back to indexDr. Casey Halpern: Biology & Treatments for Compulsive Eating & Behaviors | Huberman Lab Podcast #91
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Welcome to the Huberman Lab Podcast,
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where we discuss science and science-based tools
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for everyday life.
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I'm Andrew Huberman,
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and I'm a professor of neurobiology and ophthalmology
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at Stanford School of Medicine.
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Today, my guest is Dr. Casey Halpern.
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Dr. Halpern is the chief of neurosurgery
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at the University of Pennsylvania School of Medicine.
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His laboratory focuses on bulimia, binge eating disorder,
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and other forms of obsessive compulsive behaviors.
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Normally, when we hear about eating disorders
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or obsessive compulsive disorders of other kinds,
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the conversation quickly migrates
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to pharmacologic interventions and serotonin or dopamine
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or talk therapy interventions,
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many of which can be effective.
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The Halpern Laboratory, however,
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takes an entirely different approach.
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While they embrace pharmacologic and behavioral
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and talk therapy interventions,
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their main focus is the development and application
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of engineered devices to go directly into the brain
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and stimulate the neurons, the nerve cells,
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that generate compulsions,
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that cause people to want to eat more
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even when their stomach is full.
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In other words, they do brain surgery of various kinds,
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sometimes removing small bits of brain,
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sometimes stimulating small bits of brain
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with electrical current,
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and even stimulating the brain through the intact skull,
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that is, without having to drill down beneath the skull
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in order to alleviate
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and indeed sometimes cure these conditions.
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Today's discussion with Dr. Halpern
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was an absolutely fascinating one for me
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because it represents the leading edge
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of what's happening in modification of brain circuits
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and the treatment of neurologic and psychiatric disease.
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For instance, they just recently published a paper
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in Nature Medicine, one of the premier journals out there
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entitled Pilot Study of Responsive Nucleus Accumbens
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Deep Brain Stimulation for Loss of Control Eating.
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The nucleus accumbens is an area of our brains
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that we all have, in fact, we have two of them,
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one on each side of the brain,
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that is intimately involved in the release of dopamine
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for particular motivated behaviors.
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And while most often we think about dopamine
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for the release of behaviors that we want to engage in,
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in this context, they are using stimulation
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and control of neuronal activity in nucleus accumbens
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to control loss of control eating,
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something that when people suffer from it,
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despite knowing that they shouldn't eat,
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despite not even wanting to eat,
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they find themselves eating.
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So again, this represents really the leading edge
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of where neuroscience is going,
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and it certainly is going to be an area of neuroscience
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that's going to expand in the years to come.
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And Dr. Halpern and the members of his laboratory
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are among a very small group of scientists in the world
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that are using the types of approaches
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that I described a minute ago,
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and that you're going to hear more about in today's episode
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in order to resolve some of the most difficult
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and debilitating human conditions.
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During today's discussion, you will also learn
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about the use of deep brain stimulation and other approaches
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for the treatment of movement disorders,
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such as essential tremor, Parkinson's disease,
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and various types of dystonias,
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which are challenges in generating
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particular types of movement.
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So whether or not you or somebody that you know
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suffers from an eating disorder,
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from obsessive compulsive disorder,
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or from a movement disorder,
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today's episode is sure to teach you
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not only about what's happening in those arenas,
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but also in the arenas of neuroscience generally.
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In fact, I would say today's episode
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is especially important for anyone
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that wants to understand how the brain works
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and what the future of brain modification
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really looks like for all of us.
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Before we begin, I'd like to emphasize that this podcast
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is separate from my teaching and research roles at Stanford.
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It is, however, part of my desire and effort
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to bring zero cost to consumer information about science
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and science-related tools to the general public.
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In keeping with that theme,
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I'd like to thank the sponsors of today's podcast.
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Our first sponsor is Roca.
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that are of the absolute highest quality.
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The company was founded by two all-American swimmers
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I've spent a lifetime working on the biology
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The Huberman Lab Podcast is now partnered
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with Momentous Supplements.
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We partner with Momentous for a number of important reasons.
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First of all, the quality of their ingredients
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is exceptional, it's really second to none.
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and that was important to us
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to develop single ingredient formulations.
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Now, this turns out to be very important
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because if you're going to take supplements,
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And of course, you want to optimize the cost efficiency
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livemomentous.com slash Huberman.
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And I should just mention that the library
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of those supplements is constantly expanding.
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Again, that's livemomentous.com slash Huberman.
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And now for my discussion with Dr. Casey Halpern.
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Casey, I should say Dr. Halpern for those listening, welcome.
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Thank you, great to be here.
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Yeah, it's been a long time coming.
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We were colleagues at Stanford.
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And then recently you moved, of course,
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to University of Pennsylvania,
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also an incredible institution.
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We're sorry to lose you.
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It was bittersweet for me too.
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Stanford's loss is UPenn's gain.
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But let's talk about your work, past and present.
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As I've told the listeners already,
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you're a neurosurgeon,
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which I consider the astronauts of neuroscience
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because you're in somewhat uncharted territory
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or very uncharted territory.
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And yet precision is everything, right?
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The margins of error are very, very small.
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So for those that aren't familiar with the differences
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between neurosurgery, neurology, psychiatry,
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you just educate us a bit.
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What does a neurosurgeon do?
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And what does the fact that you're a neurosurgeon
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do for your view of the brain?
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How do you think about and conceptualize the brain?
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Yeah, the scope of neurosurgery is quite broad.
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When I was in medical school, I was drawn to neurosurgery
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because of a procedure known as deep brain stimulation.
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When I was at Penn as a college student,
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I actually watched my first deep brain stimulation surgery
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performed by Gordon Baltuck,
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who to date is one of my career mentors.
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Deep brain stimulation is one surgery
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that neurosurgeons offer,
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but it's actually sort of a very small minority
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of what neurosurgery does.
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So we take out brain tumors,
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we clip aneurysms in the brain,
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we take care of patients
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that have had traumatic brain injury,
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concussion, spine surgeries,
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90% of what neurosurgeons do around the country,
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taking care of herniated discs and lumbar fusions.
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So the scope is the entire central nervous system,
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including the peripheral nervous system,
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we take care of patients with carpal tunnel syndrome
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and nerve disorders.
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Now, over the course of the past two decades or so,
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there's been a mission in the field to subspecialize.
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And so historically, neurosurgeons did everything
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in that domain, but now we subspecialize
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and I'm lucky to be at Penn Medicine
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where we can focus on one of these areas.
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So I'm chief of stereotactic functional neurosurgery.
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All I do is deep brain stimulation surgery
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and a compliment to that is focus ultrasound
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or transcranial focus ultrasound,
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which is a non-invasive way to do an ablation in the brain,
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recently FDA approved,
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and it's FDA approved for tremor at the moment.
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These two procedures are for me, my every day,
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but still the minority of what neurosurgeons have to offer.
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The majority of neurosurgery in my mind
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is a bit more structural than it is physiology
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or deeply rooted in how the brain functions.
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When we take out a brain tumor,
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we have to find a safe trajectory to get to the brain tumor
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and then we remove it
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and we help the patient recover in the ICU,
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similar to a brain aneurysm.
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Often we don't have to go into the brain
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to clip a brain aneurysm, but we go around the brain
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or under the brain to get there.
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And in my mind, those surgeries are a bit more structural.
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Deep brain stimulation, the surgery that I do routinely,
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is a procedure where, yes, there is structure involved.
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Of course, we have to place a very thin wire
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that's insulated deep into a part of the brain
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that's involved in Parkinson's disease, for example.
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But that's actually not the therapy.
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The therapy is delivering electrical stimulation
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through the tip of that wire or one of the tips,
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as there actually are multiple contacts
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at the bottom of the wire.
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They're very small.
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But that's all done out of the operating room.
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This stimulation wire is connected to a battery pack
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or a pulse generator that's kind of like a pacemaker.
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And so we deliver this therapy and I always tell patients,
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it's a bit more like I have to implant a tool
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to deliver you a medication,
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but that medication is gonna be in the form of electricity
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and it's gonna be delivered
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into a very small region of the brain.
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And it's that procedure that's inspired me
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to not just become a neurosurgeon,
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but has really defined the focus
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of my research laboratory as well.
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Maybe by way of anecdote,
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you could tell us one of the more outrageous or surprising,
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or who knows, delightful and thrilling things
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about the brain that you've observed
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as a consequence of stimulating different brain areas.
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In textbooks, we always hear about the kind of dark stuff,
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stimulate one brain area, somebody goes into a rage,
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stimulate another brain area,
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person starts laughing uncontrollably.
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First of all, given that some of the information,
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let's hope not much,
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but some of the information in textbooks is incorrect,
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are those sorts of statements true?
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Can one observe those in the clinic?
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And what are some of the more interesting
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and I don't necessarily mean entertaining,
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but surprising things that you've seen
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when you've poked around in the brain,
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deliberately, of course.
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And what have you seen?
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What have you heard?
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I have to say, I am amazed by these effects every day.
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Yeah, I'm very privileged to be able to interact
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with the human brain in this way.
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It's always with the goal of trying to provide somebody
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with a meaningful therapy.
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But when we deliver electrical stimulation,
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these electrodes, while they might be sitting
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in a very small region of the brain,
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there are regions within a few millimeters
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of where these electrodes are that, if stimulated,
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could cause a temporary, very brief side effect,
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a moment of laughter, like you said,
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or a moment of panic.
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And of course, we can just shut that electrode off.
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But often, these side effects could be therapeutic.
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And actually, that's how we have discovered ways
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to use deep brain stimulation,
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not just for movement disorders like Parkinson's disease,
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but for example, patients with Parkinson's disease
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that have a psychiatric comorbidity like depression
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or obsessive compulsive disorder.
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A lot of these patients are highly compulsive and impulsive.
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Sometimes, these problems actually melt away.
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And we're trying to help their tremor,
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but the patients also tell us that their gambling issue
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has gotten better or their mood has improved.
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Well, there's probably more than one reason.
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You can help somebody's mood
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by making their tremor go away, of course,
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but we see laughter in the clinic sometimes.
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And that's because we're stimulating parts of the brain
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that are not just involved in these motor circuits,
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but they're also involved in what we call a limbic circuit
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or part of the brain involved in emotion.
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And if we learn how to modulate those areas therapeutically,
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step-by-step, we can actually develop these therapies
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for other indications like depression.
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I would say the most impressive and consistent effect
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we have when we have a patient with tremor
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who has been tremoring for the past 20 years,
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if we can deliver stimulation through that electrode
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in the clinic, we have immediate relief of tremor.
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And that is the effect that inspired me
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to be a neurosurgeon when I was in college.
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I've never really wanted to do anything else
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except help develop that type of therapeutic
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for another kind of symptom.
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I'm very interested in obesity and related eating disorders,
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compulsive behavior, the urge to have something
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that might be delicious but dangerous or unhealthy
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or a drug or a compulsion like we see in OCD
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or obsessive compulsive disorder.
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Interestingly, like we see tremor melt away
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when we deliver electricity to a certain part of the brain,
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we can see these more psychiatric problems.
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They're not all psychiatric disorders,
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but let's say disorders of the brain,
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we can see symptoms of those disorders also improve
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and often immediately, just like we do with tremor.
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So I see it all the time.
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To pick out one would be a challenge
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because for me, this is my everyday.
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The speed of the relief that you described for tremor
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is really incredible.
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Just thinking about drug therapies
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and there too, there are side effects,
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but there are still a lot of mysteries
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as to, for instance, why SSRIs even work when they work.
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The timing is always a challenge.
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Timing, dosage, yes, absolutely.
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I'd love to learn more from you about OCD.
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I have several reasons for asking this.
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First of all, I'm a somewhat obsessive person.
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I tend to be very narrowly focused,
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although I confess it's not a step function.
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It takes me some time to turn off the chatter,
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but once I'm into a thought train
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or a mode of being and thinking and work,
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it's very hard for me to exit that mode.
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It's like a deep trench.
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Adaptive in some circumstances, less adaptive.
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In others, as you know.
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The other is that when I was a kid,
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I had a little bit of a grunting tic.
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I used to, I had this intense, intense desire
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to clear my throat to the point where my dad said,
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you need to stop that.
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He used to squeeze my hand every time I do it.
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And I used to hide in the backseat of the car
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or in the closet to do it
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because it provided so much relief.
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And then it eventually passed.
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I wasn't medicated.
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They never did anything about it.
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Every once in a while now, if I'm very fatigued,
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if I've been working a lot, I notice it starts to come back.
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I'll do this like kind of grunting.
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And so it's been sort of like a pet neurological symptom
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for me that reminds me that these circuits exist
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in all of us and that sometimes they go haywire
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and sometimes they just have subtle, you know,
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overexcitation or something of that sort.
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And then the third reason is that I get thousands
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of questions about OCD.
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Could you perhaps just tell us what is OCD?
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What are some brain areas involved?
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What are the current range of treatments?
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And what's the difference between someone who is obsessive
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and somebody who has true OCD?
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So a brief disclosure, as a neurosurgeon,
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I do take care of patients with severe obsessive
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compulsive disorder.
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But my perspective on OCD may be a little bit different
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than a psychiatrist who lives and breathes OCD
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and sees patients every single day with OCD.
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I probably take care of three to five patients a year
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with deep brain stimulation
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for obsessive compulsive disorder.
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So I don't see these patients as routinely,
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but my laboratory is geared as a researcher.
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I'm very focused on trying to improve outcomes
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of deep brain stimulation for OCD.
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So I do feel I have expertise and a perspective to share,
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but just a brief disclosure.
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I do feel that as a neurosurgeon,
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I am obligated to better understand
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where the obsessions in the brain come from
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and how we can interrupt them to stop the compulsion
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that's associated with the obsession,
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sort of the intrinsic most feature of OCD,
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better than we're actually doing it.
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For example, if we were to offer a patient with tremor,
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deep brain stimulation surgery,
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of course there's some risk to the procedure,
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but the outcome is so consistent and positive
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that many patients are willing to take on that risk.
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For obsessive compulsive disorder,
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the surgery risk is about the same.
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However, the benefit is not quite as robust.
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And so a lot of patients,
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and they're referring psychiatrists,
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are reluctant to refer these patients to us,
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and it's completely understandable.
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I've been leading an endeavor
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with a number of collaborators around the country
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to try to better understand these circuits in the brain,
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study them in humans, both invasively and noninvasively.
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That would be with an electrode-based surgery,
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sort of like we do in epilepsy,
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understand where seizures come from,
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we wanna understand better where obsessions come from,
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but we're also working with imaging experts
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and geneticists to understand OCD
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at a broader level as well.
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I consider OCD to be a spectrum disorder in a way,
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and I apologize to those who might feel
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that I'm using that term incorrectly.
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I'm using it in a way to describe patients
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that have obsessions and even some related compulsions.
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It might not meet criteria for OCD.
