Projections: A Story of Human Emotions

In the art of weaving, warp threads are structural, and strong, and anchored at the origin—creating a frame for crossing fibers as the fabric is woven. Projecting across the advancing edge into free space, warp threads bridge the formed past, to the ragged present, to the yet-featureless future.

The tapestry of the human story has its own warp threads, rooted deep in the gorges of East Africa—connecting the shifting textures of human life over millions of years—spanning pictographs backdropped by crevassed ice, by angulated forestry, by stone and steel, and by glowing rare earths.

The inner workings of the mind give form to these threads—creating a framework within us, upon which the story of each individual can come into being. Personal grain and color arise from the cross-threads of our moments and experiences, the fine weft of life, embedding and obscuring the underlying scaffold with intricate and sometimes lovely detail.

Here are stories of this fabric fraying in those who are ill—in the minds of people for whom the warp is exposed, and raw, and revealing.

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The bewildering intensity of emergency psychiatry provides a context for all of the stories in this volume. If such a setting is to illuminate the shared fabric of the human mind, disrupted inner states should be rendered onto the page as faithfully as possible. So here, symptom descriptions from patients are unaltered and real, to reflect the essential nature, the true timbre and soul, of these experiences—though to maintain privacy, many other details have been changed.

Likewise, the powerful neuroscience technologies described—which complement psychiatry by providing a distinct way of looking into the brain—are also entirely real, despite their sometimes science-fiction-like and decidedly unsettling qualities. As depicted here, these methods are drawn unchanged from peer-reviewed papers out of laboratories around the world, including my own.

But even medicine and science are inadequate alone to describe the human internal experience, and so some of these stories are told not from the point of view of a doctor or a scientist but from a patient’s perspective—sometimes in the first or third person, sometimes with altered states reflected by altered language. Where another person’s inner depths—their thoughts or feelings or memories—are depicted in this way, the text reflects neither science nor medicine, but only a reaching out of my own imagination, with care and respect and humility, to create a conversation with voices I have never heard, but only sensed in echoes. The challenge of trying to perceive, and experience, unconventional realities from the patient’s perspective is the heart of psychiatry, working through the distortions of both observer and observed. But inevitably the true innermost voices of the departed and the silenced, the suffering and the lost, remain private.

Imagination here is of uncertain value, and none is asserted, but experience has revealed the many limitations of modern neuroscience and psychiatry in isolation. Ideas from literature have long seemed to me just as important for understanding patients—at times providing a window into the brain more informative than any microscope objective. I still value literature as much as science in thinking about the mind, and whenever possible I return to a lifelong love of writing—though for years this love was only a banked ember, covered with science and medicine, like drifts of ash and snow.

Somehow three independent perspectives, psychiatry and imagination and technology, together can frame the conceptual space needed—perhaps because they have little in common.

Along the first dimension is the story of a psychiatrist, told through a progression of clinical experiences, each centered on one or two human beings. Just as when a fabric frays, its hidden structural threads can be revealed (or when a bit of DNA mutates, the original functions of the damaged gene can be inferred), the broken describe the unbroken—and so each story underscores how the hidden inner experiences of healthy human beings, and perhaps of a doctor as well, might be revealed by the even more cryptic and shadowed experiences of psychiatric patients.

Each story also imagines the emerging human inner experience of emotions, in moments of the world today and across millennia in steps along our journey, past obstacles in our path that may not have been traversed without compromise. This second progression begins with stories of simple and ancient circuits for just being alive—the cells for breathing, or for moving with muscles, or for creating the fundamental barrier between self and other. That earliest, most primal boundary, between each of us and the world—called ectoderm, a lonely fragile layer thin as a single cell—gives rise to skin as well as brain, and so it is with this same ancient borderline that contact between human beings is felt in all its forms, physical or psychological—across the spectrum, from healthy to disordered social states.

The stories move among the universal feelings of loss and grief in human relationships, to deep fractures in the basic experience of external reality that come with mania and psychosis, and finally to disruptions encroaching even on the inner self: the lost ability to feel pleasure in our lives as can happen in depression, the lost motivation to nourish ourselves as in disorders of eating, and even the loss of the self itself—with dementia at life’s end. Along this second dimension, the emotions of the subjective inner world, we begin and end with imagination—whether in stories of prehistory (feelings leave no fossils; we cannot know what was felt in the past, and so we do not attempt to be evolutionary psychologists) or of the present (since even today we cannot directly observe another human being’s inner experience).

