Key Moments
Karl Deisseroth: Depression, Schizophrenia, and Psychiatry | Lex Fridman Podcast #274
Lex FridmanKey Moments
Karl Deisseroth discusses psychiatry, neuroscience, consciousness, and human suffering, emphasizing the biological roots of mental disorders.
Key Insights
Dysfunction reveals true function: Studying neurological disorders provides insights into the normal workings of the human mind.
Mental disorders exist on a spectrum: Conditions like depression, autism, and bipolar disorder range from mild impairment to severe, life-threatening states, often correlating with intelligence.
Optogenetics enables causal understanding: This technology allows precise control of specific neurons with light, revealing the causal relationships between brain activity and behavior or symptoms.
The brain and emotions are deeply intertwined: Freud's early work highlighted the unconscious, but modern neuroscience suggests a more integrated, less compartmentalized view of drives and motivations.
Mental health treatment involves a multi-faceted approach: Talk therapy (especially cognitive behavioral therapy), medication, and brain stimulation are crucial, but understanding the underlying biology is still elusive for many conditions.
Consciousness poses a profound paradox: While neural activity can replicate subjective experiences, the fundamental principle of how distributed neurons bind into a unified consciousness remains an unsolved mystery.
THE HUMAN MIND THROUGH THE LENS OF DISORDER
Karl Deisseroth’s book, "Projections: A Story of Human Emotions," begins with a masterful description of humanity as a tapestry woven from deep historical threads and individual experiences. He posits that studying breakdowns or “fraying” in the fabric of the mind, as seen in psychiatric maladies, is crucial for understanding its original, unbroken function. This biological principle—inferring function from dysfunction—is a core theme, highlighting that mental health exists on a spectrum from full function to debilitating disorder, with clear lines often debated in psychiatry. While quantitative tests are still lacking, disruptions in social or occupational functioning are key indicators of a disorder due to their impactful severity on human life.
THE SPECTRUM OF THE HUMAN MIND: GENIUS AND MADNESS
The conversation delves into the concept of psychiatric disorders existing on a spectrum, from nearly functional to life-threatening. Deisseroth notes that while self-reported mental health issues can be high, rigorous structured interviews provide more accurate prevalence rates, often around 25% lifetime. Surprisingly, severe disorders like autism, anorexia nervosa, and bipolar disorder are genetically linked and positively correlated with intelligence, educational attainment, and even income. This suggests a complex interplay between vulnerability and potential advantage, raising questions about the definitions of 'disorder' versus 'genius' and how suffering can coexist with high cognitive ability. The discussion also touches upon the personal dilemma of balancing empathy with objectivity as a physician facing immense patient suffering, highlighting the need for coping mechanisms.
LANGUAGE, MADNESS, AND THE JOYCEAN MIND
James Joyce's "Finnegans Wake" is used as a literary lens to explore the nature of madness. Deisseroth observes parallels between Joyce's experimental writing style—filled with clang associations, neologisms, and loose associations—and the thought disorders seen in schizophrenia. Joyce's own daughter suffered from schizophrenia, suggesting an authentic, albeit indirect, connection to the reality of altered thought processes. Deisseroth’s own writing process for "Projections" is multifaceted, with each chapter adopting a style that reflects the specific disorder being discussed, like the torrent of words for mania or the fragmentation for schizophrenia. This immersive approach allows him to inhabit the mental space of his patients, though it requires time and a quiet, disinhibited state, usually late at night.
THE MULTIFACETED MEANINGS OF "PROJECTIONS"
The title "Projections" carries several layers of meaning relevant to neuroscience and psychiatry. In neuroscience, it refers to the long-range axonal connections that link different brain regions, defining how effectively they communicate and form joint representations. For instance, reduced connectivity between auditory cortex and reward centers can diminish the enjoyment of music. Optogenetics, a technique pioneered by Deisseroth's lab, is particularly effective at controlling activity along these projections. Additionally, 'projection' relates to reducing high-dimensional information to lower-dimensional representations. Psychiatrically, it signifies the human tendency to project internal states and narratives onto others to understand their behavior, or introjection, bringing the outside world inward.
LOVE, CURIOSITY, AND THE HUMAN CONDITION
Jorge Luis Borges's love poem, quoted in the book, serves as a poignant illustration of the desire for deep connection and understanding of another human being. Deisseroth interprets this yearning—"I want your hidden look, your real smile"—as analogous to a scientist's love for their subject, demanding vulnerability and intense curiosity. Love, in his view, is the most powerful and stable connection humans can form, essential for survival and bringing profound joy. He draws a metaphor from the huddling of penguins against harsh conditions, representing love as a shared warmth against life's absurdities. This contrasts with the 'deranged' penguin who wanders alone, perhaps an explorer, which highlights the importance of diversity in behavioral traits like foraging versus staying put, even at the species level among humans.