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It may be something, Andrew, that you have,
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and as a neurosurgeon, I'm really obsessive about safety
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and compulsive about my surgical procedures.
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So I think that some aspect of OCD,
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which we often joke about,
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but we should consider seriously,
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because people do suffer from this,
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some aspect of it helps us.
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There are famous CEOs
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that probably have some level of OCD, surgeons
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and scientists alike.
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So perhaps if it can be controlled, it's an asset,
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but if it goes awry and is uncontrollable,
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then it becomes obsessive compulsive disorder.
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And I tend to see the patients that are the most severe,
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so they have failed medication,
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and there are multiple medications
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that are worth trying for OCD.
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Some can actually be very helpful.
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Which neurotransmitter systems do they tend to poke at?
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Well, SSRIs are sort of the first line for OCD,
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but also tricyclics can be helpful.
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So this is still the serotonin system.
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But as we know, the serotonin system interacts
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with the neuro-genergic system and the dopamine system.
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So it's hard to be specific to one of these things.
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And I think that's also why it's hard for us
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to predict how these medications are going to work
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for these kinds of patients.
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But tricyclics and SSRIs can be very helpful
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and are definitely first line.
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And there's others.
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Exposure response prevention
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is probably the most effective option,
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which is kind of like cognitive behavioral therapy,
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but these are different and offered by psychologists.
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And this is a whole field.
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And there's a field, or I should say a whole clinic
link |
at my institution focused, started by Ed Nafoa at Penn,
link |
who this is what they do for these patients,
link |
is offer these types of cognitive therapies,
link |
exposure to the stressor and to try to get patients
link |
to habituate to whatever it is that stresses them
link |
and causes these compulsions to help these patients
link |
live in every day and function.
link |
These are all fabulously helpful therapies
link |
for a variety of patients,
link |
but there's still about 30% of patients
link |
that still suffer from OCD and some of them have severe OCD.
link |
Sometimes it's moderate to severe.
link |
And those are the patients
link |
that I'm really motivated to try to help.
link |
Our therapies for those patients right now,
link |
I would say are worth pursuing, but not optimal.
link |
And so it's one of those things
link |
that we have to balance as a researcher,
link |
because when you see patients like this,
link |
you wanna do everything you can to help them.
link |
And I think it's important to educate patients
link |
on the risks and benefits of them.
link |
This is deep brain stimulation surgery,
link |
but also capsulotomy, which is more of an ablation approach,
link |
a little bit like deep brain stimulation,
link |
but rather than delivering stimulation through an electrode,
link |
you can actually heat the tissue and even destroy it.
link |
Some would say this part of the brain
link |
is very safe to destroy.
link |
It's kind of like an appendix.
link |
Others would say it's safer to modulate.
link |
I have seen patients do very well with these ablations.
link |
And so, you asked me earlier
link |
what I find so amazing about the brain,
link |
these effects that we can have.
link |
Sometimes the lack of effect is what's so amazing.
link |
You can actually traverse parts of the brain
link |
without having any adverse effects on patients' function,
link |
at least that you can test,
link |
but you can also destroy small parts of the brain.
link |
We're talking three or four millimeters in size.
link |
These little ablations can be really helpful for patients,
link |
but have no obvious side effects that we can tell,
link |
perhaps after a short recovery from surgery.
link |
But nonetheless, despite how safe they might be,
link |
these surgical procedures still are surgical procedures,
link |
and patients are hesitant to proceed,
link |
especially when they know that their chance
link |
of a transformative effect is quite low.
link |
We can generally achieve a responder rate of about 50%,
link |
and responders still have symptomatic OCD.
link |
So I'm really sort of inspired to really find a way
link |
to deliver these therapies in a more disease-specific
link |
or symptom-specific way,
link |
but we're years away probably from that therapy
link |
since it's all part of a research study at the moment.
link |
What brain areas should I think about
link |
when I think about OCD?
link |
Years ago, I remember opening a textbook,
link |
I think I was an undergraduate still,
link |
and work from Judith Rappaport
link |
at the National Institutes of Mental Health,
link |
this would be late 80s, early 90s,
link |
had done some neuroimaging, or maybe it was PET,
link |
or some other imaging technique,
link |
and had identified portions of the basal ganglia,
link |
caudate, putatum-type structures in OCD,
link |
and maybe some differences in boys versus girls.
link |
So what brain areas are there sex differences
link |
in terms of OCD, and were one to come into your clinic
link |
for this sort of a work of ablations or stimulation,
link |
where would you first start to probe in the brain?
link |
Yeah, this is a disorder of both cortex
link |
and the subcortex.
link |
The cortical control areas,
link |
areas that are involved in inhibitory control,
link |
we have found to not function properly in patients with OCD.
link |
So areas like the overall frontal cortex
link |
and the prefrontal cortex,
link |
if you image these areas,
link |
or study them even in a rodent model of OCD,
link |
which quite honestly, these models,
link |
they model aspects of OCD, but OCD is a human condition.
link |
You can't really model this whole condition
link |
in a mouse or a rat,
link |
but perhaps you can model compulsive behavior in a rat, sure.
link |
Pulling out their hair.
link |
You know, that's not necessarily
link |
obsessive compulsive disorder,
link |
but that is compulsive behavior,
link |
and perhaps if you can ameliorate that in a rat,
link |
that might be helpful for a patient with OCD,
link |
but we have to approach animal modeling of OCD thoughtfully,
link |
and most scientists do, I think.
link |
And when we study OCD in models or in humans with imaging,
link |
and we're trying to do it invasively with electrodes
link |
like we do in epilepsy patients,
link |
we find that areas in the cortex
link |
like the prefrontal and the prefrontal cortex
link |
are not functioning the way they would
link |
in a non-OCD patient.
link |
They are often hyper-functioning,
link |
such that while you might say,
link |
well, they're hyper-functioning,
link |
so aren't these patients, you know,
link |
functioning better?
link |
Hyper-focused, exactly.
link |
No, I would say it's not so much an up or a down.
link |
It's more that they're just dysfunctional,
link |
and we need to find a way
link |
to try to restore normal function to these areas.
link |
It's not so much directional, really.
link |
We tend to oversimplify brain function
link |
by thinking about it with directionality too much.
link |
Unfortunately, imaging studies
link |
sometimes demonstrate activation or hypoactivation,
link |
and that's where I think these kinds of things
link |
can be misconstrued,
link |
but what I would call the cortical areas of OCD
link |
is that they're dysregulated,
link |
and we need to find a way
link |
to try to normalize their function.
link |
So the frontal lobe is huge,
link |
but areas of the frontal lobe that are a bit more basal,
link |
like the OFC or orbital frontal cortex
link |
and the prefrontal cortex,
link |
definitely consistently seem to be implicated
link |
in patients with OCD,
link |
and then there are projections to the subcortex.
link |
This is the basal ganglia, like you were saying,
link |
caudate putamen or the dorsal striatum,
link |
and these are interconnected with the ventral striatum.
link |
This is an area of the brain
link |
that I focus a lot of my energy in.
link |
This is the ventral striatum,
link |
which is not limited to but includes the nucleus accumbens.
link |
This is an area of the brain
link |
that we know to be involved
link |
in gating reward-seeking behavior.
link |
When it's perturbed, it seems to gait compulsive behavior,
link |
meaning a rat will pursue a reward despite punishment,
link |
despite foot shock, for example,
link |
and that can be similar to an OCD patient.
link |
They will check their home for safety
link |
until 3 a.m. in the morning and not sleep that night.
link |
In a way, that is similar to a rat seeking out a food reward
link |
despite a foot shock,
link |
doing something because of the urge but despite the risk,
link |
and perhaps there is some normal judgment there.
link |
We all have to take risks to function in everyday society.
link |
To be successful, we have to take a risk.
link |
To take care of patients with surgery,
link |
there's some risk there.
link |
We make a judgment call, and that's not a condition.
link |
That's just normal.
link |
But when our judgment consistently sort of puts us at risk,
link |
that's where we have something like OCD.
link |
But OCD is also, you know, it's one of many conditions
link |
that suffer from these kinds of problems.
link |
We tend to label them
link |
because they tend to present in a consistent way.
link |
So we have patients with OCD
link |
that have hyper-checking behavior or contamination behavior
link |
where if they feel contaminated,
link |
they will wash their hands for hours repeatedly,
link |
or if they drop their toothbrush on the floor,
link |
this will lead to a compulsive behavior
link |
of cleaning a toothbrush or brushing your teeth consistently.
link |
Very, very common symptoms that we see
link |
or signs that the patients report to us or that we observe.
link |
But, you know, patients with eating disorders,
link |
they tend to, if they have binging disorder,
link |
If they have bulimia, they might purge,
link |
despite the risk of these things.
link |
And so addiction is similar.
link |
We tend to drug-seek if we're addicted.
link |
We'll pay off a dealer in order to get our fix,
link |
And that type of urge, despite the risk,
link |
is something that I've always been really interested in.
link |
And it's a common denominator to all of these problems.
link |
And if you think about these problems,
link |
I mean, these are some of the most common conditions
link |
in our society today.
link |
I'd like to take a quick break
link |
and acknowledge one of our sponsors, Athletic Greens.
link |
Athletic Greens, now called AG1,
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is a vitamin mineral probiotic drink
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that covers all of your foundational nutritional needs.
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I've been taking Athletic Greens since 2012,
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so I'm delighted that they're sponsoring the podcast.
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The reason I started taking Athletic Greens
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and the reason I still take Athletic Greens
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once or usually twice a day
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is that it gets me the probiotics that I need
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Our gut is very important.
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It's populated by gut microbiota
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If you'd like to try Athletic Greens,
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you can go to athleticgreens.com slash Huberman,
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and they'll give you five free travel packs
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And they'll give you a year's supply of vitamin D3K2.
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Again, that's athleticgreens.com slash Huberman
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to get the five free travel packs
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and the year's supply of vitamin D3K2.
link |
Yeah, I really appreciate that you're building this bridge
link |
from OCD to nucleus accumbens,
link |
which is, of course, associated with reward
link |
in various forms, and we'll get to that.
link |
I'll share a personal anecdote as a form of question.
link |
When I was in college and studying a lot,
link |
I relied on caffeine as a stimulant.
link |
I've never really been into drugs or alcohol.
link |
I've been lucky in that sense.
link |
I don't drink and I care less if alcohol disappeared.
link |
Never really liked recreational drugs,
link |
so I was never drawn to them.
link |
However, when I was in college,
link |
at the time there were these little epinephrine pills
link |
that were common in a lot of sports supplements.
link |
These were like pre-workout type things.
link |
Not unlike energy drinks now, which I completely avoid.
link |
And I had this experience of taking one of these
link |
and drinking some coffee,
link |
and of course it gave me a lift in energy.
link |
These are very similar to amphetamine.
link |
They were legal over the counter at the time.
link |
They're now either banned or illegal.
link |
I do not recommend them.
link |
And I had a lot of energy,
link |
but what I noticed is that my grunting tick came back
link |
and I had, I made one mistake.
link |
I still think of this as one mistake,
link |
which was I engaged in a superstitious behavior.
link |
I knocked on wood.
link |
And then somehow it felt very rewarding.
link |
Like it gave me some totally irrational,
link |
but internally rational sense of security around.
link |
I forget what I was knocking on wood about.
link |
And I found that I couldn't break
link |
that knock on wood compulsion.
link |
I felt I needed to knock on wood.
link |
And so then I started sneaking knock on woods,
link |
like in mid-exam and studying.
link |
And pretty soon I was knocking on wood often.
link |
I developed a superstition.
link |
And so I'm curious about the role of superstition
link |
and compulsion and the crossover there.
link |
It makes sense logically to me,
link |
but I was equally shocked to learn
link |
that when I stopped taking this stimulant,
link |
which I was quite happy to stop
link |
because it did make me feel too alert,
link |
couldn't sleep well, et cetera,
link |
that the superstition went away as well.
link |
And I'm guessing this has something to do
link |
with some of the reward circuitry,
link |
as it's called, related to stimulants.
link |
Again, I am not encouraging anyone to take stimulants,
link |
although healthy use of caffeine or safe use of caffeine
link |
might be the one universally accepted stimulant.
link |
It was really surprising to me how quickly this came on,
link |
how quickly it engaged my thinking and my behavior,
link |
the obsessions and the compulsions,
link |
and how quickly it turned off
link |
when I stopped taking this sports stimulant
link |
or whatever it was.
link |
I don't even remember.
link |
I think it was some form of epinephrine, ephedrine.
link |
It's not epinephrine, excuse me, I misspoke, ephedrine.
link |
Does what I described sound totally outside the bounds
link |
of logic or am I imagining it all?
link |
I'm certain it happened.
link |
Yeah, no, I don't think you're imagining it at all.
link |
The grunting that you mentioned to me,
link |
first of all, I didn't comment,
link |
but that sort of, not to put a label on it,
link |
but it sounds like a tick.
link |
And ticks in young males, extremely common,
link |
and they do tend to go away.
link |
Blinking ticks like this.
link |
I have a good friend who,
link |
he's actually a famous neuroscientist,
link |
I won't mention who it is,
link |
who's worked very hard to suppress his blinking ticks.
link |
And when he gets fatigued, it comes back
link |
and he's very high functioning in his personal life
link |
and his professional life.
link |
But when you're talking to him and he starts doing this,
link |
so you kind of start wondering what's going on.
link |
Yeah, and it's unfortunate, people with these problems,
link |
especially as they get more severe,
link |
then you get Tourette's syndrome.
link |
It's hard to function in our society.
link |
I have some friends that have Tourette's.
link |
I'll tell you, I'm just so inspired
link |
because they're so confident.
link |
And people obviously notice these problems,
link |
but they just live their life and they're very successful.
link |
And that's not typical.
link |
I have friends that I went to Penn with undergrad
link |
that had these kinds of problems,
link |
and I was always just so happy and inspired by them.
link |
But what's more typical is these problems cause people
link |
to lose their confidence and not pursue their profession
link |
as they may have done or things of that nature.
link |
So I think it's all related to the fact
link |
that our brains are very vulnerable.
link |
And to get back to your question about the stimulant,
link |
I think your brain was very vulnerable to it.
link |
You sort of may have had a predisposition to it.
link |
You mentioned that you're a little obsessive,
link |
and with the tick there, maybe you have this kind of,
link |
you know, on the mild side of the spectrum OCD.
link |
And I probably do as well, by the way.
link |
So I also have avoided drugs for that reason in my life.
link |
I'll drink a little bit of wine here and there,
link |
but that's about it.
link |
But I think most people don't avoid these things.
link |
And we see these problems in relation
link |
to not just taking a stimulant,
link |
but any kind of environmental exposure.
link |
Our own society causes so much stress.
link |
And that's why I think we have these human conditions.
link |
These are human conditions.
link |
We try to model them in animals,
link |
but most animals don't have these kinds of problems.
