Connectome

by Sebastian Seung

  Table of Contents

  Title Page

  Table of Contents

  Copyright

  Dedication

  Introduction

  Part I: Does Size Matter?

  1. Genius and Madness

  2. Border Disputes

  Part II: Connectionism

  3. No Neuron Is an Island

  4. Neurons All the Way Down

  5. The Assembly of Memories

  Part III: Nature and Nurture

  6. The Forestry of the Genes

  7. Renewing Our Potential

  Part IV: Connectomics

  8. Seeing Is Believing

  9. Following the Trail

  10. Carving

  11. Codebreaking

  12. Comparing

  13. Changing

  Part V: Beyond Humanity

  14. To Freeze or to Pickle?

  15. Save As . . .

  Epilogue

  Acknowledgments

  Notes

  References

  Figure Credits

  Index

  Copyright © 2012 by Sebastian Seung

  All rights reserved

  For information about permission to reproduce selections from this book, write to Permissions, Houghton Mifflin Harcourt Publishing Company, 215 Park Avenue South, New York, New York 10003.

  www.hmhbooks.com

  Library of Congress Cataloging-in-Publication Data

  Seung, Sebastian. Connectome : how the brain’s wiring makes us who we are / Sebastian Seung. p. cm. Includes bibliographical references and index. ISBN 978-0-547-50818-4 I. Title. II. Title: How the brain’s wiring makes us who we are. [DNLM: 1. Brain—anatomy & histology. 2. Brain—physiology. 3. Brain—pathology. 4. Cognition—physiology. 5. Nervous System Physiological Phenomena. WL 300] 612.8'2—dc23 2011028602

  Book design by Brian Moore

  Printed in the United States of America

  DOC 10 9 8 7 6 5 4 3 2 1

  Figure Credits appear on [>].

  To my beloved mother and father, for creating my genome and molding my connectome

  Introduction

  No road, no trail can penetrate this forest. The long and delicate branches of its trees lie everywhere, choking space with their exuberant growth. No sunbeam can fly a path tortuous enough to navigate the narrow spaces between these entangled branches. All the trees of this dark forest grew from 100 billion seeds planted together. And, all in one day, every tree is destined to die.

  This forest is majestic, but also comic and even tragic. It is all of these things. Indeed, sometimes I think it is everything. Every novel and every symphony, every cruel murder and every act of mercy, every love affair and every quarrel, every joke and every sorrow—all these things come from the forest.

  You may be surprised to hear that it fits in a container less than one foot in diameter. And that there are seven billion on this earth. You happen to be the caretaker of one, the forest that lives inside your skull. The trees of which I speak are those special cells called neurons. The mission of neuroscience is to explore their enchanted branches—to tame the jungle of the mind (see Figure 1).

  Figure 1. Jungle of the mind: neurons of the cerebral cortex, stained by the method of Camillo Golgi (1843–1926) and drawn by Santiago Ramón y Cajal (1852–1934)

  Neuroscientists have eavesdropped on its sounds, the electrical signals inside the brain. They have revealed its fantastic shapes with meticulous drawings and photos of neurons. But from just a few scattered trees, can we hope to comprehend the totality of the forest?

  In the seventeenth century, the French philosopher and mathematician Blaise Pascal wrote about the vastness of the universe:

  Let man contemplate Nature entire in her full and lofty majesty; let him put far from his sight the lowly objects that surround him; let him regard that blazing light, placed like an eternal lamp to illuminate the world; let the earth appear to him but a point within the vast circuit which that star describes; and let him marvel that this immense circumference is itself but a speck from the viewpoint of the stars that move in the firmament.

  Shocked and humbled by these thoughts, he confessed that he was terrified by “the eternal silence of these infinite spaces.” Pascal meditated upon outer space, but we need only turn our thoughts inward to feel his dread. Inside every one of our skulls lies an organ so vast in its complexity that it might as well be infinite.

  As a neuroscientist myself, I have come to know firsthand Pascal’s feeling of dread. I have also experienced embarrassment. Sometimes I speak to the public about the state of our field. After one such talk, I was pummeled with questions. What causes depression and schizophrenia? What is special about the brain of an Einstein or a Beethoven? How can my child learn to read better? As I failed to give satisfying answers, I could see faces fall. In my shame I finally apologized to the audience. “I’m sorry,” I said. “You thought I’m a professor because I know the answers. Actually I’m a professor because I know how much I don’t know.”

  Studying an object as complex as the brain may seem almost futile. The brain’s billions of neurons resemble trees of many species and come in many fantastic shapes. Only the most determined explorers can hope to capture a glimpse of this forest’s interior, and even they see little, and see it poorly. It’s no wonder that the brain remains an enigma. My audience was curious about brains that malfunction or excel, but even the humdrum lacks explanation. Every day we recall the past, perceive the present, and imagine the future. How do our brains accomplish these feats? It’s safe to say that nobody really knows.

