Projections, page 24
Projections fundamentally embody how effectively different parts of the brain can engage with each other, whether in health or disease; for example, it is known that interregional connectivity strength predicts interregional activity correlations. It is also known that interregional activity correlations can be linked to specific states of enjoyment—for example, reduced coordination between the auditory cortex and a deep reward-related structure (the nucleus accumbens) predicts anhedonia for music in human beings. Likewise, the specific basic reward of caring for a grandchild could be enabled by a capability for strong synaptic connectivity (and thus effective engagement) between one brain region responsible for addressing drives or rewards (like the hypothalamus or VTA/nucleus accumbens circuitry) and another brain region representing hierarchies of kinship relationships (like the lateral septum). Projection-specific synaptic strengths may allow such specific behaviors to become favored and rewarding, especially with learned positive experience.
In this way, synaptic strength at the level of brain region interconnection is an interesting quantity relevant to development and evolution of our internal feelings, since evolution is well suited to working with such interregional connection strengths. Though evolution knows nothing of music or grandchildren per se, it could set up the conditions allowing either or both to be enjoyed—to a certain level, with the right life experience. And there is no shortage of genetic complexity available to lay these specific foundations, in the richness of gene expression patterns that determine how cellular diversity and axon guidance implement brain wiring.
Value—whether negative for aversion, or positive for reward—in the end is only a neural label of sorts, one that can be attached to, or detached from, elements like experiences or memories. This flexibility is crucial for learning, for development, and for evolution. But what can be readily attached may be just as easily detached—for good or ill, in health or disease—and we now have a path for understanding how this flexibility can be enabled. Memories and values alike may both reside in synaptic strengths, learned or evolved as physical structures. And the path to the synapse—along the axon, the long-range fiber emerging from one cell to touch other cells—is set up and directed and grown according to instructions from genes (which follow all of evolution’s rules) at which point the synapse itself can be powerfully tuned by the specificity of experience. Our paths, our joys, our values all lie along thin threads that can be cut—connections bearing our memories, projections that are our selves.
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•
I signed out to the night psychiatry resident, whose Saturday swing shift was sandwiched between my two daytime Saturday and Sunday shifts. I had not met him before; he looked excessively sporty and energetic. Tired but thinking myself tolerant, I walked him through a summary of the patients on our unit with active issues before driving home to get a few hours of rest.
Driving back to the hospital again the following morning, along the deserted streets of early Sunday in Palo Alto, my thoughts drifted back to Mr. N. There remained challenging logistical issues if we were to initiate administration of a medication. We had to determine who was legally able to provide consent, and if Mr. N. was not able, the primary team needed to have a discussion with his son—someone I had not yet met. There was little I could do in the moment; I was technically only a consultant on this case, not a decision-maker.
After getting sign-out from the now-haggard night resident for the patients on our psychiatry unit and managing to listen with benign interest as he troweled on thickly the stories of his overnight valor, I went to a workstation to see if anything new had appeared regarding Mr. N. His location had changed, surprisingly—his name no longer appeared on the 4A medicine unit roster. A moment later I saw he was in the ICU—the intensive care unit.
Mr. N. had suffered a massive stroke the night before, an hour after I had left him. His body was alive, but it was unlikely he would ever recover independent living. His son had power of attorney. Code status had been set: do not resuscitate; do not intubate.
I stood dumb, staring, impotent. He had been right and needed to tell me. His night would be very long.
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•
Only at the very end of life—only when we have put away the chessboard, with all moves made, with no more surprises to come, with most consequences played out—can we fairly judge ourselves and assign credit to actions that ultimately brought success or failure. But it is also here at the end where the memories of our moves fall away, forgotten—a cruel twist, for without memory, how then can we make sense of the lives we have lived, and find meaning in the paths we took, amid the pathos?
We cannot, and so we end where we begin, helpless and uncertain.
Mr. N. surprised us by living on for several weeks before passing. I saw a man whom I presumed to be his son two or three times around the hospice unit, walking in and out—and once as he was pushing Mr. N., supine on his gurney, down the corridor. I remember that day pausing to watch them, as they eased toward a patch of sunlight by a window, and I remember hearing his son’s gentle whisper: Here’s some sun for you, Daddy.
Mr. N. looked older than I remembered—lying flat, utterly limp, his skin a paler gray, eyes closed and mouth open, atonal, utterly still. Cashed out and gone home. His bristly head, the only part of him not covered with the blanket and sheet, seemed proud and dignified to me, though. It evoked the memory of his final move, sitting up in his hospital bed, telling me something that mattered through the fog of dementia and depth of depression, with nearly everything already taken away from him.