But where the measurable effects of feelings are consistent across individuals—as far as we can tell with carefully applied technology—experimental insight into the inner workings of the brain may develop. Along a third dimension, each story reveals this rapidly emerging scientific understanding, with clues from both healthy and disordered states, supported by experiments and driven by data. Brief references, for background on the science within each story, are included in Notes at the end of the book; some curious readers might wish to wander therein, along various trails of personal interest. Many additional important contributions are referenced from within each of these links (and so the links serve primarily as initial stepping-stones, to support further exploration)—but only citations in open-source format are listed in this volume, to ensure availability for all. This final dimension is thus a scientific axis—drawn to guide the public without scientific training, people who deserve to grasp, and own for themselves, every idea and concept here.

This text, then, is not only about the experiences of a psychiatrist, nor imagining the emergence of human emotions, nor even the latest neurotechnology. Each of these three perspectives acts only as a lens, each focused in a different way on the central mystery of feelings in the mind, each providing a different view of the same scene. It’s not simple to fuse these disparate perspectives together into a single image—but it is no more easy to be human, or to become humanity—and the volume can, in the end, achieve a sort of grainy resolution.

Profound respect and gratitude is expressed here to my patients, whose challenges have provided us with this perspective—and to all whose inner suffering, known or unknown, has been inextricably part of the long, dusky, desperate, uncertain, and occasionally lovely tapestry of our shared journey.

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A word about myself, and my own path, may be helpful so that the distortions of the narrator can be better known; I am—as are we all—more subjective than objective, only a flawed bit of human optics. In early life there was no hint that the particular path I was traveling would lead to psychiatry—or that the journey would also wind through the even less congruent realm of engineering.

My childhood was set in an ever-shifting context, from small towns to big cities, from the East to the West to the middle of the North American continent and back again, following my restless family—my mother and father and two sisters, who like me all seemed to value reading above every other pursuit—as we moved every few years to a new home. I remember reading to my father for hours at a time, day after day, as we drove across the country from Maryland to California; my own free moments were occupied mostly by stories and poems—even while cycling to and from school, with the book of the moment held perilously on the handlebars. Though I read history and biology too, the imaginative uses of language seemed more compelling to me, until I collided with a different kind of idea that had been lying in wait along my path.

Creative writing was my first registered course in college, but that year I unexpectedly learned from talking with my fellow students, and then in classes, how a particular style of approaching life science—building understanding from single cells, even for inquiry into the most complex larger-scale systems—was helping to resolve some of the deepest mysteries in biology. These questions had long seemed to be nearly intractable: how a body could develop from a single cell, or how the intricate memories of immunity could be formed and preserved and awakened in scatterings of single cells drifting along blood vessels, or how the disparate causes of cancer—from genes to toxins to viruses—could be unified in a single cell-based concept, in a way that was useful, that mattered.

These diverse fields were all revolutionized by bringing small-scale elemental understanding to large-scale complex systems. The shared secret for biology, it seemed to me, was reaching down to the level of cells and their molecular principles, while retaining perspective on the whole system, the whole body. The inner feeling evoked in me by the prospect of extending this simple cellular idea to the mysteries of the mind—of awareness, of emotions, of the stirring of feeling by language—was a pure and pressured delight, like Toni Morrison’s “rogue anticipation with certainty,” that universal human state of restless joy upon suddenly seeing a path forward.

In talking with friends in our shared dormitory (fellow students who were all, inexplicably, theoretical physicists) over meals, I discovered this was a feeling shared by cosmologists probing phenomena playing out over astronomical scales of space and time. They too began by considering the smallest and most elemental forms of matter, together with the fundamental forces guiding interactions over tiny distances. The result was a process both celestial and personal. The feeling was of synthesis and analysis, together.

Crucially for what came later, at around the same time I was exposed to neural networks, a rapidly growing branch of computer science in which actual memory storage needing no guidance or supervision is achieved by simple collections of units, each cell-like and elemental—things existing in code, with only simple abstract properties—but connected to one another virtually, by operation of the program. Neural networks, as the name suggests, were inspired by neurobiology, but these ideas were so powerful that this computational field would later spawn a revolution in machine intelligence called deep learning, which today uses large collections of cell-like elements to reshape virtually every area of human inquiry and information—including, returning the original favor, neurobiology.

Large groups of connected small things, it seems, can achieve almost anything—if connected in the right way.

I began to consider the possibility of understanding something as mysterious as emotion, at the level of cells. What causes powerful feelings in the well or ill person, feelings adaptive or maladaptive? Or more directly, what in fact are those feelings, in a physical sense, down to the level of cells and their connections? This struck me as perhaps the most profound mystery in the universe—rivaled only by the question of the universe’s origin, its reason for being.