link |
I've heard that an animal like a monkey in the wild
link |
can have depression, a monkey's version of depression,
link |
but I don't think it's really typical
link |
or human depression, you know?
link |
And certainly it's not as prevalent as depression is
link |
in our human society.
link |
I think, you know, we haven't evolved
link |
to manage the stresses that are in this society
link |
that we currently have.
link |
And stimulants is probably one of them, you know?
link |
And I suspect you were probably a little bit vulnerable.
link |
It's possible the stimulant led to an overdrive
link |
of your prefrontal and orbital frontal cortex,
link |
and even brought out a little OCD behavior
link |
related to this super, this superstition that you had.
link |
So, no, I believe that entirely.
link |
And I also think, you know, that's why things like OCD
link |
and other kinds of psychiatric disorders
link |
tend to present themselves in college
link |
when people leave their home and they're in school
link |
and they're stressed and they're getting exposed to things
link |
that they haven't been exposed to before
link |
outside of the home.
link |
And, you know, their brains aren't evolved
link |
and sophisticated enough yet to help them
link |
cope with these kinds of stresses
link |
and how it manifests is in these kinds of conditions.
link |
And I don't want to put a label on those conditions,
link |
but certainly it could be a psychiatric disorder,
link |
but it could also just be lots of anxiety.
link |
It could also be the kind of problems that you had as well.
link |
So, and I think the nucleus accumbens
link |
and the cortical areas that we've been discussing
link |
that sort of send projections to these areas
link |
are probably at least one of the main circuits
link |
involved in these kinds of things.
link |
Well, I'm relieved it's no longer present,
link |
but I confess it, I always feel it close by.
link |
So, you know, being a slightly fatigued,
link |
not overly fatigued, but slightly fatigued
link |
seems to move out the kind of physical compulsion,
link |
but tried to channel it,
link |
never taken any medication for it,
link |
and here I am, so I'm still going.
link |
I may call you for a referral at some point,
link |
but at this point I'm feeling okay.
link |
Let's talk about nucleus accumbens and reward circuitry
link |
and the relationship between OCD, reward, addiction,
link |
and to just give you a sense of where I'm headed with this
link |
is into the realm of food-related
link |
and eating-related behaviors and disorders,
link |
because I know you're doing some very important work there.
link |
What is nucleus accumbens?
link |
I know we all have one or two, one on each side of the brain.
link |
What is it, what roles does it play
link |
in healthy brain behavior and in pathology?
link |
Yeah, the nucleus accumbens is a part of the brain,
link |
part of our reward circuits,
link |
the hub of the reward circuits
link |
that I've always been most fascinated in.
link |
There are scientists around the world,
link |
some of the leading,
link |
arguably some of the leading scientists in the world,
link |
the father of addiction neuroscience, I call him,
link |
although he tells me I'm nuts,
link |
Rob Malenka, who has studied the nucleus accumbens
link |
since the beginning of his career
link |
and who I worked with when I was at Stanford.
link |
Fabulous scientist and mentor,
link |
taught me so much, taught the world so much.
link |
Incredible person, scientist, and physician as well.
link |
Yes, MD, PhD, and brilliant in both ways,
link |
and very fatherly in a lot of way
link |
in terms of teaching people how to do science
link |
and be good citizens as well.
link |
But the nucleus accumbens is an area
link |
that is also very complicated
link |
because it has a lot of functions.
link |
It interconnects with many parts of the brain.
link |
But there are some things about the nucleus accumbens
link |
that are very consistent.
link |
So when I started getting interested in reward
link |
and what I could do as a surgeon
link |
to try to improve how we manage rewards,
link |
and what I mean by that specifically
link |
is if you have an urge for a reward,
link |
that's a normal phenomenon.
link |
That's not something we're trying to stop.
link |
The issue is if you have an urge for a reward
link |
that either puts you or somebody else at risk,
link |
it's probably a reward we shouldn't have.
link |
I suppose you could say,
link |
well, it depends on the size of the reward
link |
and the size of the risk
link |
and how that fits into your societal norms.
link |
But for example, if you're obese
link |
and you have a doctor who is advising that you lose weight
link |
and try to control your eating habits,
link |
perhaps better food choices is an important way
link |
for you to be healthier,
link |
and not pursuing those better food choices,
link |
that's an urge that we probably need to treat.
link |
If you're a drug addict and you use heroin or opiate,
link |
considering the opiate crisis right now,
link |
or cocaine, which is untreatable at the moment,
link |
you know, that cocaine might make you feel
link |
like you have some more energy that day
link |
to deal with your work,
link |
or that opiate might make you feel better
link |
because life is stressful.
link |
But the risk of doing those things is really high,
link |
in fact, potentially lethal.
link |
So that's an urge that's treatable.
link |
If you have OCD and you can't sleep at night
link |
because you're so nervous that you didn't lock the door
link |
and you've checked 30 times,
link |
that's a reality for some people with severe OCD.
link |
That's an urge we got to treat.
link |
Eating disorder is the same.
link |
Eating disorders and obesity are obviously linked
link |
because of the relationship of a patient with food,
link |
but they're also quite distinct.
link |
Not everybody with obesity has an eating disorder,
link |
and obviously not everybody
link |
with an eating disorder has obesity.
link |
I'm particularly interested in patients
link |
that have binge eating disorder as well as obesity
link |
because they're so heavily linked.
link |
Not everybody with binge eating disorder has obesity,
link |
but on average, most are overweight.
link |
We are doing a deep brain stimulation trial at Penn
link |
where we're trying to modulate the nucleus accumbens
link |
and understand it better in patients
link |
that have failed gastric bypass surgery,
link |
the most aggressive form of treatment for obesity.
link |
And we believe they failed gastric bypass surgery
link |
because of binge eating disorder,
link |
meaning they just can't control how much they eat.
link |
So their obesity is either related or even due to overeating,
link |
not some predisposition to that body habitus.
link |
Obesity is a phenotype, something that we can see.
link |
Not everybody is obese because of the same thing.
link |
So it's very important.
link |
I was taught this by a close mentor and friend, Tom Wadden,
link |
when he was the director of the obesity center at Penn
link |
or the Center for Weight and Eating Disorders.
link |
And he said to me, you know, Casey,
link |
be careful with obesity.
link |
You're interested in addiction,
link |
and I understand you're interested
link |
in the addictive tendencies of certain patients with obesity
link |
and their relationship with food,
link |
but not everybody with obesity has that problem.
link |
And in fact, it's probably present
link |
in about 20% of patients with obesity.
link |
But now taking a step back,
link |
20% of patients with obesity is still a massive problem
link |
of epidemic proportions.
link |
And perhaps some of these patients
link |
have either some form of binge eating disorder
link |
or I should say some degree of binge eating disorder,
link |
or at least loss of control eating, which is common to both.
link |
So that's a feature that I think eating disorder experts,
link |
obesity experts, neurosurgeons,
link |
obesity medicine experts would agree
link |
is common to eating disorders and obesity.
link |
And I also believe is common to addicts
link |
and perhaps patients with OCD
link |
is sort of a loss of control disorder.
link |
It's actually not a disorder known by like the DSM-5,
link |
some diagnostic manual,
link |
but a feature, I should say,
link |
of these conditions that's common.
link |
And that common denominator I believe can be restored
link |
or at least this problem can be ameliorated
link |
or improved upon by a better understanding
link |
and a tailored treatment
link |
to the nucleus accumbens specifically.
link |
We have learned in mice that if you expose a mouse,
link |
now this is just a model,
link |
if you expose a mouse to high fat food,
link |
not food that they would normally eat,
link |
food that is like 60% fat, high fat, it's like butter.
link |
We've learned that if you expose them to food like that,
link |
within two weeks, their nucleus accumbens is not functioning
link |
like a mouse that was never exposed to that high fat food.
link |
There's aspects of it that are hyperactive, I could say,
link |
and there's aspects of it that are hypoactive
link |
or decreased activity.
link |
But either way, it's not functioning properly.
link |
And most likely that function
link |
is predisposing continued behavior.
link |
And then probably eventually leads to things like a habit
link |
that gets developed.
link |
And that's a whole nother area of these kinds of problems
link |
that is very complicated and poorly understood.
link |
But in any case, if we just focus on the behavior at hand,
link |
it seems that repeated exposure
link |
to something like high fat food, a drug of abuse,
link |
or any type of reward that is a really strong reward,
link |
in a way it can hijack normal functioning
link |
of the nucleus accumbens.
link |
So the goal of our invasive trial
link |
is to try to restore normal functioning
link |
to that nucleus accumbens.
link |
In mice, there seems to be a signal
link |
that predicts when they're going to lose control.
link |
And we can use that signal
link |
to deliver a sort of a real-time therapy
link |
in the form of deep brain stimulation,
link |
just a brief amount of stimulation.
link |
And that actually blocks the behavior.
link |
And what's interesting is over time,
link |
that signal actually decreases in frequency,
link |
which suggests some level of restoring normal function
link |
to that circuit in a mouse.
link |
And we're trying to do that now in a human trial.
link |
Fascinating, where is the stimulation provided?
link |
Because I would imagine that if one were
link |
to stimulate nucleus accumbens,
link |
you would see a reinforcement
link |
of whatever behavior coincided or preceded the stimulation.
link |
So the stimulation, it's a brief delivery of stimulation,
link |
anywhere between five and 10 seconds,
link |
that is intended to just disrupt the perturbed signaling
link |
that's happening in the nucleus accumbens.
link |
There are disorders like depression, let's say,
link |
that I would describe as a bit more of a state disorder.
link |
And this is obviously oversimplified
link |
because we know that there's fluctuations
link |
in mood and depression as well.
link |
So don't let me oversimplify it too much.
link |
But for now, let's forgive the oversimplification.
link |
If we accept that depression is a state disorder,
link |
or maybe Parkinson's disease is a state disorder,
link |
recognizing that they do fluctuate,
link |
these types of problems most likely, but not definitely,
link |
most likely need a continuous therapy of some form,
link |
a therapy that's consistent,
link |
perhaps a therapy that fluctuates with the condition,
link |
but nevertheless still consistent.
link |
Binge eating disorder or OCD or addiction
link |
and binge eating disorder in the context of obesity,
link |
a lot of these patients are functioning
link |
quite normally every single day.
link |
It's just that intermittently throughout the day,
link |
there's brief interruptions in their normal function
link |
such that they have thoughts about food
link |
or the drug of abuse that they're really longing to have.
link |
And so we wanna deliver a episodic therapy
link |
delivered at the right time and only at the right time
link |
to try to interrupt the circuit aberration
link |
or the problem at hand
link |
that is gonna lead to that dangerous behavior
link |
and to kind of get the patient back on track
link |
to what they're doing.
link |
I don't necessarily think that it leads to a reinforcement.
link |
It's possible, we have to study that more,
link |
but rather the goal is to just disrupt
link |
perhaps what is kind of habitual
link |
or at least this kind of recurring problem that is happening.
link |
People that have binge eating disorder,
link |
at least at a severe level,
link |
they tend to binge about once a day,
link |
but they don't binge all day long, of course.
link |
They have a moment perhaps when they get home from work
link |
and they're stressed
link |
where they might have a bout of binge.
link |
What constitutes a binge?
link |
And I also want to know,
link |
does binge eating disorder come on suddenly,
link |
meaning as an entire disorder?
link |
One day people wake up,
link |
suddenly they have binge eating disorder,
link |
or is this a few too many buffets?
link |
And I'm being entirely serious here, unlimited food.
link |
And a circuit gets flipped
link |
or it kind of starts moving into the high RPMs, so to speak.
link |
So how does it come on?
link |
And I'm actually surprised to hear that it's once a day.
link |
I would think just hearing binge eating disorder,
link |
I assumed it's like OCD,
link |
which it probably fluctuates across the day as well.
link |
But I would have thought anytime people around food,
link |
they just simply can't control their intake of food.
link |
So what does this look like
link |
in terms of the onset of the disorder?
link |
And then what do you think underlies this once a day
link |
type of phenomenon?
link |
That's pretty interesting.
link |
Yeah, so severe binge eating disorder,
link |
these patients will binge about once a day.
link |
It could be a couple of times a day,
link |
but in general, it's not more than that.
link |
Moderate is about three to four times a week, for example.
link |
The reason I think that that seems surprising to you,
link |
and if you think about it, it is surprising,
link |
and I agree with you,
link |
but the reason for that is actually just
link |
in the definitions of the word.
link |
And as a neurosurgeon, in full disclosure, as I mentioned,
link |
I don't see these patients clinically.
link |
I see them for research trial purposes,
link |
and I try to understand the literature
link |
around eating disorders.
link |
And I obviously collaborate
link |
with fabulous eating disorders in these problems
link |
that are highly innovative people.
link |
But the word binge is a definition.
link |
There's a definition to that word,
link |
and you can't necessarily binge all day
link |
because our stomachs are not big enough.
link |
And so there's a limit to how much one can eat.
link |
And to meet criteria for a binge,
link |
you have to have a sense of loss of control.
link |
You have to eat an enormous amount of food
link |
in a brief period of time.
link |
And yes, generally, that doesn't happen
link |
more than about once a day
link |
in a patient with severe binge eating disorder.
link |
However, they can lose control quite often.
link |
And in fact, perhaps even at every meal,
link |
they might meet criteria for a bout of loss of control
link |
where they, yes, they may have lost control,
link |
but they might not have eaten enough
link |
to constitute what we would define as a binge.
link |
And that would be,
link |
there's no specific number to that, by the way.
link |
It's really just compared to their normal meal,
link |
perhaps it's 50% of their daily calories
link |
in that one brief moment.
link |
So that's why I think it seems surprising
link |
that binges aren't happening more often than that.
link |
What I would say is if we replace the term binge
link |
with loss of control eating,
link |
loss of control eating could happen dozens of times a week.
link |
And in fact, the patients that we're studying,
link |
we've seen patients that lose control 20, 30 times a week.
link |
And that's probably the term you have in mind
link |
when you're surprised that it's just one time a day.
link |
And it's specifically related to the fact
link |
that these patients have to eat such a large amount of food
link |
in such a brief period of time.
link |
So it's hard to do that more than once a day.
link |
You mentioned that some pre-existing anxiety
link |
might bias somebody to have a binge.
link |
I'm also fascinated by something I've observed before,
link |
which was when I was in college,
link |
my girlfriend had a roommate who we were aware was bulimic
link |
and would binge and then purge.
link |
And often when she ingested alcohol,
link |
that would lead to a binge.
link |
Which is kind of the opposite of anxiety
link |
when I think about alcohol as something
link |
that slightly reduces prefrontal activity,
link |
somewhat of a sedative
link |
or certainly a sedative at higher dosages.
link |
So this brings you to something that you said,
link |
I'm just going to, I won't say it as eloquently as you did,
link |
that it seems like it's neither the case
link |
that anxiety leads to binging
link |
nor that hypo reduced activation of the forebrain
link |
and lower anxiety leads to binging.