  Daunted by the brain’s complexity, many neuroscientists have chosen to study animals with drastically fewer neurons than humans. The worm shown in Figure 2 lacks what we’d call a brain. Its neurons are scattered throughout its body rather than centralized in a single organ. Together they form a nervous system containing a mere 300 neurons. That sounds manageable. I’ll wager that even Pascal, with his depressive tendencies, would not have dreaded the forest of C. elegans. (That’s the scientific name for the one-millimeter-long worm.)

  Figure 2. The roundworm C. elegans

  Every neuron in this worm has been given a unique name and has a characteristic location and shape. Worms are like precision machines mass-produced in a factory: Each one has a nervous system built from the same set of parts, and the parts are always arranged in the same way.

  What’s more, this standardized nervous system has been mapped completely. The result—see Figure 3 —is something like the flight maps we see in the back pages of airline magazines. The four-letter name of each neuron is like the three-letter code for each of the world’s airports. The lines represent connections between neurons, just as lines on a flight map represent routes between cities. We say that two neurons are “connected” if there is a small junction, called a synapse, at a point where the neurons touch. Through the synapse one neuron sends messages to the other.

  Figure 3. Map of the C. elegans nervous system, or “connectome”

  Engineers know that a radio is constructed by wiring together electronic components like resistors, capacitors, and transistors. A nervous system is likewise an assembly of neurons, “wired” together by their slender branches. That’s why the map shown in Figure 3 was originally called a wiring diagram. More recently, a new term has been introduced—connectome. This word invokes not electrical engineering but the field of genomics. You have probably heard that DNA is a long molecule resembling a chain. The individual links of the chain are small molecules called nucleotides, which come in four types denoted by the letters A, C, G, and T. Your genome is the entire sequence of nucleotides in your DNA, or equivalently a long string of letters drawn from this four-letter alphabet. Figure 4 shows an excerpt from the thre
e billion letters, which would be a million pages long if printed as a book.

  Figure 4. A short excerpt from a human genome

  In the same way, a connectome is the totality of connections between the neurons in a nervous system. The term, like genome, implies completeness. A connectome is not one connection, or even many. It is all of them. In principle, your brain could also be summarized by a diagram that is like the worm’s, though much more complex. Would your connectome reveal anything interesting about you?

  The first thing it would reveal is that you are unique. You know this, of course, but it has been surprisingly difficult to pinpoint where, precisely, your uniqueness resides. Your connectome and mine are very different. They are not standardized like those of worms. That’s consistent with the idea that every human is unique in a way that a worm is not (no offense intended to worms!).

  Differences fascinate us. When we ask how the brain works, what mostly interests us is why the brains of people work so differently. Why can’t I be more outgoing, like my extroverted friend? Why does my son find reading more difficult than his classmates do? Why is my teenage cousin starting to hear imaginary voices? Why is my mother losing her memory? Why can’t my spouse (or I) be more compassionate and understanding?

  This book proposes a simple theory: Minds differ because connectomes differ. The theory is implicit in newspaper headlines like “Autistic Brains Are Wired Differently.” Personality and IQ might also be explained by connectomes. Perhaps even your memories, the most idiosyncratic aspect of your personal identity, could be encoded in your connectome.

  Although this theory has been around a long time, neuroscientists still don’t know whether it’s true. But clearly the implications are enormous. If it’s true, then curing mental disorders is ultimately about repairing connectomes. In fact, any kind of personal change—educating yourself, drinking less, saving your marriage—is about changing your connectome.

  But let’s consider an alternative theory: Minds differ because genomes differ. In effect, we are who we are because of our genes. The new age of the personal genome is dawning. Soon we will be able to find our own DNA sequences quickly and cheaply. We know that genes play a role in mental disorders and contribute to normal variation in personality and IQ. Why study connectomes if genomics is already so powerful?

  The reason is simple: Genes alone cannot explain how your brain got to be the way it is. As you lay nestled in your mother’s womb, you already possessed your genome but not yet the memory of your first kiss. Your memories were acquired during your lifetime, not before. Some of you can play the piano; some can ride a bicycle. These are learned abilities rather than instincts programmed by the genes.

  Unlike your genome, which is fixed from the moment of conception, your connectome changes throughout life. Neuroscientists have already identified the basic kinds of change. Neurons adjust, or “reweight,” their connections by strengthening or weakening them. Neurons reconnect by creating and eliminating synapses, and they rewire by growing and retracting branches. Finally, entirely new neurons are created and existing ones eliminated, through regeneration.

  We don’t know exactly how life events—your parents’ divorce, your fabulous year abroad—change your connectome. But there is good evidence that all four R’s—reweighting, reconnection, rewiring, and regeneration—are affected by your experiences. At the same time, the four R’s are also guided by genes. Minds are indeed influenced by genes, especially when the brain is “wiring” itself up during infancy and childhood.

  Both genes and experiences have shaped your connectome. We must consider both historical influences if we want to explain how your brain got to be the way it is. The connectome theory of mental differences is compatible with the genetic theory, but it is far richer and more complex because it includes the effects of living in the world. The connectome theory is also less deterministic. There is reason to believe that we shape our own connectomes by the actions we take, even by the things we think. Brain wiring may make us who we are, but we play an important role in wiring up our brains.