THE EVOLUTION OF PSYCHIATRY: FROM FREUD TO NEUROSCIENCE
Psychiatry originated from neurology and pathology, but early pioneers like Freud ventured into the mysterious realm of verbal communication to understand the human mind, leading to the distinction between conscious and unconscious. Freud’s emphasis on libido as the core of the unconscious differed from Jung’s broader view of the unconscious encompassing a wider range of motivations. While psychoanalysis, focusing on insight rather than cure, has significantly influenced art and philosophy, modern neuroscience questions its detailed subdivisions like id, ego, and superego, seeing them as potentially artificial distinctions. Current research, involving monitoring individual neurons, suggests that choices and actions don't originate in a single brain region but rather emerge from widespread, simultaneous activity, challenging the hunt for a 'free will neuron'.
OPTOGENETICS: CAUSAL PROBING OF THE BRAIN
Deisseroth describes optogenetics, a revolutionary technique his lab developed, as a way to causally determine what matters in brain activity for sensation, cognition, and action. Inspired by Francis Crick's vision for a light-based control, optogenetics makes specific neurons responsive to light by introducing genes from microbes (like algae) that encode light-sensitive ion channels. Shining light on these modified neurons precisely activates or deactivates them, offering unprecedented specificity compared to electrical stimulation. The technology has rapidly advanced from cultured neurons (2005) to controlling hundreds of individually specified cells in a living mouse's visual cortex (2022), enabling the induction of specific perceptions and behaviors, like making a mouse 'see' a visual stimulus that isn't there.
OPTOGENETICS IN HUMANS: RETINA AND BEYOND
While primarily a discovery tool for animal models, optogenetics is beginning to be explored for human therapies. Botond Roska, in collaboration with Deisseroth, performed the first human optogenetics therapy, restoring partial vision to a blind patient with retinal degeneration by making their retinal cells light-sensitive. This achievement, published in Nature Medicine, serves as a proof of concept. Deisseroth believes the main therapeutic value of optogenetics lies in uncovering fundamental principles of brain function. By identifying causal cells and circuits for symptoms like lack of motivation, anhedonia, or altered sleep, optogenetics can inform the development of more targeted medications and brain stimulation treatments, moving beyond current low-resolution diagnostic and therapeutic tools.
BRAIN-COMPUTER INTERFACES AND THE DEEP BRAIN
Deisseroth acknowledges the innovative engineering of efforts like Neuralink, which use electrical signals for high-resolution brain stimulation and data collection. He highlights that while surface cortical approaches are interesting, much of critical brain function—driving motivation, hunger, thirst, social interaction, fear, and anxiety—resides in deeper, evolutionarily older structures like the striatum and thalamus. His lab and others employ long, penetrating electrodes to access these deep regions, emphasizing the diversity of methods. The combination of optical and electrical recording (optoelectric interfaces) is particularly powerful, as light and electricity offer orthogonal channels of information flow. Overcoming light scattering in brain tissue through longer wavelengths and advanced optics engineering allows for increasingly precise and deep control, pushing the boundaries of brain manipulation.
THE MYSTERY OF DEPRESSION AND ITS TREATMENTS
Deisseroth specializes in treatment-resistant depression patients, drawn by the tantalizing closeness to helping those suffering from seemingly unprovoked, profound hopelessness. Depression, characterized by anhedonia, psychic pain, and an inability to envision a future, has strong biological and genetic links, though it's exacerbated by stressors. Unlike cardiology, which understands the heart as a pump causing diverse symptoms, psychiatry lacks a physical interpretation for depression, with no known unique chemical, structure, or brain activity pattern. However, individual symptoms like motivation or social interaction can be robustly modulated in animals using optogenetics. Effective treatments include medications, brain stimulation (like ECT), and talk therapy. Talk therapy, especially cognitive behavioral therapy (CBT), is crucial, working synergistically with other treatments to reshape cognitions and intercept negative thought patterns, especially for mild to moderate cases where patients have insight and motivation. Exercise and sleep regulation also play key roles in mood maintenance. The challenge for loved ones is overcoming the very symptoms of depression (hopelessness, low energy) that hinder treatment-seeking.
THE SOCIAL SIGNAL OF CRYING AND SUICIDALITY
Crying, an involuntary display of emotion, serves as a powerful social signal, honestly reporting need and frailty. Studies show tears significantly increase empathy and the desire to help in onlookers. Biologically, the lacrimal gland, initially for eye cleaning, seems to have been co-opted for this social function. Long-range projections from fear and anxiety regions in the forebrain, intended to regulate respiratory rate, may have slightly misdirected to the tear ducts, making crying an involuntary truthful display linked to internal states of distress. Suicide, though often correlated with depression, remains poorly understood biologically, as no other animal known exhibits this concept of self-termination. While individual symptoms contributing to suicidality (anhedonia, psychic pain, lack of motivation) have research handles (e.g., the habenula's role in negative states), the ultimate action of ending the self is far more complex and lacks clear biological prediction or effective intervention tools beyond containment and therapy.