link |
It's this dysregulation of circuitry
link |
that the seesaw could go either way
link |
and it can throw things off,
link |
it's off balance in both cases.
link |
And that seems to be, that seems to pose a problem.
link |
It seems like it's a particularly tricky problem
link |
and kind of explains to me in my nonclinical awareness
link |
why medication might be really hard to use
link |
as a way to treat this,
link |
but that being able to poke around in the brain
link |
and assay in real time, how do you feel?
link |
Do you feel like binging now
link |
or do you feel further from the binge impulse?
link |
Is that what you do with these patients?
link |
Are they awake while you're stimulating the brain?
link |
Because it's one thing to say,
link |
I stimulate a brain area and the binging goes away
link |
or partial relief or complete relief,
link |
but how do you know?
link |
Are they in there with a donut and you're tempting them?
link |
So how do you actually know if a blading of brain area
link |
is going to lead to a relief or exacerbation
link |
or no impact on this disorder?
link |
Yeah, so there's a lot to unpack there.
link |
I'll try to go one step at a time.
link |
And if I miss something, please remind me.
link |
And I tend to ask these three-part questions
link |
specifically of neurosurgeons
link |
because I like to challenge you guys.
link |
Because again, you are the astronauts of neuroscience.
link |
Also, I'm just going to take a moment to poke at neurosurgeons
link |
because I have a couple close friends who are neurosurgeons
link |
and I consider Casey a friend.
link |
I don't know if he considers me a friend,
link |
but I consider him a friend.
link |
I'm teasing there too, which is first of all,
link |
they all have incredible hands, right?
link |
They have, I'm not, they all guard their hands
link |
with the kind of protection that you would guard,
link |
the tools of, the most important tools of your trade.
link |
So they're very careful with their hands.
link |
You're not going to see them doing heavy deadlifts.
link |
You're not because of the way that impacts the motor neurons.
link |
It's all about fine control.
link |
So if your neurosurgeon does heavy deadlifts,
link |
you might want to consider getting a different neurosurgeon.
link |
Hope I didn't put anyone out of work there.
link |
And then the other thing is that you all are,
link |
tend to be very calm people, at least on the exterior.
link |
We'll return to this later,
link |
but I do throw three or four questions out at once.
link |
So elevated autonomic arousal and alertness,
link |
as well as decreased autonomic arousal and alertness,
link |
both seem to be able to lead to binging.
link |
And then there's this question of how do you know
link |
whether or not to stimulate or to ablate
link |
or whether or not to leave a structure alone?
link |
In other words, what does one of these experiments
link |
look like in the laboratory?
link |
Clinic, excuse me.
link |
Yeah, these are questions I think about all the time.
link |
And I do want to come back to the deadlifting comment.
link |
But regarding, and you referred to this earlier as well,
link |
and I don't know if I addressed it sufficiently either,
link |
is sort of like what comes first here
link |
or how does this develop?
link |
I think, first of all, I like to understand
link |
these kinds of problems in sort of the construct
link |
of what I consider to be a bit of a two-hit hypothesis.
link |
So you sort of need, like in the concussion literature,
link |
you need, the second hit can be devastating.
link |
So if you have a concussion, you know,
link |
you want to only return to play when your symptoms are gone
link |
and cleared by a physician.
link |
So in the context of eating disorders,
link |
or let's say binge eating disorder,
link |
and first of all, I didn't mention earlier,
link |
but this is the most common eating disorder,
link |
affects anywhere between three and 5% of the population.
link |
And is probably under-diagnosed in obesity, by the way.
link |
And if obesity affects 35% of our population,
link |
most likely binge eating disorder
link |
affects more than three to 5%.
link |
But that's the current literature estimate
link |
on the prevalence.
link |
So how do we develop binge eating disorder
link |
and is it related to this anxiety question?
link |
You know, I think that there is a predisposition,
link |
that's the first hit.
link |
I actually think all humans have this predisposition,
link |
just some have it more than others.
link |
I don't think that we've evolved to live in a society
link |
where foods are so readily available
link |
and enormously delicious,
link |
and have so much sugar and fat in them.
link |
Not that there's any particular problem
link |
with either of these macronutrients,
link |
it's just the excess of it and how they're refined
link |
that I think is the problem.
link |
You know, there's high fructose corn syrup
link |
in almost everything we eat, it's in bread.
link |
I don't even know why it's in bread sometimes.
link |
It's just kind of crazy.
link |
So I don't think we're evolved to live in a society
link |
that has food that's so readily available like that,
link |
and cheap, by the way.
link |
In fact, the cheaper the foods are,
link |
sort of the more refined and palatable,
link |
and I would argue, dangerous to eat.
link |
I think they change our reward circuits for the worse,
link |
and put us at risk for wanting more.
link |
I tend to get a headache when I eat food like that,
link |
and perhaps that's an evolutionary advantage
link |
because I don't want to eat those foods
link |
because they actually do make me sick.
link |
So in a lot of ways, I kind of wish
link |
that headache on everybody
link |
because perhaps we wouldn't have all these problems,
link |
or at least some of them would go away.
link |
So I think that's the first issue,
link |
is a predisposition to, or a vulnerability
link |
to these types of foods,
link |
which we undoubtedly all have to a certain extent,
link |
but some more than others.
link |
And then, so that's the first hit,
link |
is this predisposition in the context
link |
of this sort of food-focused society.
link |
And then the second hit is probably a stressful event,
link |
or a stressful life,
link |
and probably a recurring stressful event.
link |
I'm not sure this is published.
link |
I've never sat down with like a eating disorder expert
link |
and had this question about how this develops,
link |
and I'm not sure it's actually well-known.
link |
But in a lot of ways,
link |
I think that that answer anybody would agree with,
link |
that we need sort of a predisposition in the exposure,
link |
the environmental exposure and the genetic predisposition,
link |
but also a stressor.
link |
And that stressor is probably one that's recurring,
link |
and it's obvious in our society,
link |
these stressors are everywhere,
link |
and how we can manage them is often poor.
link |
And I think we can all relate with that.
link |
And then there's something else in the background
link |
that I think is really important to mention,
link |
is that patients with these kinds of problems are embarrassed
link |
because our society doesn't think fondly
link |
of these kinds of patients.
link |
Binging disorder patients, they do tend to be overweight.
link |
That's obviously a stigma.
link |
Obesity is another stigma.
link |
Then there's the opposite, in a way it's an opposite,
link |
by the way, from a phenotype standpoint, that's anorexia.
link |
I mean, that's another stigma.
link |
And gosh, not to make this about one sex over another,
link |
but when girls are told they're pretty because they're thin,
link |
it just reinforces this problem.
link |
And of course you want to compliment people
link |
and make them feel good about themselves,
link |
but the problem is that in this vulnerable society,
link |
that that can lead to problems
link |
because people start thinking,
link |
oh, I should be thin or thinner.
link |
So I think that it's a little bit of a societal understanding
link |
that our brains are very vulnerable.
link |
And I think that will really help changing society.
link |
And most of society is not ill-meaning.
link |
It's all done by accident,
link |
but that is the society that we live in.
link |
So if we can try to improve that stigma
link |
and be kinder to people in that way,
link |
I think a lot of these problems would get better.
link |
People that are obese,
link |
that feel embarrassed by their obesity, it doesn't help.
link |
It only makes it worse because they give up.
link |
Same thing might be true for anorexics.
link |
So I really think it's important
link |
to consider all of these things.
link |
And that's why it's so complicated.
link |
And it would be so hard to do a well-controlled study
link |
to understand it better
link |
because there's so many of these variables to control for
link |
that you really can't control for.
link |
You might be able to control for them
link |
in a mouse's home cage,
link |
but not in the society that we live in.
link |
So that's kind of my brief sort of summary
link |
of how I would answer your first question.
link |
Then I think your second question,
link |
I sort of take that as,
link |
well, how do you study such a complicated problem
link |
in the operating room and in the clinic?
link |
Because I mentioned the operating room
link |
because that's sort of the first step here.
link |
First, we have, just to clarify,
link |
we have a NIH-funded trial approved by the FDA for research
link |
to do this first in human study.
link |
We've treated two patients.
link |
We have four more to come at Penn.
link |
And in this study,
link |
it's something I've been working towards my entire career.
link |
What we don't know is where in the nucleus accumbens
link |
in the nucleus accumbens.
link |
Will we identify cells or regions
link |
that seem to be involved
link |
in this sort of reward-seeking behavior?
link |
I would call it appetitive.
link |
It's kind of like appetite,
link |
but the word appetitive is I think a good word to use.
link |
What part of the nucleus accumbens is appetitive?
link |
Is the whole thing appetitive?
link |
In my world, it's huge.
link |
As a neurosurgeon, I target parts of the brain
link |
that are three or four millimeters in size.
link |
The nucleus accumbens is almost a centimeter in size.
link |
I didn't realize it was that large.
link |
This sort of reminds me of discussions
link |
around the amygdala.
link |
Everyone thinks amygdala fear,
link |
but amygdala's got a lot of different subregions.
link |
And stimulation of certain areas of the amygdala
link |
makes people feel great.
link |
And stimulation of other areas
link |
makes them feel terribly afraid.
link |
And that shouldn't surprise us
link |
because when we treat patients with Parkinson's disease,
link |
for tremor, if we're in one part of the subthalamic nucleus,
link |
we'll help their tremor.
link |
If we're in another part of the subthalamic nucleus,
link |
the neurologist is looking at me like,
link |
why isn't this working?
link |
And that shouldn't surprise us.
link |
We already know that two or three millimeters deviation
link |
or two or three millimeters away from where we wanna be,
link |
and you might not have the result you want.
link |
And that's probably also true
link |
for these more limbic structures
link |
like the amygdala and the nucleus accumbens.
link |
So regarding the nucleus accumbens,
link |
we traverse some of the nucleus accumbens, not all of it,
link |
in order to place the electrode that we want to use
link |
to detect when cravings are happening, for example,
link |
and to try to block the cravings
link |
from leading to the behavior related to the reward seeking,
link |
which is the overeating in this case.
link |
So what we decided to do in the operating room
link |
was to actually try to leverage a tool
link |
that we use all the time
link |
when we take care of patients with Parkinson's.
link |
So with Parkinson's, a lot of these patients,
link |
not all, have tremor.
link |
And so when we place an electrode
link |
into this motor structure
link |
to try to improve their movement disorder,
link |
we often can hear tremor cells,
link |
and they sound, we convert their electrical signal
link |
to an audible signal so we can actually hear it.
link |
And it sounds kind of like the tremor looks,
link |
like the frequency of the signal
link |
is the same as the hand shaking.
link |
So a zzz, zzz, zzz, zzz. Exactly.
link |
And so the patient with Parkinson's is trembling.
link |
And you're poking around in a dedicated,
link |
careful way, of course.
link |
One poke at a time.
link |
One poke at a time with a very fine wire,
link |
a set of wires, listening to the electrical activity
link |
until you encounter some cells
link |
that are sending out electrical activity
link |
at a similar frequency.
link |
And then you can stimulate them or quiet them
link |
and see if the tremor goes away.
link |
So we are very confident
link |
that when we stimulate that area of,
link |
in this case, the subthalamic nucleus,
link |
we will make that tremor,
link |
we will disrupt that tremor circuit
link |
and that tremor will dissolve.
link |
That's why Parkinson's is so beautiful and inspiring
link |
and from a surgical-
link |
It makes us feel we understand the brain,
link |
at least in that limited way.
link |
So what is the analog to tremor
link |
in terms of appetite and desire to binge?
link |
So craving is a term that,
link |
there's probably other terms we could use by the way,
link |
but that's the term we've chosen to use
link |
for a number of reasons.
link |
One, because people relate with that term.
link |
People that have binge eating disorder or obesity,
link |
they, if you ask them if they crave,
link |
the answer will often be yes.
link |
If you ask them if they lose control or binge,
link |
they might not know what you mean,
link |
or they might not actually feel out of control,
link |
even when they are.
link |
So, but the word craving is relatable.
link |
And so we set out to see if we could identify craving cells.
link |
In a patient with OCD, which is related,
link |
in fact, we target a very similar part of the brain,
link |
we tried to identify cells related to obsessions.
link |
And we believe we did do that.
link |
It was a single case study where we tried to optimize
link |
where our electrode was placed.
link |
So we had some proof of concept
link |
that we would be able to elicit
link |
a sort of disease-specific symptom in the operating room,
link |
assuming the patient could tolerate being awake.
link |
Not everybody needs to be awake for this procedure,
link |
but at least for these first human trials
link |
where we're trying to establish
link |
where in the brain we need to be,
link |
I think this type of approach is really critical.
link |
And by the way, none of this has been published,
link |
but I think it's so important for people to know this.
link |
So I am willing to share some aspects
link |
of what we're trying to do, but that's really the first goal
link |
of this trial is to identify
link |
where in the nucleus accumbens
link |
we can detect these craving cells.
link |
So we have to provoke food craving in the operating room.
link |
That's the first thing.
link |
How do you do that?
link |
Ah, well, there are some somewhat validated ways to do that.
link |
So for example, we asked patients to provide pictures
link |
of food that they rate very highly
link |
as something that they would typically crave.
link |
And, you know, depending on the patient,
link |
it might be something that's very salty.
link |
It could be very sweet, like a donut.
link |
Right, donuts are great.
link |
You should try the Cronut when you're here in New York City.
link |
I just might, I try not to eat that sort of thing.
link |
For all the reasons they change your brain,
link |
it's worth one bite.
link |
Just try to stop yourself after that one bite.
link |
So if I were one of these patients,
link |
given the fact that the binges come on pretty seldom
link |
once a day, do you, I imagine you have them come
link |
to the operating room fasted or semi-fasted?
link |
They're fasted, yep.
link |
Okay, they're fasted, which probably,
link |
there are probably surgical reasons for wanting that too.
link |
Yes, they kind of have to be.
link |
Right, and then you've done the craniotomy,
link |
you've removed a patch of skull,
link |
lowered the wire into the nucleus accumbens,
link |
and then they are viewing pictures of food that they crave
link |
and thinking about it.
link |
Do they have olfactory cues, smells of Cronuts and donuts?
link |
Yeah, I would love to do the olfactory cues.
link |
We haven't implemented that,
link |
but that is a great thank you,
link |
and I'll give you full credit when we do.
link |
Sure, I didn't review the grant, but it sounds,
link |
I'm so glad this work is funded because I mean,
link |
this is what I, I'll make, this time it's not a joke.
link |
When I referred to you all, you neurosurgeons,
link |
as the astronauts of the brain,
link |
this is out on the extreme edge of what we don't know
link |
about how the brain functions.
link |
And this is so far and away different
link |
than giving a mouse access to a high fat food.