Clearly, the human brain would be important in approaching this challenge, because only human beings can adequately describe their emotions. Neurosurgeons (I thought) had the most physical and privileged access to the human brain; therefore, the logical path for me, the one that provided the most direct approach to helping, healing, and studying the human brain, seemed to be neurosurgery. So throughout graduate school and into my medical training, I steered myself in this direction.

However, toward the final year of medical school, like all medical students, I was required to complete a brief rotation in psychiatry, without which I could not graduate.

Until that point, I had never felt any particular affinity for psychiatry; in fact I had experienced the field as unsettling. Perhaps it was the seeming subjectivity of the diagnostic tools available, or perhaps there was within me some unknown, even deeper issue I had not addressed. Whatever the reason, psychiatry was the last specialty I would have selected. On the other hand, my early experiences with neurosurgery had been invigorating: I loved the operating room, the life-or-death drama juxtaposed with meticulous precision and attention to detail, the focus and intensity and rhythm of suturing set against the high charge of arousal. And so it was stunning to my friends and family, and to myself, when I chose psychiatry instead.

I had been trained to see brains as biological objects—as they indeed are—organs built from cells and fed by blood. But in psychiatric illness, the organ itself is not damaged in a way we can see, as we can visualize a fractured leg or a weakly pumping heart. It is not the brain’s blood supply but rather its hidden communication process, its internal voice, that struggles. There is nothing we can measure, except with words—the patient’s communications, and our own.

Psychiatry was organized around the deepest mystery in biology, perhaps in the universe, and I could only use words, my first and greatest passion, to crack open a gate leading to the mystery. This conjunction, once realized, reset my path entirely. And it all began, as life-changing disruptions so often do, with a singular experience.

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On the first day of my psychiatry rotation, I was sitting in the nurses’ station flipping through a neuroscience journal when, after a brief commotion outside, a patient—a man in his forties, tall and thin, with a sparse, bedraggled beard—burst in through a door that should have been locked. In arm’s reach, standing above me, he fixed his gaze to mine—his eyes wide in fear and rage. My gut clenched as he began to shout at me.

Like any city dweller, I was no stranger to people saying strange things. But this was no street encounter. The patient appeared completely alert, not shrouded in a fog; his experience was stable and crystalline, the hurt was bright in his eyes, the terror was real. In a shaking voice that seemed to be all he had left, with profound bravery, he was meeting the threat.

And his speech—it was creative in its agony, full of phrases used not for traditional meaning but seemingly for their own sake, as communicative effects, with their own grammar and aesthetic, self-contained. He was directly confronting me—though we had not met before, he had an idea that I had violated him—but was doing so with sounds as feelings, with their relationships beyond syntax or idiom. He spoke a novel word that sounded like one in a phrase of Joyce’s I had read long ago: it was telmetale; this was Finnegans Wake on the locked unit, as he told what was deeper than skin or skull, than stem or stone. I sat agape, my brain rewiring as he spoke. He evoked in me science and art together, not in parallel but as the same idea, fused: with both the steady inevitability and the uncontrolled blaze of a sunrise. It was shocking, it was unitary, it mattered, and it brought my intellectual life fully together for the first time.

I later learned that he was suffering from something called schizoaffective disorder, a destructive storm of emotion and broken reality that combines the major symptoms of depression, mania, and psychosis. I also learned that this definition mattered not at all, since the categorization had little impact on treatment beyond simply identifying and treating the symptoms themselves, and there was no underlying explanation. Nobody could give answers to the simplest questions regarding what this disease really was in a physical sense, or why this person was the one suffering, or how such a strange and terrible state had come to be part of the human experience.

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Being human, we try to find explanations, even when that quest seems hopeless. And for me, after that moment, there was no turning back—and the more I learned, no turning away. I formally chose psychiatry as my clinical specialty later that year. After completion of four more years of training and board certification in psychiatry, I launched a lab in a new bioengineering department—at the same university, in the heart of Silicon Valley, where I had been a medical student. I planned to treat patients while also building tools for studying the brain. Perhaps new questions, at least, could be asked.

As complicated as the human brain seems to be, it is only a clump of cells like every other part of the human body. These are beautiful cells, to be sure, including more than eighty billion neurons specialized for conducting electricity, each shaped like a richly branched bare tree in winter—and each forming tens of thousands of chemical connections called synapses with other cells. Tiny blips of electrical activity continually course through these cells, pulsing along fat-insulated electrical-conduction fibers called axons that together form the white matter of the brain, each pulse lasting only a millisecond and measurable in picoamps of current. This intersection of electricity and chemistry somehow gives rise to everything that the human mind can do, remember, think, and feel—and it is all done with cells, which can be studied and understood and changed.