As they neared the window and its broad sunbeam, I could hear a medicine team hustling our way, chattering about atrial flutter. Mr. N.’s son could hear them too—he pushed a little faster to make space, clumsily guiding the gurney toward the window at the corridor’s edge.
As the team swept past me, humming along in a crescendo of discussion, the gurney jolted gently to a halt as its bumpered corner tapped the wall. At that moment of impact, both of Mr. N.’s arms suddenly swept up toward the ceiling, askew but together—the sheet dropping away as one arm ended firmly skyward, the other weaker, halfway up, both hands open and fingers splayed. Stable and strong. A frantic reach, a shocking strength.
A stunned moment of silence seized the hallway, and its motley collection of spectators, as Mr. N.’s son and the interns and I looked on at the reaching, grasping arms, all of us locked together in the surreal scene for a beat or two—and then the arms eased back to the gurney, together. Mr. N. was once again at rest.
The medicine team had slowed but never stopped. It took a few seconds for their chatter to build and re-form, as they turned a corner at the end of the hall, but now humming in a minor key, the neurology of reflexes surfacing in their minds from a whirlpool of memories and desires.
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•
In dementia, the infantile reflexes come back, movements choreographed by evolution for the survival of primate babies: the Moro reflex (arms sweep up when the body is suddenly dropped or accelerated, a relic from our tree-climbing forebears, saving infant lives of those who became our ancestors) and the root (light touch on the cheek triggering a turn of the head and an opening of the mouth, to find milk). Falling from height, and losing contact with mother—the basic unlearned fears of human newborns.
Both action patterns disappear after a few months of life but come back with dementia or brain damage—not re-created at the end of life, but rather never really gone, always present but latent for decades, layered over with higher function, coated with inhibition and cognitive control, with all the threads of lived life. As the fabric frays and texture is lost, the original self finds voice again in a heart-wrenching grasp for safety, reaching for a long-dead mother.
All the details of life that mattered so much over the years, that brought moments of happiness or pain, had only covered her over, weaving across with so many weft threads that she could no longer be seen. But always there, and now at the end, the framework for everything surfaces again. As the fine threads fall away, she becomes, once more, the whole world. She might be reachable again, the mammal who kindled her baby to life, who shakingly held, and nursed, and shielded her child—from the rain and sun.
As the threads of the mind disintegrate, as massive insulated fibers fragment and fray, when memory and agency have dissolved away, what was there since birth is all that is left…a human infant in a thin cloth of gray, now exposed again to the cold.
Now all there is, in the confused darkness, is a gentle sway….And when balance suddenly shifts, as the dry weak branch snaps, the baby is released into the night, unpinned from the world, and falls—hands sweeping, in a desperate grasp.
A branch breaks, and this is all at the end. A tree-dwelling baby, a grasping for mother, a falling through space.
EPILOGUE
My great blue bedroom, the air so quiet, scarce a cloud. In peace and silence. I could have stayed up there for always only. It’s something fails us. First we feel. Then we fall. And let her rain now if she likes. Gently or strongly as she likes. Anyway let her rain for my time is come….
So. Avelaval. My leaves have drifted from me. All. But one clings still. I’ll bear it on me.
—James Joyce, Finnegans Wake
The shuttle swings on, ticking back and forth at the leading edge of the tapestry, marking time in space like a pendulum, embedding moments and feelings. Warp threads point the way into unformed space, framing—but not determining—what happens next.
This steady progression of experience clarifies patterns and buries structural threads. Either outcome serves as a resolution of sorts.
My oldest son, with whom I lived as a single father for many of these experiences—and whose broken home frightened me in the context of what I was seeing clinically—has now grown into a hardworking computer scientist and medical student, with caring relationships and a talent for guitar. Intersecting threads can either interrupt, or create, a pattern—and life gives no explanation. I now have four lovely younger children with an eminent physician-scientist—also at my university—whose mission is studying, and treating, the very same brainstem tumor that had grown in the little girl with eyes misaligned, who had almost brought to an end my path in medicine. At the heart of every story here, there is a lost child—but one who might still be found.
Every sensation described here, each individual feeling and thought that guided me to this point, now seems more richly textured than when first experienced, and more deeply interwoven. But is the original feeling better defined by, or instead obscured by, these connections formed with time? In some ways it doesn’t matter—any more than buried warp threads can be meaningfully revealed without destroying a tapestry, any more than we can expose and experience our original feelings again without cutting connections and memories, and losing ourselves.
Ongoing scientific developments will continue to provide more textured interpretations for the stories told here. With each new discovery, our own construction by evolution becomes ever less simply described, and even the extinction of Neanderthals acquires more dimensionality as paleogenetics progresses. Of course they live on in us, and so are not extinct in any definitive sense, but an even more profound truth has now become apparent. We now know that when the last Neanderthals died, they were already part modern human—because the intermingling went both ways, and the last Neanderthal may have been also the last survivor of a wave of modern humans that had left Africa first. Their extinction is truly human, our own.
