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

I'm Andrew Hubertman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine.

And now, from my discussion with Dr. Casey Helpern. Casey, I should say, Dr. Helpern, welcome. Thank you. Great to be here. You're a neurosurgeon, which I consider the astronauts of neuroscience. For those that aren't familiar with the differences between neurosurgery and neurology, psychiatry,

“you just educate us a bit. What does a neurosurgeon do and what do you think about and conceptualize the brain?”

Yeah, the scope of neurosurgery is quite broad. We take out brain tumors. We clip aneurysms in the brain. We take care of patients that have had traumatic brain injury, concussion, spine surgeries, 90% of what neurosurgeons do around the country. You know, taking care of herniated discs and lumbar fusions. So, you know, the scope is the entire central nervous system, including the peripheral nervous system. We take care of patients with carpal tunnel syndrome

and nerve disorders. 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. So, I'm a chief of stereotyping, functional neurosurgery. All I do is deep brain stimulation surgery and a compliment to that is focus ultrasound or trans-cranial focus 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. Deep brain stimulation is a procedure where we have to place a very thin wire that's insulated deep into a part of the brain that's involved in Parkinson's disease, for example. 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 they're actually are multiple contacts at the bottom of the wire. Very small. It's a bit more like I have

to implant a tool to deliver you a medication. 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. I'm very privileged

to be able to interact with the human brain in this way. It's always in them with the goal of trying

to provide somebody with a meaningful therapy. But when we deliver electrical stimulation, 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 moment of laughter, like you said, or a moment of panic. And of course, we can just shut that electrode off. But often the side effects could be therapeutic. And actually

“that's how we have discovered ways to use deep brain stimulation, not just for movement disorders,”

like Parkinson's disease. But for example, patients with Parkinson's disease that have a psychiatric comorbidity like depression or obsessive compulsive disorder. A lot of these patients are highly compulsive and impulsive. 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, there's probably more than one reason,

you can help somebody's mood by making their tremor go away, of course. But we see laughter in the clinic sometimes. 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 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 tremoring 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 another kind of symptom. I'd love to learn more from you about OCD. Could you perhaps just tell us what 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 true OCD? My perspective on OCD may be a little bit different than a psychiatrist who lives in breeds OCD and sees patients

every single day with OCD. I'd probably take care of a 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

I do feel that as a neurosurgeon, I am obligated to better understand where the obsessions and 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 noninvasively 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 spectrum disorder in a way and 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 criteria for OCD. As a neurosurgeon, I'm really obsessive about safety and compulsive

“about my surgical procedures. 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 and but if it goes a rye and is uncontrollable, then it becomes obsessive compulsive disorder. 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. Which neurotransmitter systems do they tend to poke at?

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 neurogenergic system and the dopamine system. So it's hard to be specific to one of these things.

“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, who started by Edna Fowa, at Penn, who this is what they do for these patients is

offered 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 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 caps a lot of me, 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, functionally, so 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

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you know, for this sort of work of ablations or stimulation, where would you first start to probe

in the brain? Yeah, this is a disorder of both cortex and the sub-sub-cortex. We find that areas

“in the cortex like the prefrontal and over-frontal cortex are not functioning, the way they would in”

a non-hosted 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 sub-cortex. This is the basil ganglia, like codapeputamin or the dorsal stratamin. These are interconnected with the vegetable stratamin. This is an area of the brain that I focus a lot of my energy in. This is the ventral stratamin, which is not limited to, but includes the nucleus of convents. 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 the foot shock, for example. And that can be similar to an OCD patient. They will check their home for safety until 3 AM 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 they feel contaminated, they will wash 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, a 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 bingeing 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. We'll palp a dealer in order to get our fix, and 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 nuclear succumbins 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. What is nuclear succumbins? What roles does it play in healthy brain behavior and in pathology? Yeah, the nuclear succumbins 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 an 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.

and you check 30 times, that's an urge we got to treat. Eating disorders the same, this problem

“can be ameliorated or improved upon by a better understanding and a tailor treatment to the”

nucleus accumbins specifically. It seems that repeated exposure to something like a drug abuse or any type of reward that is a really strong reward. In a way, it can hijack, normal function of the nucleus accumbins. 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 been gene disorder at least at a severe level, they tend to bitch 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 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, 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. So exactly. And you're poking around in a dedicated careful way of course. One poke at a time. One poke at a time. And with very

fine wire, set of wires, listening to the electric activity until you, you encounter some cells that are sending out electric activity at a similar frequency. Exactly. And then you can stimulate them or quiet them and see if the tremor goes away. So we are very confident that when we stimulate that area of, in this case the subphilemic nucleus, we will disrupt that tremor circuit and that tremor will dissolve. And it does. So what is the analog to tremor in terms of appetite and desire

to binge? 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 been cheating disorder or obesity, they, 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.