AUTISM: A DIFFERENT WAY OF PROCESSING INFORMATION
Autism spectrum disorder (ASD) reflects a spectrum of social abilities, from hypersocial to profound social cognition deficits. It is highly genetic and sometimes positively correlated with intelligence. Deisseroth conceptualizes autism not purely as a social dysfunction but as a challenge in processing unpredictable information, whether social cues, unexpected sounds, or lights. Individuals with ASD may excel in dealing with static, predictable, or complex, non-moving information, making them valuable contributors to human innovation. Current treatments are primarily behavioral, focusing on early intervention to prevent developmental delays in social interaction. While there's no medical cure, individual symptoms like anxiety, often stemming from the unpredictability of the world, can be treated with medication. Deisseroth highlights a major opportunity for theoretical neuroscience to model and understand the brain states optimized for unpredictable versus predictable information, and the mechanisms for switching between them.
THE PARADOXICAL NATURE OF CONSCIOUSNESS
The hard problem of consciousness—the subjective, inner sense of experiencing information—remains neuroscience's ultimate challenge. Deisseroth poses a thought experiment: if hyper-optogenetics could perfectly replicate every neuron's activity during a subjective experience (e.g., seeing red), would the subjective feeling persist if those neurons were spatially distributed across the continent? Most intuitively say 'yes' if the activity pattern is identical. However, this reveals a paradox: if spatial proximity is irrelevant for consciousness, then what truly binds these distributed activities into a unified, subjective experience? This implies a missing, fundamental principle of how neural activities become mutually relevant and form a joint representation, a question being probed through dissociation experiments with optogenetics, linking specific rhythms to the separation of self-body awareness, as seen in ketamine effects.
MORTALITY AND THE MEANING OF WHY
Deisseroth reflects on mortality and the ubiquitous human question of 'why.' His personal drive stems from a constant feeling of not having 'done enough,' a productive form of inner negativity, but one that requires careful monitoring. He acknowledges the transient nature of life and the inherent human design to ask and seek answers to profound questions, suggesting that true happiness, in an Aristotelian sense, comes from fulfilling this design. However, he muses that perhaps humans are given just enough cognitive ability to long for answers but not to fully comprehend them, making the quest for understanding an inherent, lifelong process. He emphasizes the importance of celebrating human 'weirdness' and diversity, seeing it as a source of joy, humor, and resilience in confronting life's suffering and injustices, rather than succumbing to conformity.
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Common Questions
By examining 'broken' or dysfunctional states, biologists can infer the original function of the unbroken parts of the mind, similar to how studying mutated genes reveals original function.
Topics
Mentioned in this video
Professor of bioengineering, psychiatry, and behavioral sciences at Stanford University, acclaimed psychiatrist and neuroscientist, and author of 'Projections: A Story of Human Emotions'.
The father of psychoanalysis, who focused on the unconscious mind being tightly linked to libido and sexual drives.
A friend of both Lex Fridman and Carl Deisseroth, mentioned in relation to the belief that optogenetics deserves a Nobel Prize and for his advice on drowsiness boosting creativity.
An actor and comedian, whose role in 'Goodwill Hunting' as a therapist is discussed. His own suicide is later mentioned in the context of depression and Lewy body dementia, highlighting that even seemingly joyful individuals can suffer.
Mentioned along with Camus in the context of existential questions about 'why live,' related to the discussion of suicidal thoughts.
Co-discoverer of the DNA double helix, who later became interested in neuroscience and proposed the need for a method to turn individual neuron types on or off with light, anticipating optogenetics.
Mentioned as a philosopher whose work, like 'The Myth of Sisyphus,' grapples with the 'basic question of why live,' relevant to thoughts of suicide.
Mentioned in the context of categorizations of the human mind, similar to Freud's id, ego, and superego, with his concepts of System 1 and System 2.
A botanist in St. Petersburg who, in 1866, first observed single-celled green algae moving in response to light, a foundational discovery for optogenetics.
A philosopher mentioned in the context of channeling suffering into personal growth, noting his own stomach issues might have influenced his writings.
A researcher at Yale who has conducted studies on post-COVID neurological aspects, including myelin loss.
A contemporary of Freud who felt there was more to the unconscious than libidinous aspects, viewing it as a more complete representation of the conscious self.
A friend and colleague of Carl Deisseroth who performed the first human optogenetics therapy, enabling a blind patient to see.
Mentioned in the context of Neuralink and efforts in brain-computer interfaces.
Carl Deisseroth's wife and a researcher at Stanford who has done work on post-COVID neurological function, particularly myelin loss.
An agent that, along with PCP, was used in dissociation experiments to understand how altered rhythms in the retrosplenial cortex can cause separation of the sense of self from the body.
A psychedelic mentioned as causing altered perceptual states, whose brain manifestations could be explored with recording methods.
An agent that, along with ketamine, was used in dissociation experiments to understand how altered rhythms in the retrosplenial cortex can cause separation of the sense of self from the body.
A scientific journal where Botond Roska published his groundbreaking paper on the first human optogenetics therapy.
Carl Deisseroth's book, which draws insights about the human mind for modern psychiatry and neuroscience, exploring human emotions through patient stories.
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