Most of the medical discoveries described here will, over time, be identified as just elements of a much larger picture—and those will be the success stories. A few will be forgotten, or found flawed enough to require patching and replacement. But this process of discovery and repair of flaws in our understanding is identical with the progress of science. Gaps and flaws by their very nature—like the disease processes themselves—illuminate and reveal.
Light in the natural world passes only through gaps already present—like cracks in the cloud cover or passages through the forest canopy blown open. But with this biology, and in these stories, visible light inverts that paradigm by physically opening a gate—information creating a path for itself, illuminating the whole human family as it streams through. Sometimes it seems the channel is only clumsily stuck open, a rural cow gate in damp sod; we have not fully prepared the pathway, or ourselves, to deal with the information coming through. But the gate is open.
Recent years have even brought insight into the gate itself. Hearkening back to feelings experienced near the very beginning of my scientific journey—crossing scales, exploring mysteries of the whole brain while grounded all the way down at the cellular level in our scientific methods—we have also now delved even deeper, to the molecular and atomic levels of resolution, in exploring how the light-gated protein called channelrhodopsin actually works. We have been able to elucidate the mystery of how light can be detected by a molecule and then turned into electrical current flowing through a pore in that same individual molecule. These experiments use intense beams of X-rays—the same kind of scientific method, crystallography, that enabled the discovery of the double-helical structure of DNA.
There had been intense controversy: some prominent investigators had claimed that there was not a light-gated pore within the channelrhodopsin molecule. But X-ray crystallography allowed us not only to see the pore directly and prove its existence, but also to use that knowledge to redesign the pore and show the depth of our understanding in many ways: changing atoms around—reupholstering the pore’s inner lining—to create channelrhodopsins that conduct negatively charged instead of positively charged ions, or to make these molecules responsive to red rather than just blue light, or to change the timescale of the electricity elicited, speeding or slowing the currents manyfold. These new channelrhodopsins have already proven useful for neuroscience across a broad range of applications, and so cracking the structural code of this mysterious light-gated channel—thereby solving a fundamental mystery rooted in the basic biology of a most amazing plant—also opened up a scientific pathway to new explorations of the natural world, and of ourselves.
Today, even as science in my own lab at Stanford progresses, I still treat patients in an outpatient clinic focusing on depression and autism (and serve as attending physician for a block of inpatient call time every year)—all the while working with a new generation of psychiatry residents, teaching and learning as we journey together through a field that still feels as enthralling and mysterious as it did in my first moment with the schizoaffective disorder patient. We achieve cures in many patients, and in others we can only manage symptoms—a path followed in many fields of medicine, where we manage intractable diseases because we can, and because if we don’t, the patient dies. We are honest peddlers of herbs that help—of feverweed and foxglove.
As our understanding of psychiatry and our insight into the neural circuit control of behavior progress together, we might be wise to begin awkward conversations for which we feel unready. We will need to stay philosophically, and morally, ahead—rather than trying to catch up once it is too late. An uncertain world is already demanding from psychiatry answers to difficult questions about ourselves in health, not only in disease. The reasons for this pressure are important—to discover, and then grapple with, and then embrace, humanity’s uplifting and disturbing contradictions.
And so here, in the form of epilogue, we can look briefly to the future, along three dark and deeply forested paths only dimly illuminated by the stories in this volume that each need more profound exploration soon: our process of science, our struggle with violence, and the understanding of our own awareness.
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Scientific breakthroughs are difficult to predict or to control—forming an odd contrast with much of the process of science, which is an exercise in controlled, and ordered, thought. Indeed, ordered thought seems natural to the human mind in general, and control over the flow of complex thoughts is taken for granted, just as we assume the steady forward passage of time. And yet we cannot use our appetite for order and control to plan the process of science completely. This is a major lesson from most scientific breakthroughs, including that of optogenetics—revealing the need to support basic research that at some level is unplanned. It would have been impossible to predict the impact—on neuroscience—of research into microbial light responses over the past 150 years. Similarly unexpected developments have launched many scientific fields; indeed, because this volume is partly memoir the stories focus on optogenetics, but other pioneering fields have also converged from unexpected directions to define the landscape of biology today.
Thus optogenetics has revealed not only a great deal about the brain but also, in an accessible way, the nature of the basic scientific process. This idea is important to keep at the forefront of our minds as we move together into the future: scientific truth—a force that can rescue us from weaknesses of our own construction—arises from free expression and pure discovery. That, and perhaps also from a little bit of disordered thinking.