So, 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 human trials where we're trying to establish where in the brain we

“need to be. I think this type of approach is really critical. As many of you know, I've been taking”

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“What is the status of non-invasive brain stimulation, ablation, and blocking activity in the brain?”

My understanding is that trans-cranial magnetic stimulation is being used to treat depression, and number of other brain syndromes non-invasive, so no drilling through the skull. My understanding is that the spatial precision isn't that great. Yes. Ultra sound is something I hear a lot about these days, and my understanding is that

thoughts on these forms of non-invasive, meaning no flipping open of a piece of the skull, type brain stimulation, and blockade of brain activity? We need to embrace non-invasive 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, so, 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, trans-cranial magnetic stimulation, it is FDA-proof for depression, by the way, it's also FDA-proof 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 non-invasively 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, and so it is an area that we need to work on. So ultrasound right now, trans-cranial

magnetic magnetic resonance guided focus ultrasound. So this is an FDA-approved method to deliver an oblation to the brain non-invasively. There are researchers, myself included, that are trying to use trans-cranial magnetic guided magnetic resonance guided focus ultrasound, or MRI guided focus ultrasound. To use it in a modulatory way, not just as an oblation, but to drive neural 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 a central 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 electric

into the brain to achieve a similar result. It's fabulously effective for these patients. It treats patients on one side usually they're dominant hand or they're worse hand. And it really speaks to the fact that, wow, you can deliver non-invasively an oblation 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 capsuleatomy. But really the outcome is probably going to be about the same. It's a nice method because it's not 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 modular Tory 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 stereo and cephalography, 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 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 those electrodes

“to see if there was a symptom that was important. And I tried to identify a region that we thought”

we could either remove, surgically, a blade 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,

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 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, her haps, there it 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 are 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 co-morbid depression, for example, and that can really validate this approach as well. But in the end, it's getting into the human

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Again, that's Rora, RORRA.com/Huberman. If people 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 you'd veering towards suicidal thinking. Seems like that awareness seems like maybe

among the best tools that people could develop. Yes, I've always thought that if we could

“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 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 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 had this studied in the lab. So we will bring patients to the laboratory with this implanted device

to try to provoke this electric or ethical signal that can be detected by the actual device that will stimulate them when they're at home. But before we initiate stimulation, we want 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,

I should say, thousands of cells responses. And we actually have a way to provoke

“binges is 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 these sort of psychiatric monitoring unit or the food monitoring unit, we actually have a psychiatrist and each sort of specialist common induce a mood that is related to each patient's sort of self-described binge episode. So the psychiatrist comes in and provokes a feeling that can evoke the negative behavior. 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 they're there 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'm 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 cognitive behavioral

therapy. The problem with cognitive behavioral therapy, or I say the limitation of it, I actually don't have any problem with it. 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. 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 key. But in these really refractory”

patients, this is kind of like this is the disease despite the awareness that 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? There are a couple laboratories up at the University of Washington that are using particular signature patterns of within voice to try and help suicidal people who are suicidal, depressed. No 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 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 people talk all

day. They're also paying attention to patterns of breathing and how well people slept. It's an integrating a huge number of cues. And then signaling somebody with a yellow light, you know, you're headed into a depressive episode. The person might say, "Well, if you'll find, or if you'll pretty good, this is kind of baseline state for me." And they say, "Ah, ah, 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. 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 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, you know, going after a reward or the urge, just by the risk. Impulsivity is similar, but different. It's kind of going after something a little bit, but 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. I've been that mouse. Yeah, we all think we could all

relate with this to a certain extent, again, it's a spectrum. So in any case, I'm not in

to anticipate when these impulses are coming online. 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, largest public health problems in this country, in this world, obesity, opioid crisis, depression, suicide, I mean, that's like a third of our country. Maybe more. We need scalable solutions. I'm a neurosurgeon. I'm only going to be able to treat the most severe of patients with these problems. We've only done about 200,000 deep brain stimulation

surgeries ever. 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 and initiative to go after that kind of problem. We're help make it more rigorous. Because the last thing we need is some sort of wearable fancy tool that waste people's money in time. 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.”

We use machine learning in the lab all the time. I'm not a 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 definitely think there's a future for it. I suspect we're scratching the surface on how best to do it. 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. Well, certainly need to be a physician before you can become a neurosurgeon. So, and neurosurgery in some cases, and that would be beautiful. And I predict that will happen. That will happen. Excuse me as a consequence of what you've shared today. I really want 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 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, so very much. I'm honored. Thank you so much for having me.