link |
Not that that, I'm not being disparaging of the mouse work,
link |
but so the person says, well, I'm the patient in this case,
link |
so I might say, you know, I'm hungry,
link |
a donut sounds really good right now,
link |
but craving to me is like, I, you know,
link |
I'll cross the street, cross town, be late for my meeting,
link |
eat three of these, maybe even hide that
link |
from somebody that cares about me,
link |
that doesn't want me doing this, this kind of thing,
link |
hide it from myself.
link |
This, these kinds of behaviors I'm projecting,
link |
I'm fortunate that I have cravings for things in life,
link |
but donuts are not among the more extreme of them.
link |
So this is all happening in real time
link |
and you're listening to the cells
link |
the same way you would listen to it
link |
and search for tremor cells.
link |
Exactly, same exact tools.
link |
And you're doing that by recording
link |
from a small population of cells in the area?
link |
Yeah, in fact, we do get multi-unit activity,
link |
which is multiple cells, but we really try to find one,
link |
a single unit to listen to.
link |
Yeah, because it's just much easier to understand
link |
what that one neuron is doing
link |
versus trying to listen to multiple.
link |
And we also measure local field potential recordings,
link |
but those are analyzed,
link |
which is more of a population response, thousands of cells.
link |
Kind of a chorus of cells.
link |
Exactly, that we measure offline.
link |
The device that we use to sort of treat these patients
link |
or intervene that we're studying,
link |
it can't do single unit recordings.
link |
It's only doing these more population responses.
link |
So we correlate what we see in the operating room
link |
at the single unit level to the population response,
link |
but we do that all offline.
link |
I can explain that in a moment.
link |
But yeah, so we try to identify these craving cells
link |
and because this is a feasibility study
link |
and we can't be in the operating room
link |
searching for hours and hours and hours,
link |
we do have some sort of,
link |
we have guidelines that we've set for ourselves,
link |
that we've developed with the NIH or the FDA
link |
to make sure that what we're doing
link |
is feasible and safe as well.
link |
So we will spend a limited time
link |
trying to identify these craving cells.
link |
But another sort of strategy
link |
that we think is really important
link |
is the effect of the stimulation.
link |
So a lot of patients,
link |
and this gets to sort of your question earlier
link |
about what comes first.
link |
A lot of people when they binge
link |
or they lose control over food or seek drugs,
link |
that moment of vulnerability is preceded
link |
by what we call a moment of sort of pre-meal negative affect
link |
which basically means right before they binge,
link |
they're feeling down or they feel stressed or anxious
link |
and they compensate for that momentary symptom
link |
by binging or losing control over food.
link |
Not everybody meets criteria for a binge
link |
so I try to specify
link |
that we are looking at loss of control eating
link |
specifically just because the criterion of a binge
link |
is not as critical for us.
link |
So what we wanna be able to do is trigger stimulation
link |
when this craving is detected by the device.
link |
But we trigger it only when the craving is there
link |
and we believe that if we can sort of
link |
temporarily elevate their mood ever so briefly,
link |
again this is about five to 10 seconds of stimulation only,
link |
that perhaps that elevation in mood
link |
could actually sort of disrupt the craving to binge cycle.
link |
Maybe that's a habit, maybe it's not.
link |
But if you crave and then you binge,
link |
if we can interrupt that with this moment of feeling good,
link |
that might be a really good therapy for a patient.
link |
And in fact, when we do deep brain stimulation
link |
for obsessive compulsive disorder,
link |
we can fairly reliably induce a positive affect.
link |
The problem is that it's not sustained
link |
and the reason it's likely not sustained
link |
is because with obsessive compulsive disorder,
link |
we treat that condition with continuous stimulation.
link |
And it's not surprising that over time
link |
the effect kind of goes away.
link |
So when they're in the clinic and we turn the device on,
link |
our patients feel great
link |
and we feel like we've solved the problem.
link |
But they call us the next day and they're like,
link |
my depression came back or my OCD hasn't gotten better
link |
and my mood's back to where it was.
link |
Can you get it back to where it was yesterday?
link |
Because that felt great.
link |
The brain loves homeostatic regulation.
link |
And it does not like to shift patterns.
link |
It's regression to the norm.
link |
And I think there's sort of a tolerance effect there
link |
that is limiting the effect of continuous stimulation.
link |
And actually in a mouse, if you do continuous stimulation,
link |
the sort of blockade of binge eating goes away.
link |
So actually in a mouse, we've actually demonstrated,
link |
we published this not too long ago in PNAS,
link |
that if you deliver stimulation intermittently
link |
and only when sort of a craving signal is detected,
link |
so to speak, that effect will be the most robust
link |
But if you deliver it continuously,
link |
actually the benefit goes away over time.
link |
So I've always encouraged my colleagues
link |
to consider more of an episodic stimulation approach
link |
rather than continuous deep brain stimulation.
link |
But of course that's for these more episodic conditions.
link |
Whereas these more quote unquote state disorders,
link |
as I oversimplified earlier,
link |
they might need more of a continuous therapy.
link |
So that's definitely subject
link |
for a lot of research in the future.
link |
So in any case, the goal in the operating room
link |
was to identify a craving cell,
link |
deliver stimulation safely,
link |
but also to capture a moment of elevated mood.
link |
We were able to do that
link |
as we are in our OCD patients as well.
link |
And also to get an intraoperative CAT scan.
link |
We have devices now in the operating room
link |
that allow us to get imaging in real time.
link |
They're fabulous tools that we didn't have 10 years ago.
link |
So we can confirm accuracy.
link |
You can see where the electrode is precisely.
link |
With 0.5 millimeters of error.
link |
or as precise as we think we need to be.
link |
And we use connectomics.
link |
So there's a tool in brain imaging called tractography
link |
where we can actually measure circuit connections.
link |
It's an indirect assay,
link |
but we believe it's powerful.
link |
It has its assumptions,
link |
but like anything in science.
link |
But we can actually map out
link |
where the nucleus accumbens
link |
connects to the prefrontal cortex.
link |
Sort of the cortical control and inhibitory control pathway
link |
and where that pathway intersects
link |
with the nucleus accumbens.
link |
And we can target that area structurally.
link |
So those three goals of the surgery
link |
we aim to set out to accomplish.
link |
And we believed if we achieved two of those three
link |
that we would have a successful result in our early trial.
link |
Given that at least to me, the non-clinician,
link |
that anorexia is the mirror image of binge eating disorder.
link |
And at least from what I learned,
link |
one of the more deadly psychiatric conditions,
link |
but also quite common.
link |
Is it possible that nucleus accumbens,
link |
this so-called reward circuit,
link |
is also involved in anorexia,
link |
but somehow it is the resistance to eating,
link |
the craving of the fasted state
link |
or something like that that's being reinforced.
link |
And I asked this for two reasons.
link |
One, because I'm genuinely curious about anorexia.
link |
I've observed anorexia in a number of people I know,
link |
and it's a striking thing to see somebody
link |
just resist food despite all better knowledge
link |
of the fact that they're getting quite ill,
link |
maybe even at risk of death.
link |
But the other reason is that if in fact nucleus accumbens
link |
is the site which can harbor cells to promote craving
link |
and craving of fasted states, so to speak,
link |
then that I think might tell us something fundamental
link |
about how the brain works,
link |
which is that structures don't control functions per se,
link |
structures control dynamics of interactions.
link |
Sort of like a orchestra conductor
link |
has a certain number of operations that they perform,
link |
but really their main function
link |
is to coordinate the actions of a lot of things,
link |
not to make sure that the violins always play
link |
in a certain way alongside the oboes.
link |
You can tell I'm not a musician here.
link |
I actually have an appreciation for the oboes.
link |
Those usually get left out.
link |
What's that, the oboes?
link |
Yeah, they usually get ignored.
link |
My partner plays the oboes.
link |
I think it's a great analogy, by the way.
link |
I make this statement, it's a little controversial,
link |
but I actually think people would understand
link |
where I'm coming from across all of these
link |
sort of subspecialties of medicine.
link |
But I actually think, especially with obesity,
link |
remember it's a phenotype that's reflective often,
link |
but not always of a behavior.
link |
But if you consider patients that have obesity
link |
and they exhibit some sort of compulsion towards food,
link |
so they overeat despite the risk of it,
link |
I think those kinds of patients are more similar
link |
to anorexics than they are different.
link |
Anorexia and obesity are both phenotypes that are,
link |
at least in this specific case of obesity and anorexia,
link |
a result of a compulsion to either over or under eat
link |
These types of compulsions are driven by societal pressures,
link |
brain vulnerabilities that are probably more similar
link |
than they are different.
link |
They just happen to manifest differently.
link |
Why they manifest differently is probably related
link |
to each patient's predisposition,
link |
or perhaps preference, that's hard to know.
link |
Like you, I have a personal connection
link |
to these eating disorders, anorexia included,
link |
and yeah, I think it's very scary.
link |
And it's a condition that often instills fear
link |
in psychiatrists, because I think not everybody,
link |
by the way, I have some phenomenal psychiatrists
link |
that I work with, both at Stanford and at Penn.
link |
They're also involved in my obesity study
link |
that take care of these patients.
link |
I mean, these are heroes, but there's a lot of psychiatrists
link |
that are not in this domain that find anorexia scary
link |
for the reason you said.
link |
It has the highest mortality of all psychiatric conditions.
link |
That includes depression, because not only
link |
can these patients die of suicide,
link |
but they die of metabolic complications
link |
of being underweight.
link |
So it is a scary condition.
link |
I relate with that.
link |
I am trying, over time, to bridge what I'm doing
link |
in obesity and binging disorder to anorexia,
link |
One, because I think these problems are more similar
link |
than they are different, and two, because of the need.
link |
And I think we're well positioned to sort of tackle
link |
anorexia using similar approaches, not identical,
link |
but similar approaches.
link |
The nucleus accumbens has been studied in patients
link |
with anorexia in China.
link |
Actually, my postdoc, my first postdoc,
link |
who I had the honor to train when I was at Stanford
link |
as a neurosurgeon in China, before he came to me,
link |
actually was involved in a trial of anorexia
link |
that had some benefits.
link |
And there's studies in Europe and elsewhere
link |
that have examined, preliminarily, the effects
link |
of deep brain stimulation targeting the nucleus accumbens.
link |
Four anorexia colleagues of mine in Canada,
link |
Andres Lozados, a wonderful neurosurgeon scientist,
link |
has been studying the effects of going after area 25,
link |
which is directly connected to the nucleus accumbens
link |
by, you know, it's a monosynaptic connection,
link |
so in a lot of ways, you know,
link |
perhaps delivering stimulation there could be very similar
link |
to delivering stimulation with the nucleus accumbens.
link |
It's all part of one critical inhibitory control circuit.
link |
He's seen benefits as well.
link |
So I definitely think there's some evidence
link |
that this is an area that we need to be studying.
link |
I think our more episodic approach
link |
with responsive stimulation going after sort of a signal
link |
in the nucleus accumbens that seems to be related
link |
to the compulsion to withhold for meeting,
link |
I think is what we will be trying to accomplish
link |
It's right now just being conceived, though.
link |
These studies, they move so slowly
link |
because you have to get a grant.
link |
That grant gets reviewed by the NIH
link |
six months after you submit it,
link |
often gets rejected because it's too innovative
link |
and too high risk, so then you have to edit it
link |
and decrease the risk.
link |
So it takes, my obesity study took two years to get funded.
link |
And I worry about that timeframe
link |
because that's a lot of time for patients
link |
with anorexia to suffer that I might be able to help
link |
at least in a small sample of patients.
link |
So, but that is the nature of how these things go.
link |
You also have to get FDA approval
link |
to do these kinds of things.
link |
We try to do all of this in parallel.
link |
It's an enormous undertaking.
link |
And in a lot of ways, we're starting from scratch,
link |
but in some ways, we have some preliminary data
link |
So my hope is in about a year,
link |
we'll have a similar trial for anorexia at Penn,
link |
so more to come on that.
link |
And we're not the only lab that's trying to go after it
link |
because of the clear need, so.
link |
What is the status of non-invasive brain stimulation,
link |
ablation, and blocking activity in the brain?
link |
I get a lot of questions
link |
about transcranial magnetic stimulation.
link |
I've actually had that done as a research subject.
link |
When I was at Berkeley, Rich Ivory's lab
link |
put a coil on my head.
link |
I was tapping my finger in concert to a drum beat.
link |
And then all of a sudden, because of the stimulation,
link |
it was impossible for me to keep time.
link |
With the drum beat.
link |
It's a pretty wild experience to not have motor control
link |
and then to have motor control returned
link |
at the flip of a switch
link |
when someone else is controlling the switch.
link |
It makes it especially eerie.
link |
So my understanding is
link |
that transcranial magnetic stimulation
link |
is being used to treat depression
link |
and a number of other brain syndromes non-invasively,
link |
so no drilling through the skull.
link |
Surgeons don't like that.
link |
Surgeons love to cut and drill with purpose,
link |
With purpose, yes.
link |
But my understanding is that the spatial precision
link |
Ultrasound is something I hear a lot about these days.
link |
And my understanding is that ultrasound
link |
can allow researchers and clinicians
link |
to stimulate specific brain areas,
link |
perhaps with more precision.
link |
Maybe you could just give us a brief coverage
link |
of what those are being used for.
link |
What are your thoughts on these forms of non-invasive,
link |
meaning no flipping open of a piece of the skull
link |
type brain stimulation and blockade of brain activity?
link |
Yeah, I wanted to clarify also.
link |
These surgeries generally don't, by the way,
link |
require a full craniotomy.
link |
It's usually just a small opening
link |
about the size of a dime in the bone.
link |
So just to clarify.
link |
Painless too, right?
link |
Well, usually without pain.
link |
Yeah, a little bit of scalp numbing.
link |
We give a scalp block
link |
and the patients are getting IV sedation.
link |
So they, in general, don't feel anything.
link |
And if they do, they tell me
link |
and we give them more local anesthetic,
link |
but they're usually asleep during that part.
link |
So it's minimally invasive.
link |
But in a lot of ways, there's no such thing
link |
as a minimally invasive procedure in the brain.
link |
It's kind of a misnomer.
link |
I'm so glad to hear you say that.
link |
Oh no, I am not one of those neurosurgeons
link |
that you've probably encountered.
link |
And we have mutual friends that,
link |
and these mutual friends are some of my favorite people
link |
And they probably actually think more like me than not.
link |
But there are neurosurgeons
link |
that you're absolutely right.
link |
And this is true for all surgeries.
link |
They really, in a lot of ways,
link |
they think what they do is sort of the ground truth
link |
or closer to the ground truth.
link |
And I get that, you know, probing with purpose.
link |
I actually really liked that.
link |
I'm gonna use that, if you don't mind.
link |
It's just describing what you do.
link |
But I actually have always said this.
link |
I've said it publicly.
link |
I've said it to my boss.
link |
I've said this to my team.
