Projections, page 26
Suppose one could control (as with this new form of single-cell optogenetics) the exact pattern of activity, over some period of time, of every cell in the brain of an animal capable of subjective sensation—say, of a pleasurable, intensely rewarding, internal feeling. And suppose such control could even be precisely guided by first observing and recording those activity patterns in the same animal during natural exposure to a real, rewarding stimulus—just as we already know we can do for simple visual percepts in the visual cortex.
The seemingly trivial question, then, is: would the animal feel the same subjective sensation? We already know that a mouse and its visual cortex will both behave as if it had received and processed the real stimulus—but would the animal also feel the same internal awareness, experiencing its quality beyond the information itself, like natural subjective consciousness except now when the activity pattern is presented artificially?
It is important that this be a thought experiment—of course we cannot fully know the subjective experience of another individual, even of another human being, nor have we yet achieved the total control contemplated here—but like Einstein’s original Gedankenexperimente that illuminated relativity so powerfully, this thought experiment rapidly brings us to a conceptual crisis—one that, in its eventual resolution, could be highly informative.
The problem is that answering either yes or no to this question seems essentially impossible. Saying no implies there is more to subjective sensations than the cellular patterns of activity in the brain—since in the thought experiment, we are allowed to match the precise patterns of all physical phenomena that cellular activity elicits, including neuromodulators, biochemical events, and so on that are the natural consequences of neural activity. As a result, we have no framework to understand how that answer could be no. How can there be more to what the cells of the brain do than what they do?
Saying yes raises equally unsettling questions. If all the cells are actively controlled and a subjective sensation is being felt, then there is no reason the cells all need to be in the head of the animal. They could be spread all around the world, and controlled in the same way with the same relative timing, over as long a time period as was interesting, and the subjective sensation should still somehow be felt, somewhere, somehow, by the animal—an animal no longer existing in any discrete physical form. In a natural brain, neurons are near one another, or connected to one another, only to influence one another. But in this thought experiment, neurons no longer need to influence one another—the exact effect of what that influence would have been, over any period of time, is already being provided by the artificial stimulus.
This answer intuitively seems wrong, as well, though we are not sure how—it just seems to fail an absurdity test. How, and why, could individual neurons spread around the world still give rise to the inner feelings of a mouse or a human? The question is only interesting because we are considering an inner feeling. If instead we were to divide a basketball into a hundred billion cell-like parts to be distributed around the world and controlled individually to move as they would during a bounce, there would be no philosophical debate as to whether this new system feels as though it were bouncing. The answer would be, presumably: no more or less than the original ball.
We are left with a philosophical problem, one that optogenetics has framed sharply and clearly. There are certain to be many such mysteries about the brain, like the nature of our inner subjective states, that don’t fall into current scientific frameworks: questions that are deep and unanswered, but some that—it seems now—can be well posed.
And those subjective states, called qualia or feelings, are not just abstract or academic concepts. These are the same inner states that were the central focus of this volume, that first brought me to psychiatry years ago, each one inseparable from its own projection across time—over seconds, and over generations. These subjective experiences underlie our common identity and define the path we have traveled, together, as humanity—even if shared only as stories, in a book or around a fire.
For our family
ACKNOWLEDGMENTS
I am deeply indebted to so many people who helped nurture this work, and who provided motivation and energy through difficult times.
Heartfelt gratitude to Aaron Andalman, Sarah Caddick, Patricia Churchland, Louise Deisseroth, Scott Delp, Lief Fenno, Lindsay Halladay, Alizeh Iqbal, Karina Keus, Tina Kim, Anatol Kreitzer, Chris Kroeger, Rob Malenka, Michelle Monje, Laura Roberts, Neil Shubin, Vikaas Sohal, Kay Tye, Xiao Wang, and Moriel Zelikowsky for their notes and comments—along with my perceptive and tireless literary agent Jeff Silberman, and my deeply thoughtful editor and publisher Andy Ward, whose belief in these stories was always greater than my own.
