Connectome (2 page)

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.

The other self is much more stable. It retains memories from childhood over an entire lifetime. Its nature—what we think of as personality—is largely constant, a fact that comforts family and friends. The properties of this self are expressed while you are conscious, but they continue to exist during unconscious states like sleep. This self, like the connectome, changes only slowly over time. This is the self invoked by the idea that you are your connectome.

Historically, the conscious self is the one that has attracted the most attention. In the nineteenth century, the American psychologist William James wrote eloquently of the stream of consciousness, the continuous flow of thoughts through the mind. But James failed to note that every stream has a bed. Without this groove in the earth, the water would not know in which direction to flow. Since the connectome defines the pathways along which neural activity can flow, we might regard it as the streambed of consciousness.

The metaphor is a powerful one. Over a long period of time, in the same way that the water of the stream slowly shapes the bed, neural activity changes the connectome. The two notions of the self—as both the fast-moving, ever-changing stream and the more stable but slowly transforming streambed—are thus inextricably linked. This book is about the self as the streambed, the self in the connectome—the self that has been neglected for too long.

 

In the pages ahead, I will present my vision for a new field of science: connectomics. My primary goal is to imagine the neuroscience of the future and share my excitement about what we'll discover. How can we find connectomes, understand what they mean, and develop new methods of changing them? But we cannot chart the best course forward until we understand where we came from, so I'll start by explaining the past. What do we already know, and where are we stuck?

The brain contains 100 billion neurons,
a fact that has overwhelmed even the most fearless explorers. One solution, as I explain in Part I, is to forget about neurons and instead divide the brain into a small number of regions. Neurologists have learned much about the functions of these regions by interpreting the symptoms of brain damage. In developing this method, they were inspired by the nineteenth-century school of thought known as phrenology.

Phrenologists explained mental differences as arising from variations in the
sizes
of the brain and its regions. By imaging the brains of many human subjects, modern researchers have confirmed this idea, using it to explain differences in intelligence as well as mental disorders like autism and schizophrenia. They have found some of the strongest evidence we have for the idea that minds differ because brains differ. The evidence is statistical, however—revealed only by averages over populations. The sizes of the brain and its regions remain almost useless for predicting the mental properties of an individual.

This limitation is no mere technicality. It is fundamental. Although phrenology assigns functions to brain regions, it does not attempt to explain
how
each region performs its function. Without that, we cannot explain in a satisfying way why the region might function especially well in some people and malfunction in others. We can, and must, find a less superficial answer than size.

In Part II, I introduce an alternative to phrenology called
connectionism,
which also dates back to the nineteenth century. This approach is conceptually more ambitious, because it attempts to explain how regions of the brain actually work. Connectionists view a brain region not as an elementary unit but as a complex network composed of a large number of neurons. The connections of the network are organized so that its neurons can collectively generate the intricate patterns of activity that underlie our perceptions and thoughts. The organization of connections can be altered by experience, which allows us to learn and remember. The organization is also shaped by genes, as described in Part III, so that genetic influences on the mind can also be explained. These ideas may sound powerful, but there is a catch: They have never been subjected to conclusive experimental tests. Connectionism, despite its intellectual appeal, has never managed to become real science, because neuroscientists have lacked good techniques for mapping the connections between neurons.

In a nutshell, neuroscience has been saddled with a dilemma: The ideas of phrenology can be empirically tested but are simplistic. Connectionism is far more sophisticated, but its ideas cannot be evaluated experimentally. How do we break out of this impasse? The answer is to find connectomes and learn how to use them.