link |
We need to embrace non-invasive approaches.
link |
Some of them are a little fluffy.
link |
Fluffy in that we don't understand how they work.
link |
We don't necessarily understand
link |
how deep brain stimulation works, by the way.
link |
But because we don't know exactly how they work,
link |
they're not as precise as we would like them to be.
link |
So we have work to do there.
link |
And I actually think that work is doable
link |
and actually underway.
link |
At Stanford, we have great collaborators
link |
that I think are doing this.
link |
People like Nolan Williams and Connor Liston
link |
at Cornell and others.
link |
So we, I think that TMS,
link |
transprinomagnetic stimulation,
link |
it is FDA-approved for depression, by the way.
link |
It's also FDA-approved for OCD and for nicotine addiction.
link |
Where do they put the coil for those three, or more or less?
link |
Yeah, so they put it over, well, it's always on the scalp
link |
and over the frontal lobe.
link |
And there's different parts of the frontal lobe
link |
that have been demonstrated to be a little better
link |
or a little bit worse.
link |
But what the FDA has approved for depression,
link |
I believe is similar to what's been approved for OCD.
link |
But for addiction, I believe it is a different target.
link |
But we'd have to ask our TMS experts on that.
link |
Can they direct the transprinomagnetic stimulation
link |
deep below the cortex?
link |
And we're actually studying this in OCD patients now.
link |
As a part of our invasive trial,
link |
we are trying to pull patients from a TMS trial
link |
that's in parallel to what we're doing,
link |
all funded by the Foundation for OCD Research,
link |
where we believe we can use TMS to define a circuit
link |
that, if modulated, improves OCD, albeit temporarily.
link |
And in those patients, if it's temporary,
link |
they would be appropriate for an invasive study.
link |
So something we're actively working on.
link |
I've always believed that neurosurgeons need to be part
link |
of the discussion with these non-invasive approaches.
link |
We don't need to do them.
link |
But I think we can help make them more precise
link |
and to probe non-invasively with purpose,
link |
rather than this more kind of, I don't know,
link |
a non-invasive blast effect kind of, you know,
link |
I just can't imagine how that is gonna be as effective
link |
as probing with purpose.
link |
But you can do that non-invasively as well.
link |
And I think we need to do better in that way.
link |
I do believe that's possible,
link |
and I think people are actively trying to do it.
link |
Getting deep in the brain with TMS,
link |
I think, will always be hard.
link |
But you can get there indirectly
link |
by using connectivity assays
link |
and targeting superficial structures
link |
that have high connectivity to deep structures.
link |
So for example, perhaps one day,
link |
there will be a TMS target for anorexia and obesity.
link |
If we are scratching the surface
link |
with invasive approaches to these problems,
link |
we're even doing less with the brain stimulation.
link |
So we have so much work to do there.
link |
Eating disorders and TMS have been so sort
link |
of scarcely studied,
link |
or there have been such little research done in that space.
link |
So it is an area that we need to work on.
link |
For the obvious reason, for example,
link |
in a patient with anorexia, just thinking practically,
link |
you know, placing a device in a patient
link |
who is significantly underweight
link |
might not be the best approach.
link |
You know, wound erosion and issues like that could come up.
link |
So developing a non-invasive approach, I think, is critical.
link |
The problem is, where do we target?
link |
And so the only way to answer that, I think, reliably,
link |
is to accept that we have to get into the brain
link |
before we're out of the brain.
link |
And with these kinds of conditions,
link |
we're only just starting to get into the brain, you know?
link |
So I worry that we're a long way away
link |
from a non-invasive approach
link |
that really works consistently.
link |
I'm sorry to interrupt.
link |
I want to make sure we touch on ultrasound.
link |
Because historically it seemed
link |
that there was a bit more permission
link |
for people to probe around in the human brain.
link |
I sometimes refer podcasts to some of these papers
link |
that were done allowing patients
link |
to self-stimulate in the brain.
link |
These are work done in the sixties,
link |
and now his name escapes me, Robert.
link |
Anyway, there's a couple of papers published in Science
link |
allowing patients to stimulate
link |
a couple of different brain areas,
link |
asking which ones they preferred.
link |
And I was always shocked and slightly intrigued
link |
by the fact that the brain area
link |
that all three of these patients,
link |
who I don't think had any syndromes,
link |
I think they volunteered for these experiments.
link |
I don't think you could do this anymore.
link |
Yes, regulatory was not the same as it is now.
link |
Things have changed, fortunately.
link |
But all three of them
link |
seem to like some midline thalamic structure,
link |
which for those listening is just an area
link |
kind of in the dead center of the brain, more or less,
link |
that evoked a sense of kind of frustration and anger,
link |
which surprised me because I would have thought,
link |
oh, it's Robert Heath, these experiments,
link |
rather than patients preferring to stimulate areas
link |
that evoke laughter or joy
link |
or a feeling of drunkenness or delight.
link |
It also explains a lot of what I observe in social media,
link |
the sort of kind of people repeatedly engaging in battles
link |
that are kind of trivial.
link |
It seems like frustration and anger
link |
might have its own reward circuitry.
link |
Anyway, I don't want to go too far down that rabbit hole,
link |
And kind of gets to our nature as humans
link |
and what we find interesting or rewarding.
link |
But the inability to probe around the brain in a safe way
link |
without the need for somebody to be very sick
link |
would be, I think, would be enormously powerful.
link |
And at least to my mind, if I were in charge,
link |
which I'm not, would offer the opportunity
link |
to really come to an understanding
link |
about how the human brain works without all these issues
link |
of how to translate for mouse studies.
link |
And again, there's huge value to animal studies
link |
but so many of the things that we want to know
link |
about the human brain involve asking the person,
link |
hey, what do you feel when that set of neurons
link |
is stimulated and what don't you feel?
link |
And a mouse, we can ask and ask,
link |
but they're not going to tell us them.
link |
They do tell us, they're not going to tell us in English.
link |
So how do we overcome this challenge?
link |
But first ultrasound, or if you prefer after ultrasound,
link |
is ultrasound going to be really useful
link |
towards solving these clinical issues
link |
and these basic issues?
link |
Yeah, so I think, let's start with ultrasound
link |
and then we'll come back to it.
link |
So ultrasound right now,
link |
transcranial magnetic resonance guided focus ultrasound.
link |
So this is an FDA approved method
link |
to deliver an ablation to the brain noninvasively.
link |
There are researchers, myself included,
link |
that are trying to use transcranial magnetic guided,
link |
magnetic resonance guided focus ultrasound
link |
or MRI guided focus ultrasound
link |
to use it in a modulatory way, not just as an ablation,
link |
but to drive neuronal activity or inhibit it perhaps.
link |
We're still learning how to do that.
link |
There are trials that are trying to understand
link |
if you can use ultrasound to open the blood-brain barrier
link |
so you can deliver a medication to that specific area,
link |
perhaps for a brain tumor or something like that.
link |
So it's a very exciting field
link |
and it is FDA approved for tremor right now.
link |
And so I actually do it routinely
link |
for patients with tremor,
link |
with Parkinson's or a central tremor.
link |
And so I love doing it.
link |
It's often just kind of a miracle
link |
because there's no incision.
link |
I don't have to place an electrode into the brain
link |
to achieve a similar result.
link |
How early into the pathology of Parkinson's
link |
can someone think about approaching this?
link |
So for instance, if somebody has a parent or a sibling
link |
and they're developing some resting tremor,
link |
obviously they should talk to a neurologist,
link |
but a neurosurgeon,
link |
but this noninvasive approach could be incredible for them
link |
as opposed to just only taking drugs
link |
to increase dopamine levels.
link |
Yeah, so depending on the reason you have tremor
link |
would dictate the kind of medication you would use.
link |
It could be Parkinson's,
link |
but if it's not, it might be a central tremor.
link |
By the way, central tremor is 10 times
link |
as common as Parkinson's.
link |
Essential tremor is the most common neurologic condition
link |
in patients over the age of 70.
link |
We often aren't aware of that.
link |
People with a central tremor
link |
feel they have their forgotten disease
link |
because there's no Michael J. Fox for a central tremor.
link |
I sent a letter to Bill-
link |
Sorry, is it essential tremor or-
link |
Yes, essential tremor.
link |
Yeah, E-S-S-E-N-T-I-A-L.
link |
I actually sent a letter to Bill Clinton.
link |
I've observed tremor in him
link |
and I think he's actually disclosed that he has it
link |
and I hoped he'd become a champion
link |
for patients with a central tremor.
link |
Sandra Day O'Connor does as well.
link |
She's also public about it,
link |
but I was not able to get them eager
link |
to become the champion for this condition,
link |
but like Michael J. Fox,
link |
these patients need a champion like that,
link |
but unfortunately, it's a bit of a forgotten disease.
link |
Nevertheless, because of the FDA approval
link |
of Focus Ultrasound for tremor,
link |
they're just trying to get some attention for sure
link |
and it's fabulously effective for these patients.
link |
It treats patients on one side,
link |
usually their dominant hand or their worse hand,
link |
and it really speaks to the fact that, wow,
link |
you can deliver noninvasively an ablation to the brain
link |
in a hypothesized zone that we think is related
link |
to the problem at hand,
link |
and at least with tremor, it works really well.
link |
Could this be effective for psychiatric disease,
link |
obesity, eating disorders?
link |
Actually, that would be the ideal.
link |
The problem is we don't know where to do the ablation.
link |
There is a trial that we would like to do for OCD
link |
where we would deliver an ablation
link |
to the same area of the brain
link |
that we've been delivering ablations to for years
link |
for patients with OCD and it helps a bit.
link |
That's called a capsulotomy, but really,
link |
the outcome is probably gonna be about the same.
link |
It's a nice method because it's noninvasive,
link |
but we need to find a new target for these conditions,
link |
and because of the common denominator of the urge
link |
despite the risk, sort of that compulsion,
link |
perhaps it could be the same target.
link |
I don't know, but I would argue we need
link |
to do these modulatory experiments either with a device
link |
or with invasive recordings to better understand
link |
where these problems are coming from
link |
to define where we should do an ultrasound treatment.
link |
Historically, without much regulation,
link |
we've probed the brain.
link |
The problem, we can't learn a lot
link |
from those experiments now, well, in this way at least.
link |
We don't know exactly where those electrodes were.
link |
We didn't have MRI scanning or high-quality CAT scanning
link |
to know where those electrodes were with certainty,
link |
and we know two or three millimeters matters,
link |
and we also didn't have the tools to place electrodes
link |
in a precise way back then.
link |
So unfortunately, we can't learn a lot
link |
from those experiments right now.
link |
So we're sort of redesigning them,
link |
and there is a way to do it now.
link |
Patients with epilepsy benefit from this all the time.
link |
There has been a revolution in America.
link |
It was in Europe before it was in America
link |
where we would do stereoencephalography,
link |
which is basically like doing an EEG
link |
of patients with epilepsy, but with invasive electrodes,
link |
and we would place tiny little wires,
link |
less than a millimeter in diameter,
link |
all throughout the brain into parts of the brain
link |
that we believe are involved in seizures,
link |
and we would admit the patients to the hospital
link |
and figure out where the seizures were starting
link |
and propagating, and then we could stimulate
link |
through these electrodes to see if there was a symptom
link |
that was important and try to identify a region
link |
that we thought we could either remove surgically,
link |
ablate with a laser, or put a stimulator in it, perhaps.
link |
That's commonplace now for epilepsy,
link |
and it works extremely well, and it's very safe.
link |
Of course, it's still a brain procedure,
link |
but the complication rate is surprisingly low,
link |
quite honestly, for the amount of electrodes that we place,
link |
and it's extremely well tolerated.
link |
Most of these patients leave the hospital,
link |
and they don't even feel like they've had surgery.
link |
So there's actually a lot of interest
link |
in using that procedure to study mental health disorders.
link |
We are trying to do it for patients
link |
with obsessive-compulsive disorder.
link |
We're awaiting an FDA decision on that,
link |
but actually, I credit our colleagues at Baylor
link |
and at UCSF for studying this already.
link |
We have fabulous colleagues at UCSF
link |
that have studied depression using this type of approach,
link |
a mutual friend of ours, you know, Eddie Chang,
link |
who's a wonderful friend and colleague,
link |
somebody I've emulated for many years as well,
link |
and the psychiatry team at UCSF have worked together
link |
on this, sort of bringing together the epilepsy technique
link |
and the psychiatry expertise to study
link |
how we could better target electrodes in depression,
link |
and I'll tell you, if they have a consistent target,
link |
perhaps there becomes an ultrasound target,
link |
but right now, the approach is a bit more reversible
link |
because you can always shut that electrode off
link |
or even remove the electrode
link |
if perhaps it's not in the optimal location
link |
to treat the depression,
link |
but actually, after a large volume of cases,
link |
perhaps they could pool that data
link |
to develop a new ultrasound target for depression.
link |
I think that would be fabulous
link |
and probably is their long-term goal,
link |
not to speak for them,
link |
but that would be something that I'm sure is on their radar,
link |
and Baylor's trying to do the same thing for depression.
link |
Their approaches are a little bit different,
link |
but a similar tool to try to understand depression,
link |
and we're working with all of these types of colleagues,
link |
some of these are our friends,
link |
to try to bring this to OCD as well,
link |
and it makes sense to try to do this for addiction
link |
and obesity and anorexia.
link |
You might ask, well, why aren't you doing this
link |
for obesity right now in our study,
link |
and the reason is that we've developed a target for obesity
link |
and binge eating disorder developed out of mice
link |
that we believe is relevant for the human state,
link |
because you can model this problem in a mouse
link |
a bit better than you can model depression or OCD,
link |
so we feel like we can rely on the preclinical studies more,
link |
whereas with these perhaps more,
link |
I don't wanna say more complicated,
link |
but more human mental health conditions
link |
that are hard to model in a mouse,
link |
you really have to study it in the human,
link |
and you can perhaps start in an epileptic patient,
link |
a patient that has electrodes
link |
that try to provoke a depressed state or study epileptics,
link |
like Dr. Chang has done,
link |
that have comorbid depression, for example,
link |
and that can really validate this approach as well,
link |
but in the end, it's getting into the human brain
link |
that we need to do in the disease specifically
link |
that will eventually lead to a non-invasive approach,
link |
either a lesion or a modulatory approach.
link |
Modulatory would be like TMS,
link |
or lesion approach would be with ultrasound.
link |
I couldn't agree more.
link |
Meanwhile, because there are many, many millions
link |
of people suffering from depression, eating disorders,
link |
Parkinson's and essential tremor, et cetera.
link |
Well, first of all, I should say,
link |
based on everything you've told me thus far,
link |
it's amazing to me that any pharmacologic treatments work
link |
because of how systemic they are
link |
and impacting serotonergic neurons over here
link |
and dopaminergic neurons over there
link |
and not targeting any specific batch of cells.