I am most grateful to all the people who shared this path with me—merging their stories with my own, for a time.
NOTES
Brief references, for background on the science within each story, are included here. All of the articles are freely accessible; you can either copy and paste the link into a browser search bar (if you’re reading on a connected device) or for the notes labeled PMC (for PubMedCentral) go to https://www.ncbi.nlm.nih.gov/pmc/articles/ and at the search bar enter the digital identifier shown (for PMC4790845, enter 4790845), whereupon articles can be read online or free pdfs downloaded.
PROLOGUE
actual memory storage needing no guidance or supervision: https://en.wikipedia.org/wiki/Hopfield_network; https://en.wikipedia.org/wiki/Backpropagation.
In optogenetics we borrow genes from diverse microbes: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790845/.
tricks from chemistry are used to build transparent hydrogels: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846712/.
All the interesting parts remain locked in place, still within 3-D tissue: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359929/.
national and global initiatives to understand brain circuitry: https://braininitiative.nih.gov/sites/default/files/pdfs/brain2025_508c.pdf; https://braininitiative.nih.gov/strategic-planning/acd-working-group/brain-research-through-advancing-innovative-neurotechnologies.
many thousands of insights into how cells give rise to brain function and behavior: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069282/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790845/.
connections defined by their origin and trajectory through the brain could now be precisely controlled: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780260/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5729206/.
CHAPTER 1: STOREHOUSE OF TEARS
they traveled into, and dwelt within, our cellular forebears more than two billion years ago: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5426843/.
with optogenetics, microbial DNA has yet again returned to animal cells: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723383/.
how much of modern Eurasian human genomes arose from this interaction—about 2 percent: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5100745/.
a hidden cave, alone in a final redoubt near the coast of Iberia: https://en.wikipedia.org/wiki/Gorham%27s_Cave; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485383/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935692/.
from an extension of the amygdala called the bed nucleus of the stria terminalis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690364/.
A fiberoptic can be placed not in the BNST but in an outlying region: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069282/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154022/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775282/.
In the mouse version of place preference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5262197/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743797/.
Thus a complex inner state can be deconstructed into independent features: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690364/.
parenting, in the form of intimate care of mammals for their young, was soon deconstructed into component parts, mapped onto projections across the brain: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908752/.
Tears are powerful for driving emotional connection: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882350/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363367/.
missing even this one part of the conversation may come at a cost: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4934120/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402489/.
collections of cells, sixth and seventh and parabrachial, jostle together in a small spot in the pons: https://en.wikipedia.org/wiki/Cranial_nerves.
In 2019 cells were studied across the entire brain of the tiny zebrafish: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726130/.
optogenetics and other methods had implicated these same two structures in mammals: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929119/.
Even the tiny nematode worm Caenorhabditis elegans appears to calculate: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942133/.
Each mammalian species, on average, gets a run of about a million years: https://en.wikipedia.org/wiki/Background_extinction_rate.
population sizes around the world may have plummeted to a few thousand individuals: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161557/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381518/.
CHAPTER 2: FIRST BREAK
the 767, slowly banking harborward, nearing the burning steel tower: https://en.wikipedia.org/wiki/United_Airlines_Flight_175.
Mood elevation has the capability to bring forth energy: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3137243/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847485/.
mania is often not threat-triggered at all, and does not even approach utility: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796427/.
bouffée délirante in West Africa and Haiti, a state of sudden agitated behavior: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4421900/.
broken fragments of the yolk genes persist, even within our own genomes: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2267819/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474779/.
Cave fish and cave salamanders—in sunless colonies, blocked off from the surface world: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182419/.
dopamine neurons have attracted attention for their known roles in guiding motivation and reward seeking: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160519/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188722/.