  To restate the theory more simply:

  You are more than your genes. You are your connectome.

  If this theory is correct, the most important goal of neuroscience is to harness the power of the four R’s. We must learn what changes in the connectome are required for us to make the behavioral changes we hope for, and then we must develop the means to bring these changes about. If we succeed, neuroscience will play a profound role in the effort to cure mental disorders, heal brain injuries, and improve ourselves.

  Given the complexity of connectomes, however, this challenge is truly formidable. Mapping the C. elegans nervous system took over a dozen years, though it contains only 7,000 connections. Your connectome is 100 billion times larger, with a million times more connections than your genome has letters. Genomes are child’s play compared with connectomes.

  Today our technologies are finally becoming powerful enough that we can take on the challenge. By controlling sophisticated microscopes, our computers can now collect and store huge databases of brain images. They can also help us analyze the torrential flow of data to map the connections between neurons. With the aid of machine intelligence, we will finally see the connectomes that have eluded us for so long.

  I am convinced that it will become possible to find human connectomes before the end of the twenty-first century. First we’ll move from worms to flies. Later we’ll tackle mice, then monkeys. And finally we’ll take on the ultimate challenge: an entire human brain. Our descendants will look back on these achievements as nothing less than a scientific revolution.

  Do we really have to wait decades before connectomes tell us something about the human brain? Fortunately, no. Our technologies are already powerful enough to see the connections in small chunks of brain, and even this partial knowledge will be useful. In addition, we can learn a great deal from mice and rats, our close evolutionary cousins. Their brains are quite similar to ours and are governed by some of the same principles of operation. Examining their connectomes will shed new light on our brains as well as theirs.

  In the year a.d. 79, Mount Vesuvius erupted with fury, burying the Roman town of Pompeii under tons of volcanic ash and lava. Frozen in time, Pompeii lay waiting for almost two millennia until it was accidentally rediscovered by construction workers. When archaeologists began to excavate in the eighteenth century, they discovered to their amazement a detailed snapshot of the life of a Roman town—luxurious holiday villas of the wealthy, street fountains and public baths, bars and brothels, a bakery and a market, a gymnasium and a theater, frescoes depicting daily life, and phallic graffiti everywhere. The dead city was a revelation, giving insight into the minutiae of Roman life.

  Right now, we can conceive of finding connectomes only by analyzing images of dead brains. You could think of this as brain archaeology, but it’s more conventionally known as neuroanatomy. Generations of neuroanatomists have gazed at the cold corpses of neurons in their microscopes and tried to imagine the past. A dead brain, its molecules fastened in place by embalming fluid, is a monument to the thoughts and feelings that once lived inside. Until now, neuroanatomy resembled the act of reconstructing an ancient civilization from the fragmentary evidence of coins and tombs and pottery shards. But connectomes will be detailed snapshots of entire brains, like Pompeii stopped in its tracks. These snapshots will revolutionize the neuroanatomist’s ability to reconstruct the functioning of the living brain.

  But, you ask, why study dead brains when there are fancy technologies for studying live ones? Wouldn’t we learn more if we could travel back in time and study a living Pompeii? Not necessarily. To see why not, imagine some limitations on our ability to observe the living town. Let’s say we could watch the actions of a single townsperson but would be blind to all other inhabitants. Or let’s say we could look at infrared satellite images revealing the average temperature of each neighborhood but could not see finer details. With such
constraints, studying the living town might turn out to be less illuminating than we’d hoped.

  Our methods for studying living brains have similar limitations. If we open up the skull, we can see the shapes of individual neurons and measure their electrical signals, but what’s revealed is only a tiny fraction of the billions of neurons in the brain. If we use noninvasive imaging methods for penetrating the skull and showing us the brain’s interior, we can’t see individual neurons; we must settle for coarse information about the shape and activity of brain regions. We can’t rule out the possibility that some advanced technology of the future will remove these limitations and enable us to measure the properties of every single neuron inside a living brain, but for now it’s just a fantasy. Measurements of living and dead brains are complementary, and the most powerful approach, in my view, combines them.

  Many neuroscientists don’t agree with the idea that dead brains can be informative and useful, however. Studying living brains is the only true way of doing neuroscience, they say, because:

  You are the activity of your neurons.

  Here “activity” refers to the electrical signaling of neurons. Measurements of these signals have provided ample evidence that the neural activity in your brain at any given moment encodes your thoughts, feelings, and perceptions in that instant.

  How does the idea that you are the activity of your neurons square with the notion that you are your connectome? Though the two claims might seem contradictory, they are in fact compatible, because they refer to two different notions of the self. One self changes rapidly from moment to moment, becoming angry and then cheering up, thinking about the meaning of life and then the household chores, watching the leaves fall outside and then the football game on television. This self is the one intertwined with consciousness. Its protean nature derives from the rapidly changing patterns of neural activity in the brain.