link |
It makes perfect sense
link |
as to why all the side effects exist.
link |
But earlier you said something
link |
that really grabbed my attention I want to come back to,
link |
which is that if people can be made to feel
link |
or make themselves feel just a little bit better,
link |
a little less anxious just prior to a craving episode
link |
or a binge episode,
link |
maybe even if people can become better
link |
at detecting their own internal states
link |
and when they're kind of veering toward a binge
link |
or veering toward using a drug
link |
or maybe even veering towards suicidal thinking.
link |
Based on what you said earlier,
link |
that those kind of pre-behavioral states
link |
kind of drift on the steering,
link |
those sound like powerful levels of awareness,
link |
at least for now until we have specific sites in the brain
link |
that we can target non-invasive methods
link |
that could be deployed to millions and millions of people.
link |
Seems like that awareness seems like
link |
maybe among the best tools that people could develop.
link |
Yes, I 100% agree with you.
link |
You know, so for the person with OCD
link |
who suffers from anorexia or binge eating disorder
link |
and to their clinicians,
link |
I just want to highlight that you said that.
link |
I mean, again, I'm not a clinician.
link |
I always say this, I don't prescribe anything.
link |
But awareness of one's thinking
link |
seems immensely powerful in this context.
link |
And after all, it is the clinical probe that you use
link |
because let's say the patient were to lie to you
link |
about their experience of what happens in their mind
link |
when you stimulate, you could basically,
link |
the whole thing, the whole surgery,
link |
the whole procedure could go badly wrong.
link |
So it's up to the patient to be, of course,
link |
honest with you and they're incentivized to do that.
link |
But to be honest with themselves about,
link |
ah, you know, I've gone all day without a binge,
link |
but you know, the smell of a donut
link |
or the thought of a donut
link |
is starting to have a particular allure.
link |
That awareness seems like an incredibly powerful thing
link |
to own and to build and cultivate.
link |
Yes, I've always thought that if we could improve awareness,
link |
we can improve outcomes.
link |
I think that's probably true for many of these patients.
link |
The problem I think comes down to the fact
link |
that some of these patients are so resistant to treatment.
link |
And the patients that we see as a surgeon, for example,
link |
are the patients that they've tried
link |
cognitive behavioral therapy,
link |
certainly they've tried medications,
link |
they've tried behavioral management.
link |
They are aware of their problem
link |
and they've shown that to us.
link |
They can tell us when they're craving,
link |
but despite the craving and despite being involved
link |
in this invasive brain surgical trial,
link |
highly, you know, first in human novel study,
link |
which I think will have a positive effect,
link |
but it's still experimental.
link |
They still can't stop themselves.
link |
So they're sort of as made aware as could possibly be.
link |
Did I use grammar there correctly?
link |
They're as aware as they could possibly be
link |
and they still lose control.
link |
We've had this studied in the lab.
link |
So we will bring patients to the laboratory
link |
with this implanted device to try to provoke
link |
this electrographic electrical signal
link |
that can be detected by the actual device
link |
that will stimulate them when they're at home.
link |
But before we actually initiate stimulation,
link |
we want to see can this device detect
link |
this craving cell signal,
link |
which is gonna be different
link |
than what we saw in the operating room
link |
because that's a single cell,
link |
but these devices, these electrodes
link |
are about a millimeter in diameter
link |
instead of like a 10th of a millimeter,
link |
which is what we use in the operating room.
link |
So they're only hearing or detecting,
link |
I should say, thousands of cells' responses.
link |
And we actually have a way to provoke binges.
link |
It's called a mood provocation.
link |
It's very well validated.
link |
It's a little bit like provoking seizures
link |
in the epilepsy monitoring unit,
link |
but here in the sort of psychiatric monitoring unit
link |
or the food monitoring unit,
link |
we actually have a psychiatrist
link |
and each sort of specialist come
link |
and induce a mood that is related
link |
to each patient's sort of self-described binge episode.
link |
So the psychiatrist comes in
link |
and provokes a feeling that can evoke
link |
the negative behavior.
link |
That's exactly right.
link |
So that we can video and synchronize the video
link |
to the brain signal recordings.
link |
The patients all wear an eye tracker
link |
so we can see what they're eating at all times
link |
and what they're looking at specifically.
link |
And that allows us to have
link |
the best temporal resolution possible
link |
to understand what is happening right before the bite.
link |
And even under video surveillance
link |
through a one-way mirror in a laboratory setting
link |
when patients are very well aware
link |
that they're there to be studied
link |
if they're going to binge,
link |
And we believe they do because they just can't control it
link |
as aware as they are of it.
link |
And it's probably because they're the most severe.
link |
So I think if we can improve awareness,
link |
not just the societal awareness
link |
that I was talking about earlier,
link |
but the patient awareness around their problem,
link |
I think that could be a powerful way
link |
to help so many of these patients.
link |
And that's sort of the role of cognitive behavioral therapy.
link |
The problem with cognitive behavioral therapy
link |
or I should say the limitation of it,
link |
I actually don't have any problem with it.
link |
I think it's a wonderful treatment,
link |
is that if you stop it,
link |
many of these patients go back to their old behaviors.
link |
I don't want to say old habits,
link |
but it might be a habit, but the old behaviors.
link |
And so that's the problem is that it's not necessarily
link |
lasting in the absence of continued
link |
cognitive behavioral therapy.
link |
Some people can benefit from it long-term, but some can't.
link |
But I think in the less severe patients,
link |
improving awareness, key.
link |
But in these really refractory patients,
link |
this is kind of like, this is the disease.
link |
Despite the awareness, they can't control themselves.
link |
And that's what we're trying to restore
link |
is that improved ability to control their behavior.
link |
Do you think there's a role for machines
link |
and artificial intelligence here?
link |
There are a couple laboratories up
link |
at the University of Washington
link |
that are using particular signature patterns
link |
within voice to try and help suicidal,
link |
people who are suicidally depressed,
link |
know when they're headed towards an episode
link |
before they even can consciously know.
link |
So this gets right down to issues of free will
link |
and whether or not machines can be smarter than we are.
link |
But one could argue that some of the search algorithms
link |
on Google and other search engines
link |
are actually more aware of our preferences than we are.
link |
Basically what these are,
link |
these are devices that are listening to people talk all day.
link |
They're also paying attention to patterns of breathing
link |
and how well people slept, et cetera.
link |
Integrating a huge number of cues
link |
and then signaling somebody with a yellow light,
link |
like you're headed into a depressive episode
link |
and the person might say,
link |
oh, I feel fine or I feel pretty good.
link |
This is kind of baseline state for me.
link |
And they say, ah, ah.
link |
This is where you were preceding the last episode
link |
that took you down a deep, dark trench
link |
and it took months to get out of.
link |
I wonder whether or not some of these devices
link |
could help with the sorts of things
link |
that we're talking about today.
link |
I've always said we have to get in the brain
link |
before we get out of it.
link |
And if we get in the brain
link |
and understand what these signals look like,
link |
we'll know what those non-invasive signals are.
link |
I think it's possible
link |
that we are scientifically sophisticated enough
link |
to use machine learning
link |
and sort of this kind of bot technique
link |
to anticipate when somebody is going to be highly impulsive.
link |
Suicide is the most dangerous impulse.
link |
It's something that is immensely a focus of the lab
link |
We've talked mostly about compulsion.
link |
Compulsion being going after a reward
link |
or the urge despite the risk.
link |
Impulsivity is similar but different.
link |
It's kind of going after something a little bit.
link |
If you model impulsivity in a mouse,
link |
it's related to going after a food reward
link |
without the sort of paired tone
link |
that the mouse is supposed to wait for.
link |
The mouse doesn't want to wait anymore.
link |
They just go after the food.
link |
I've been that mouse.
link |
Yeah, we all have been.
link |
We can all relate with this to a certain extent.
link |
Again, it's the spectrum.
link |
So in any case, non sequitur.
link |
But I certainly think that there is a way
link |
to use our own body's physiology
link |
to anticipate when these impulses are coming online.
link |
How best to do that?
link |
I think we're just scratching the surface
link |
but these are the kinds of solutions we need.
link |
These are, some of these problems
link |
are of epidemic proportions.
link |
Largest public health problems in this country,
link |
Obesity, opiate crisis, depression, suicidality.
link |
I mean, that's like a third of our country, maybe more.
link |
Probably more if you think about it.
link |
And a colleague of ours at Stanford Psychiatry
link |
told me something that still just blows my mind
link |
which is that something like 75% of the antidepressant
link |
and anti-anxiety medication that exists in the world
link |
is consumed in the United States.
link |
Which is, I mean, that's an outrageous number.
link |
Yeah, we do have an obsession in this country for pharmacy.
link |
And the pharmaceutical industry is very powerful here
link |
and probably related to some aspect of capitalism.
link |
I'm capitalistic and just like everybody else.
link |
But I do worry about that a little bit.
link |
But we tend to over-prescribe
link |
and I think we as patients tend to over-want medication.
link |
We like quick solutions
link |
and sometimes medications provide it, sometimes not.
link |
Or they're often just a band-aid.
link |
It depends on the problem, of course.
link |
But I agree that we need scalable solutions.
link |
I'm a neurosurgeon.
link |
I'm only gonna be able to treat the most severe of patients
link |
with these problems.
link |
You know, we've only done about 200,000
link |
deep brain stimulation surgeries ever.
link |
So, I mean, the problem we're talking about here
link |
is 50 million Americans.
link |
There's no possibility that surgeons
link |
can address that problem.
link |
But we could help inspire an initiative
link |
to go after that kind of problem
link |
or help make it more rigorous.
link |
Because the last thing we need
link |
is some sort of wearable fancy tool
link |
that wastes people's money and time.
link |
We need real therapies for these things.
link |
Not that these devices that we're discussing are not.
link |
I think actually there's lots of promise.
link |
We use machine learning in the lab all the time.
link |
I'm not an electrical engineer
link |
or the computational neuroscientist
link |
doing this type of work.
link |
I just help develop the hypotheses around it
link |
and help fundraise around it.
link |
But I definitely think there's a future for it.
link |
I suspect we're scratching the surface on how best to do it.
link |
Let's talk about your hands.
link |
All the neurosurgeons I know
link |
are very faithfully protect their hands.
link |
And let's talk about-
link |
It's because hand insurance is too expensive.
link |
But I'm guessing that you all are not the ones
link |
to reach into the garbage disposal
link |
even if your eye is on the switch
link |
to make sure that it isn't going to get turned on.
link |
They're just too precious.
link |
They are your livelihood.
link |
And earlier we talked about deadlifts.
link |
There are other forms of exercise.
link |
There are things like tennis.
link |
They're drawing and painting a full range of things
link |
that one can do with their hands.
link |
Use your imagination, folks.
link |
Is it true that neurosurgeons
link |
don't do any really heavy grip activity
link |
because it can refine the motor circuits
link |
in the brain and elsewhere
link |
that can throw off their neurosurgery game?
link |
I would say that many neurosurgeons avoid activities
link |
that put their hands at risk.
link |
Another one, by the way,
link |
there's an annual softball tournament
link |
that neurosurgeons come to in New York City
link |
in Central Park and play. With a very softball.
link |
No, I'm just kidding.
link |
Well, actually it's actually a very typical hard softball.
link |
I don't know why they call it softball.
link |
And actually two close colleagues of mine
link |
have gotten injured at that tournament.
link |
It's also, I must say, and here I'm poking fun,
link |
but for those of you who are going
link |
to the medical profession,
link |
it's also one of the more, how should I say this?
link |
Well, I'm just going to say it.
link |
There's a steep hierarchy of training in neurosurgery.
link |
There's a certain harshness that's been conveyed to me
link |
about the training, much like astronaut training,
link |
to be totally fair.
link |
And so maybe this is a tactic to weed out
link |
either the younger or the older generation.
link |
This is evolution, right?
link |
We have to evolve and weed out the weak, I guess.
link |
Well, I could say that one of the individuals
link |
that got injured is one of the more senior surgeons
link |
that I work with now and is one of the best athletes
link |
that I know and he's definitely not weak.
link |
But you can get injured playing these sports.
link |
And that being said, I can tell you briefly
link |
is I think that, it's funny, my mother came to me recently.
link |
She has osteopenia and she told me, her doctor told her,
link |
she's not allowed to do deadlifts.
link |
And I was like, okay, that's fine.
link |
I'm not telling you you should do deadlifts.
link |
I just don't exactly understand the relationship.
link |
But I can say that I do think,
link |
I'll give you a little story here.
link |
The reason why I'm being a little hesitant to confirm
link |
that I agree with you on the deadlifts is
link |
when I was operating,
link |
this was when I was at Stanford University operating.
link |
And as I mentioned earlier,
link |
we get an intraoperative CAT scan
link |
to confirm accuracy of our lectures.
link |
I do this for all of my surgeries.
link |
When I was reviewing that CAT scan,
link |
the X-ray technician looked at me and said,
link |
whispered into my ear, he's like,
link |
your posture is really bad.
link |
It's embarrassing.
link |
Your physical posture while doing your surgeries.
link |
And I looked at him and I kind of wanted to say,
link |
I won't curse, but I, yeah, exactly.
link |
I've been doing it intermittently during our conversation
link |
because he made me realize
link |
that I really did have bad posture.
link |
And we kind of had a little brief aside
link |
and I learned he was a personal trainer.
link |
And his name was Zach.
link |
And he said to me, your posture is weak because,
link |
or your posture is poor because you're weak.
link |
You need to strengthen your body and strengthen your core.
link |
He's like, powerlifting.
link |
And I'm like, I'm a little hesitant to do this.
link |
And I'll tell you, I started very slowly
link |
and I can't prescribe powerlifting to everybody
link |
for the exact reason you said.
link |
And I've gotten hurt doing it, by the way.
link |
But I do think, I wish I started a little younger.
link |
And I would argue that with close supervision
link |
and very well, if you have a very experienced trainer,
link |
which I would argue if you're a neurosurgeon or an astronaut
link |
or have a highly specialized profession
link |
where you need your limbs to function,
link |
dentists, things like that.
link |
If you're gonna take something on like this,
link |
it really needs to be extremely carefully supervised.
link |
And I can tell you that my trainer had a profound impact
link |
on my life and my posture and my physical health.
link |
And so we did deadlift, I'll admit.
link |
So when you brought it up, I kind of chuckled to myself.
link |
But yes, I have gotten mildly hurt deadlifting,
link |
but it was when I was doing it by myself
link |
and I was kind of cocky and I wasn't paying attention.
link |
But when I was with him and he was all over my technique,
link |
it actually was the most efficient way
link |
for me to feel stronger.
link |
And it improved my posture significantly.
link |
And I miss him since I've left California.
link |
I have a new trainer in Philadelphia who's great,
link |
and I still deadlift occasionally with him.
link |
But I can say I am opposed to deadlifting callously.