In 2015 the dopamine and circadian aspects were brought together with optogenetics: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492925/.
the dopamine neuron population is not monolithic but composed of many distinct types that can be separably identified early in mammalian brain development: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362095/.
ankyrin 3 (also known as ankyrin G), which organizes the electrical infrastructure: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856665/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2703780/.
In 2017 a mouse line was created with “knocked out”—insufficient—ankyrin 3: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625892/.
CHAPTER 3: CARRYING CAPACITY
Two or three hundred milliseconds elapse before the response to a ping: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC166261/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467230/.
Despite anxiety and cognitive impairment, Williams patients can seem extremely socially adept: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896837/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378107/.
“That incredibly thin, hairlike wasp waist”: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3016887/.
“ants and hornets and bees, all the social groups—later reverted away from this life cycle”: https://www.sciencedirect.com/science/article/pii/S0960982217300593?via%3Dihub; https://www.sciencedirect.com/science/article/pii/S0960982213010567?via%3Dihub.
researchers studying parenting in mice had used optogenetics: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908752/.
many of the genes linked to autism are related to these processes of electrical and chemical excitability: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402723/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624267/; https://www.biorxiv.org/content/10.1101/484113v3.
people on the autism spectrum exhibit signs of increased excitability: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105225/.
speculated that a unifying theme in autism could be an increased power of neuronal excitation—relative to countervailing influences like inhibition: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748642/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742424/.
elevating the activity of excitatory cells in the prefrontal cortex caused an enormous deficit in social behavior: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155501/.
mice (altered in a single gene called Cntnap2): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390029/.
this autism-related social deficit could be corrected by optogenetic interventions: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723386/.
causing high excitability of prefrontal excitatory cells (an intervention that elicited social deficits) actually did reduce the information-carrying capacity of the cells themselves: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155501/.
“The tree thrives in salt, and makes the soil salty too”: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570027/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836421/.
PTSD (a common and deadly disease that is often resistant to treatment by medication): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126802/.
CHAPTER 4: BROKEN SKIN
Skin arises from ectoderm, in embryos: https://en.wikipedia.org/wiki/Germ_layer.
a meteor strike upended everything: https://www.youtube.com/watch?v=tRPu5u_Pizk.
sensory skin organs then spread across the body: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4245816/.
the patient or the psychiatrist might fit into a role from the past: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481907/.
Suicide is more common in borderline than in any other psychiatric disorder: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4102288/.
an unjust burden: psychological or physical trauma at a young age: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402130/.
trauma during dependency—early in life when warmth and care are needed at all costs—predicts nonsuicidal self-injury later: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5201161/.
Our brains are building even basic structure—the electrical insulation, the myelin: https://www.sciencedirect.com/science/article/pii/S0092867414012987?via%3Dihub.
an individual can instead be guided chiefly by suppression of internal discomfort as the motivation for action: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723384/.
cause animals to become more or less aggressive, defensive, social, sexual, hungry, thirsty, sleepy, or energetic: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708544/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790845/.
swift to react strongly with value assignments: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472065/.
causes the animal to begin to avoid the harmless room, as if it were a source of intense suffering: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743797/.
turning down the dopamine neurons in the midbrain naturally, just as optogenetics does experimentally: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493743/.
early-life stress and helplessness can increase habenula activity: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726130/.
outpatient referral for a specialized group behavioral therapy: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6584278/.
CHAPTER 5: THE FARADAY CAGE
installing a true modern Faraday cage as a shield: https://en.wikipedia.org/wiki/Faraday_cage.
the Kalman filter, an algorithm for modeling complex unknown systems: https://en.wikipedia.org/wiki/Kalman_filter.
“Optimal filters will still block a few things that you actually wanted to go through”: https://en.wikipedia.org/wiki/Chebyshev_filter; https://en.wikipedia.org/wiki/Butterworth_filter.
Matthews had imagined something he called an “Air Loom”: https://en.wikipedia.org/wiki/James_Tilly_Matthews.
schizophrenia genetics: the collection of DNA sequence information from human genomes: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112379/; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912829/.