As was required for the modern ascendance of other fields of biology (like development and immunology and cancer), new methods first had to be enabled for neuroscience that would allow deeper cellular understanding within the intact brain. Before 2005, we had no way of causing precise electrical activity to happen in specific cells within brains. To that point cellular-level electrophysiological neuroscience had been largely limited to observation—listening with electrodes to cells as they fired away during behavior. This was an immensely valuable perspective in its own right, but we could not provide or take away those firing events within specific cells to see how cellular activity patterns might matter for the elements of brain function and behavior: sensation, cognition, and action. One of the earliest technologies developed in my laboratory beginning in 2004 (called optogenetics) began to address this limitation: the challenge of causing or suppressing precise activity in specific cells.

Optogenetics begins by transporting foreign cargo—a special kind of gene—as far as imaginable in biology: from the cells of one major kingdom of life all the way to the cells of another. The gene is just a piece of DNA that directs its cell to produce a protein (a small biomolecule designed for certain jobs in the cell). In optogenetics we borrow genes from diverse microbes such as bacteria and single-cell algae, and deliver this alien cargo to specific brain cells of our fellow vertebrates like mice and fish. It’s a strange thing to do—but with a certain logic, for the particular genes we borrow (called microbial opsins), upon delivery to a neuron, immediately direct the creation of remarkable proteins that can turn light into electrical current.

Normally these proteins are used by their original microbial hosts to convert sunlight into electrical information or electrical energy—by guiding movement of the free-swimming algal cell to the optimal level of light for survival, or (in certain ancient forms of bacteria) by setting up conditions for harvesting energy from the light. In contrast, most animal neurons normally do not respond to light—there would be no reason to, as it is quite dark inside the skull. With our optogenetic approach (using genetic tricks to produce these exotic microbial proteins only in specific subsets of neurons in the brain, but not others), those brain cells newly endowed with microbial proteins become much different from their neighbors. At this point the modified neurons are the only cells in the brain able to respond to a pulse of light delivered by a scientist—and the result is called optogenetics.

Because electricity is a fundamental currency of information in the nervous system, when we send in laser light (delivered through thin fiberoptics, or with holographic displays that project spots of light into the brain) and thereby change the electrical signals flowing through these modified cells, remarkably specific effects on animal behavior result. Discovered in this way are the targeted cells’ capabilities for giving rise to mysteries of brain function, like perception and memory. These optogenetic experiments have proved so useful in neuroscience because they allow us to link the local activity of individual cells to the global perspective of the brain. Tests of cause and effect now play out in the right context; only cells within intact brains can give rise to the complex functions (and dysfunctions) underlying behavior—just as individual words only matter for communication within the context of their sentence.

We do this mostly in mice, rats, and fish: animals with many nervous system structures in common with us (structures that are just quite a bit scaled up in our lineage). Like us, these fellow vertebrates sense, and decide, and remember, and act—and in so doing, if observed in the right way, they reveal the inner workings of brain structures that we share. And so a new approach to investigating the brain has emerged, with methods that recruit tiny and ancient achievements of evolution to work for us—borrowed from forms of life that diverged from our own lineage almost at the very beginning, at the earliest and deepest anchor of the warp of life itself.

A subsequent technology my team developed, also inspired by this principle of cellular resolution in intact brains, is called hydrogel-tissue chemistry (which we first described in 2013, in a form called CLARITY; many variations on this theme have emerged since). In this approach, tricks from chemistry are used to build transparent hydrogels—soft water-based polymers—within cells and tissues. This physical transformation helps turn an intact structure like the brain (normally dense and opaque) into a state that allows light to pass freely, which in turn allows high-resolution visualization of component cells and their embedded biomolecules. All the interesting parts remain locked in place, still within 3-D tissue, evoking images of childhood treats—clear gelatin desserts with embedded bits of fruit that can be seen deep within.

A theme common to both optogenetics and hydrogel-tissue chemistry is that we can now observe the brain intact, and study the components that give rise to function, without disassembling the system itself, whether in health or in disease. Detailed analysis, always an essential part of the scientific process, can be carried out within systems that remain whole. The excitement resulting from these technologies (and diverse complementary methods) has spread beyond the scientific community—and helped give rise to national and global initiatives to understand brain circuitry.