link |
But if you're extremely well monitored
link |
by an experienced personal trainer or weightlifter,
link |
I think it could be a great exercise.
link |
Great, I'd love to be wrong in this case
link |
because I'm a huge proponent.
link |
And now on the podcast, I go on and on.
link |
I mean, there's so much data now pointing to the fact
link |
that 180 to 200 minutes of zone two cardio
link |
kind of jogging, cycling, swimming type behavior
link |
is very healthy for everybody.
link |
And we should all be doing that, at least that.
link |
Yes, I need to as well.
link |
And that resistance training on the order of, you know,
link |
six hard sets per muscle group per week
link |
is really important just to offset deterioration of muscles.
link |
I'm learning as we go here.
link |
All function and tendon strength,
link |
and that's just to maintain.
link |
We're not talking about all outsets to absolute failure,
link |
but as you point out with proper form.
link |
So even the neurosurgeons are doing this,
link |
which I think is wonderful.
link |
As a final question, but one that I think really,
link |
or maybe second to final question,
link |
earlier I commented on the remarkable calm,
link |
at least perceived calm of neurosurgeons.
link |
It could be cause or it could be effect of the training,
link |
but it's obvious to me why one would want that trait
link |
in their neurosurgeon.
link |
I wouldn't want a hyperactive,
link |
certainly not an impulsive neurosurgeon,
link |
given that the margins of error are so, so tiny
link |
spatial scale and probably on the temporal scale too.
link |
You don't want people doing things in time
link |
that are, you know, or being spontaneous at all.
link |
Do you think that this branch of medicine that you're in
link |
selects for people that at least can know how to control
link |
any kind of fluctuations in autonomic arousal,
link |
they can calm themselves in real time?
link |
And here's a specific question.
link |
I've never operated on the human brain,
link |
although I've had the privilege of being
link |
in the operating room and seeing this
link |
with some of our experiments with people in VR.
link |
It's a remarkable thing.
link |
I wish for everybody that would get this experience
link |
at some point, not hopefully as a patient,
link |
unless they have a need, but to observe it.
link |
But what was just striking to me is the various
link |
stereotype behaviors of the surgeon.
link |
And when I did surgeries as a graduate student,
link |
as a postdoc in the brains of other types of animals,
link |
I would find, for instance,
link |
that if I started to tremble a little bit,
link |
if I tapped my left foot, that my hand would stabilize a bit
link |
that there's this kind of need to move the body
link |
or one feels the impulse.
link |
Maybe that's my Tourette's-like compulsions again,
link |
but that one can kind of siphon off some of that energy
link |
into another limb so that you could remain precise.
link |
So are these sorts of things that I'm talking about,
link |
maybe it's entirely my imagination,
link |
but are these the sorts of things that one learns
link |
as a neurosurgeon how to still the body and still the mind?
link |
Do you have a meditative practice?
link |
When you go into the operating room,
link |
if you had a particularly challenging morning
link |
or a poor night's sleep,
link |
do you have tools that you use to calibrate yourself
link |
and get yourself into the zone?
link |
I think this would be very interesting for people
link |
to get some insight into,
link |
even if they don't want to be a neurosurgeon.
link |
Yeah, I completely agree.
link |
And I appreciate the earlier reference to neurosurgeons
link |
as astronauts, because I've also heard us
link |
compared to cowboys before,
link |
and it's a little bit less flattering.
link |
Some of what we do surgically really does require
link |
a substantial amount of confidence.
link |
And that confidence hopefully comes from years
link |
of training and experience.
link |
You always worry that the confidence is sort of misplaced,
link |
and that is problematic.
link |
Luckily, you so rarely see that,
link |
because our training is so rigorous.
link |
We have a board of,
link |
American Board of Neurological Surgeons
link |
that sort of allows and assesses surgeons
link |
to continue practice and holds us to a really high bar.
link |
I do think it tends to attract a certain personality.
link |
In my subspecialty, as a deep brain stimulation surgeon,
link |
we call it stereotactic and functional neurosurgery.
link |
Some people have likened us
link |
to the neurologists with a scalpel.
link |
We tend to be a bit more intellectual.
link |
Maybe bedside manner is a little bit friendlier.
link |
And then there's the vascular neurosurgeon
link |
who doesn't sleep, and so they're not as friendly.
link |
There's the spine surgeons who operate the most,
link |
and so they're busy, busy, busy.
link |
There are some of these kind of reputations going around.
link |
But I agree with you.
link |
There is sort of a common feature of a calmness
link |
across neurosurgeons.
link |
And there's some of my, obviously my favorite people,
link |
my closest friends.
link |
And I can relate with them probably because of that.
link |
Sort of a big picture.
link |
They don't get sort of flustered.
link |
They tend to be really good
link |
at figuring out how to have quality time
link |
because we work really hard.
link |
Our hours are significant.
link |
And so the time with our families, our friends,
link |
is less than we would like it to be.
link |
Obviously, that's true for people who work hard
link |
across any profession,
link |
but definitely true for neurosurgeons.
link |
And I think that we're very good at figuring out
link |
how to make that time high quality.
link |
You know, even just texting with some of my friends
link |
that are neurosurgeons,
link |
a great friend of mine just became chairman at Duke,
link |
and just connecting with him by text, which takes seconds,
link |
you know, we feel connected, you know?
link |
And I think that's a trait amongst neurosurgeons.
link |
We sort of know how to cut to the chase in a way
link |
and prioritize our time.
link |
It's a skill that we probably have innately,
link |
but it's also part of the training.
link |
You know, when we are interns now,
link |
there's a lot of work hour regulations
link |
that is probably quite appropriate, by the way.
link |
I think our hours before were bordering on not necessarily,
link |
let's just say they were not ideal
link |
for mental health and sleep,
link |
which we know are very important components.
link |
Certainly, we had no time for meditation.
link |
I definitely did not.
link |
Now, knowing what I know about meditation,
link |
my wife's a health coach.
link |
I get it, I see it, I practice it myself with her.
link |
I wish I had that tool when I was in training
link |
because it's stressful.
link |
Even with the work hour restrictions,
link |
we still don't sleep very much.
link |
We're still at work a lot, about 80 hours a week.
link |
Throughout the entire career?
link |
There are times when it's more,
link |
because after training, there's no work hour restrictions.
link |
So sometimes I feel like as faculty, we get abused,
link |
and the trainees are a little bit more protected now.
link |
It definitely was the reverse at one point.
link |
That's also a huge problem, probably more of a problem.
link |
And I'm joking a little bit.
link |
I don't necessarily think we're abused,
link |
but certainly our hours are significant.
link |
But they come a bit more here and there.
link |
On my OR days when I'm operating, those are long days,
link |
but on the days that I'm lucky enough to be a researcher,
link |
like you, those days tend to be a bit gentler
link |
unless I'm grant writing.
link |
Those days can be long, as you know.
link |
So to answer your question,
link |
I do think we're sort of self-selected for it,
link |
but I also think it's part of the training.
link |
You know, because of the long hours
link |
that we're in the hospital,
link |
we're taking care of sick patients,
link |
and we have sort of a type A mentor approach
link |
where our mentors are hard on us.
link |
You know, we learn to cope with our stress
link |
and be efficient and prioritize things
link |
despite the stress of it all.
link |
And I think we take from that this sort of calm demeanor,
link |
and perhaps it just amplifies what we're probably drawn to,
link |
because before we come to neurosurgery,
link |
we might rotate in neurosurgery.
link |
We might spend a month pretending to be a neurosurgeon,
link |
learning from residents and faculty
link |
that are practicing the specialty.
link |
But prior to actually starting your training,
link |
you never experience anything
link |
like being a resident in neurosurgery.
link |
The stress and the volume of patients
link |
that you have to take care of and the long nights.
link |
It can be quite lonely, by the way.
link |
You develop friends in the hospital,
link |
but sometimes you're on your own when you're on call,
link |
and you have backup.
link |
You can call your chief resident or your attending,
link |
but you really have to learn
link |
how to take care of patients yourself.
link |
You obviously form teams with nurses and staff
link |
and things like that and other residents,
link |
but it can be lonely.
link |
It can be really challenging.
link |
And I think because of those experiences
link |
that all neurosurgeons go through,
link |
we tend to have this sort of unflappable personality
link |
that perhaps we started with a bit
link |
compared to the average person,
link |
but the training definitely amplifies it.
link |
And do you have tools that you implement
link |
if you ever feel that you're getting slightly off-center?
link |
You know, when I was in training,
link |
I actually remember in my second year,
link |
so most neurosurgery programs,
link |
when you're a junior resident,
link |
in some ways that's your toughest year, not in every way.
link |
It is your toughest year because you're young
link |
and you're inexperienced
link |
and you don't know what you don't know.
link |
And that's why it's such a tough year
link |
because you have to learn a lot very quickly
link |
for patient safety reasons, for self-survival.
link |
You know, you just have to learn a lot
link |
and you're on call by yourself in the hospital.
link |
And it's a real challenge.
link |
And I think that, you know,
link |
personally, I gained a lot of weight during that year.
link |
The only exercise I did consciously was taking the stairs.
link |
I refused to take the elevator.
link |
And I was at Penn, at HUP, where I currently practice now.
link |
And I remember I would see patients
link |
anywhere from sort of the ground floor
link |
where the trauma bay was or the ER,
link |
all the way up to Founders 12, the 12th floor.
link |
And I would never take an elevator.
link |
That was my rule for the year
link |
because I knew I would not have time to exercise,
link |
but I would just take the stairs.
link |
And in the beginning of the year,
link |
I would be a little winded when I got to the 12th floor.
link |
But by the end of the year, actually,
link |
it didn't really faze me
link |
and it became a great habit to have.
link |
The problem with that, though,
link |
is I paired that, unfortunately,
link |
with a lot of sleepless nights,
link |
or not enough sleep, let's say.
link |
And I had this terrible habit
link |
of drinking coffee late at night
link |
and I would put a lot of sugar in it.
link |
And it was sort of the only way for me to get a quick,
link |
you know, a quick bout of energy
link |
that for some reason I prioritized at that time,
link |
obviously knowing that I would crash, which I always did.
link |
And I always kind of regretted it, but I still did it anyway.
link |
And I attribute that to poor decision-making,
link |
inexperience, and perhaps being a little vulnerable,
link |
like I think we all are.
link |
That's why I relate with a lot of the research that I do.
link |
And I remember I got married in my third year,
link |
the year after my second year.
link |
And my wife and I, or my fiance at the time,
link |
we started going to the gym together in the morning
link |
and my hours were a little better.
link |
So I would actually be able to exercise
link |
before I operated that day.
link |
And I operated almost every day as a third year resident.
link |
So I remember I'd get to the gym really early.
link |
And in three months I lost like 20 pounds
link |
and I wasn't trying to lose weight.
link |
I just was sleeping better and taking care of myself.
link |
And I remember when we got married,
link |
I fit into a tuxedo that I had in college
link |
or it would have fit me in college.
link |
It actually was a new tuxedo admittedly,
link |
but it was the same size as my tuxedo from college.
link |
So I think that I've always related with the problems
link |
that our patients have to a certain extent.
link |
And when I've been most vulnerable,
link |
which is when I was working the hardest
link |
with the least amount of sleep, I related with it the most.
link |
And yes, exercise for me has always been my tool.
link |
More recently, exercise, some strength training,
link |
I think is important, paired with cardio.
link |
I don't do enough of either, but I definitely do some.
link |
Meditation helps me a bit.
link |
I do that every night before I go to sleep.
link |
I use an app for it.
link |
It's probably not the best way to do meditation, but-
link |
If it keeps you doing it regularly,
link |
it's the best way to do it.
link |
Andrew, I couldn't agree with you more.
link |
It's one of those things
link |
where I look forward to it every night.
link |
And sometimes my wife falls asleep
link |
and I come to bed a little later and I whisper,
link |
I'm like, are you okay if I turn the app on?
link |
So, you know, and she does the same to me
link |
because I think we both value it.
link |
And I think that's been very helpful.
link |
And I didn't have that tool probably when I needed it most,
link |
but I have it now and it's very helpful.
link |
I really appreciate you sharing those tools.
link |
A number of people, I'm guessing out there,
link |
might want to become neurosurgeons.
link |
I really believe that in hearing today's conversation
link |
that you will spark an interest in medicine
link |
and or neurosurgery.
link |
Well, certainly you need to be a physician
link |
before you can become a neurosurgeon.
link |
So end neurosurgery in some cases,
link |
and that would be beautiful.
link |
And I predict that will happen, excuse me,
link |
as a consequence of what you've shared today.
link |
I really appreciate your mentioning
link |
of the emphasis and appreciation on quality time.
link |
I very much see this as quality time.
link |
I know that our listeners will as well.
link |
Really want to thank you for taking time out of your,
link |
not just immensely busy, but very important schedule
link |
because again, the work that you're doing
link |
is really out there on that cutting,
link |
I don't want to say bleeding edge,
link |
because in this context, it's not going to sound right,
link |
but on that extreme cutting edge of what we understand
link |
about how the human brain works and how it can be repaired.
link |
They're doing marvelous work.
link |
We will point people to various places
link |
they can find you online,
link |
and should they need the help of your clinic,
link |
to your clinic and your laboratory as well.
link |
So on behalf of everybody and myself as well,
link |
thank you so, so very much.
link |
Thank you so much for having me.
link |
Thank you for joining me today
link |
for my discussion with Dr. Casey Halpern
link |
about the use of deep brain stimulation
link |
and novel technologies for the treatment of eating disorders
link |
and movement disorders of various kinds.
link |
For those of you that are interested
link |
in learning more about Dr. Halpern's research,
link |
please see the links in our show note captions
link |
that include links to his laboratory website
link |
and to his clinic, as well as various research publications
link |
that are available in complete form as downloadable PDFs.
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If you're learning from and or enjoying this podcast,
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please subscribe to our YouTube channel.
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That's a terrific zero cost way to support us.
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In addition, please subscribe to the podcast
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And on both Spotify and Apple,
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Please also check out the sponsors mentioned
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That's the best way to support this podcast.
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Not so much today, but in many previous episodes
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of the Huberman Lab Podcast, we talk about supplements.
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While supplements aren't necessary for everybody,
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many people derive tremendous benefit from them
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for things like enhancing sleep and focus
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and hormone optimization.
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The Huberman Lab Podcast has partnered
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If you'd like to see the supplements
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And there you'll see a number of the supplements
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I should just mention that that catalog of supplements
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If you haven't already signed up
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this is a monthly Huberman Lab Podcast newsletter
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Many people find these very useful for distilling out
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So for instance, if you go to HubermanLab.com,
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Again, it's Huberman Lab on all platforms.
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Once again, thank you for joining me today
link |
for my discussion with Dr. Casey Halpern.
link |
I hope you learned as much as I did,
link |
and as always, thank you for your interest in science.
link |
I'll see you in the next one.