe they do because they just can't control it, as aware as they are of it. And it's probably because they're the most severe. So I think if we can improve awareness, not just the societal awareness that I was talking about earlier, but the patient awareness around their problem, I think that could be a powerful way to help so many of these patients. And that's sort of the role of, of cognitive behavioral therapy. The problem with cognitive behavioral therapy, or I should say the limitation of it, I actually don't have any problem with it. I think it's a wonderful treatment. Is that if you stop it, many of these 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 that's the problem is it's not necessarily lasting. In the absence of continued cognitive behavioral therapy. Some people can benefit from it long term, but some can't. But I think in the less severe patients improving awareness is key. But in these really refractory patients, this is kind of like this is the 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.

Andrew Huberman (32:51)

Do you think There's a role for machines and artificial intelligence here. There are a couple laboratories up at the University of Washington that are using particular signature patterns within voice to try and help suicidal people who are suicidally depressed know when they're headed towards an episode before they even can consciously know. So this gets right down to issues of free will and whether or not machines can be smarter than we are. But you know, one could argue that some of the search algorithms on Google and other search engines are actually more aware of our preferences than we are. Basically what these are. These are devices that are listening to

Andrew Huberman (33:31)

people talk all day.

Andrew Huberman (33:32)

They're also paying attention to patterns of breathing and how well people slept, et cetera. Integrating a huge number of cues and then signaling somebody with a yellow light. You're headed into a depressive episode. The person might say, I feel fine or I feel pretty good. This is kind of baseline state for me. And they say this is where you were preceding the last episode that took you down a deep dark trench and it took months to get out of. I wonder whether or not some of these devices could help with the sorts of things that we're talking about today.

Dr. Casey Halpern (34:03)

Yeah, I think so. 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 those non invasive signs signals are. I think it's possible that we are scientifically sophisticated enough to use machine learning and sort of this kind of bot technique to anticipate when somebody is going to be highly impulsive. You know, suicide is the most dangerous impulse. It's something that is immensely a focus of the lab is impulsivity. We've talked mostly about compulsion, compulsion being going after a reward or the urge despite the risk. Impulsivity is similar, but different. It's kind of going after something a little bit. If you model impulsivity in a mouse, it's related to going after a food reward without the sort of paired tone that the mouse is supposed to wait for. The mouse doesn't want to wait anymore. They just go after the food.

Andrew Huberman (35:10)

I've been that mouse.

Dr. Casey Halpern (35:11)

Yeah, we've all been. We can all relate with this to a certain extent. Again, it's a spectrum. So in any case, non sequitur. But I certainly think that there is a way to use our own body's physiology to anticipate when these impulses are coming online and how best to do that. I think we're just scratching the surface, but these are the kinds of solutions we need. Some of these problems are of epidemic proportions. The 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. We need scalable solutions. You know, I'm a neurosurgeon. I'm only going to be able to treat the most severe of patients with these problems. You know, we've only done about 200,000 deep brain stimulation surgeries ever. So I mean, the problem we're talking 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, because the last thing we need is a, you know, some sort of wearable fancy tool that, you know, wastes people's money and time. You know, we need real therapies for these things. Not that these devices that we're discussing are not. I think actually there's lots of promise and we use machine learning in the lab all the time. I'm not an electrical engineer or the computational neuroscientist doing this type of work. I just help develop the hypotheses around it, but help fundraise around it. But I, I definitely think there's a future for it. I suspect we're scratching the surface on how best to do it.

Andrew Huberman (36:56)

I really appreciate you sharing those tools. A number of people, I'm guessing out there might want to become neurosurgeons. I really believe that in hearing today's conversation that you will spark an interest in medicine and. Or neurosurgery. I hope so. Well, certainly you need to be a physician before you can become a neurosurgeon. So end neurosurgery in some cases and that would be beautiful. And I predict that will be happening. That will happen. Excuse me. As a consequence of what you've shared today, really want to thank you for taking time out of your not just immensely busy but very important schedule because again, the work that you're doing is really out there. On that cutting, I don't want to say bleeding edge, because 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 behalf of everybody and myself as well, thank you so much, so very much.

Dr. Casey Halpern (37:45)

I'm honored. Thank you so much for having me.

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