By taking this approach—and integrating technological advances from other laboratories as well, in microscopy, genetics, and protein engineering—the scientific community has now obtained many thousands of insights into how cells give rise to brain function and behavior. For example, researchers identified specific axonal connections projecting across the brain (like warp threads embedded in a tapestry, entwined with countless other crossing fibers) through which cells in the frontal parts of the brain reach deep into regions that govern powerful emotions like fear and reward seeking, and help restrain behaviors that would otherwise turn these emotions and drives into impulsive action. These findings were made possible because specific connections defined by their origin and trajectory through the brain could now be precisely controlled—in real time, at the speed of thought and feeling, during the complex behaviors of animal life.

These deeply embedded axons help define brain states and guide expression of emotions. By grounding our understanding of inner states at the level of precisely defined physical structures in this way, we also obtain a concrete perspective on the past, on our evolution. This insight emerges since these physical structures were formed during our early development and infancy by the operation of our genes, and genes are what evolution has worked with in shaping human brains over the millennia. So our inner threads, in some sense, project across the time we have inhabited as well as across the space within us—a legacy anchored in humanity’s prehistory, needed by our forebears to survive.

This connection to the past is not magical—this is nothing like “collective unconscious” communication, in the way that Carl Jung invoked mystical connections with distant ancestors across time—but arises from brain-cell structure, a physical heritage from our predecessors. Beings that by chance created the first early forms of these connections we possess (and study) today—with some variation from individual to individual—were likely to have survived and reproduced more effectively, and as a result, they passed the genes governing that brain-structure predisposition down to us, and to other mammals in the modern world. So we do feel what our ancestors likely also felt—not just incidentally, but at times and in ways that mattered greatly to them.

These inner states were bequeathed to us through the relentless will (and sometimes good fortune) of their survival—giving rise to humanity, with our feelings and our failings.

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The promise of modern neuroscience even extends to the prospect of addressing human frailty and easing human suffering: from guiding therapeutic brain-stimulation methods with our newfound knowledge of causation (what actually makes things happen, with cellular precision) in brain circuits, to discovering the roles in brain circuitry of genes that are linked to psychiatric disorders, to simply stirring hope in long-suffering and long-stigmatized patients. So scientific progress has deeply informed clinical thinking—this is the value of basic research, nothing new though wonderful still—but my perspective is also inverted, in that clinical work has just as powerfully guided my scientific thinking. Psychiatry has helped drive neuroscience in return—and this is enthralling to consider: the experiences of suffering human beings, and thoughts about mouse and fish brains, are informing each other. Neuroscience and psychiatry are pulling together, bootstrapping, connected at a deep level.

In light of these developments over the past fifteen years, it is interesting to reflect on my initial self-perceived lack of personal connection with psychiatry. So profound was the impact of my first unexpected encounter on the psychiatry ward—the shouting, the fear, the vulnerability of experiencing a terrifying reality through another’s eyes—that I sometimes wonder if I was by chance unwittingly prepared, already tuned, to be positively affected in a particular way by that moment, which for many people would have been, understandably, nothing more than a disturbing encounter. Personal inspiration (like scientific discovery) can come from unexpected directions, and so I now think of my course correction in that moment as a kind of parable about the perils of prejudgment, and the need for direct personal exposure to find true understanding of almost anything human.

There is another allegorical aspect as well, in which the story of optogenetics provides a lesson for the broader sociopolitical world on the value of pure science. Historical work on algae and bacteria dating back more than a century was essential for us to create optogenetics and gain insight into emotion and mental illness—but this path could not have been predicted at the outset. The story of optogenetics demonstrates, as transformations of other scientific fields have before and will again, that the practice of science should not become too translational, or even too biased toward disease-related questions. The more we try to direct research (for example, by concentrating public funding too focally in large projects targeted to specific possible treatments), the more likely we are to instead slow progress, and the undiscovered realms where ideas that will truly change the course of science, of human understanding, and of human health, will remain in shadow. Ideas and influences from unexpected directions are not only important but essential—for medicine, for science, and for all of us, in finding and following our trajectories through the world.

These days, I sometimes imagine seeking out that schizoaffective disorder patient, with whom I shared that heart-pounding first awakening, to sit down together for a quiet moment of communion—though it has been a long time. A receptivity to the improbable comes very close to the essence of illness on the schizophrenia spectrum, and so he might not be at all surprised to learn that his crossing of the threshold of the nurses’ station that day could have helped in its own way to advance psychiatry and neuroscience. In a real sense, our conversation now could confirm for him, and for me, that despite the depth of his suffering, from some angle, some perspective, his warp aligns with all of ours, and blends completely into the shared tapestry of the human experience, within which he is no more ill than humanity itself.