BY SUSAN SCUTTI

THE BRAIN CAN BE both best friend and worst enemy. It’s our most trustworthy ally, sharing all our experiences, affirming our beliefs and helping us act on our passions. Yet despite everything we’ve learned about the biomechanics of the human body, we’re still in kindergarten when it comes to the workings of the brain. It’s our biological black box: We can figure out what goes in and most of what comes out, but we know almost nothing of what goes on inside. Finally, though, we’re getting some glimpses of this mysterious machine, thanks to technological innovations. The following article is the first in a series of stories that explores the emerging new picture of the human brain, in a special section of our latest issue​.

“Can the human brain understand the human brain?” asks David Van Essen. “Perhaps never.”

Despite those doubts, Van Essen is co-principal investigator of the Human Connectome Project (HCP), an international effort to map out the “wiring” of the human brain. Among the goals is to reveal what, exactly, all the different parts of the brain do.

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Van Essen calls himself a “brain cartographer” and compares the brain to the Earth: The planet’s surface, with its many geographic rumples and folds (known to us as valleys and mountains), is analogous to the wrinkles of the brain. While these geographical features are significant, the need-to-know information “is the political subdivisions and social organization—what we think of as states and countries—that are created by the organization and communications amongst the billions of people on the planet,” he says. Similarly, when it comes to understanding how the human mind works, what matters more than the location of the almost 100 billion neurons in the brain is how they are wired and communicate. The connectome Van Essen seeks is essentially a wiring diagram of the brain.

He and the more than 100 scientists in the HCP consortium—led by Washington University, the University of Minnesota and the University of Oxford—are peering into human skulls and gathering information for this mapping using the most sophisticated technologies available. For example, the scientists rely on diffusion magnetic resonance imaging to track the various neural communication pathways through the white matter of the brain, which, says Van Essen, contains only axons, the long, branchlike nerve fibers that carry information away from the cell body “pretty much like wires in a computer or another electronic circuit.” DMRI is used primarily to study and treat neurological disorders—but it can also give researchers a view into the abnormalities in the brain’s white matter.

A related technology, known as functional MRI, allows Van Essen and his colleagues to look at all the “fluctuations up and down”—the activity occurring in the gray matter when impulses are sent to or from brain cells. (Gray matter is brain tissue that contains mostly nerve cell bodies and is thought to be the part of the brain that processes the information carried by the white matter.) Participants rest or perform tasks while lying in an MRI machine, allowing the scientists to observe which areas of their brains show activity in the gray matter. If two or more brain regions signal in a coordinated way, it means their nerve cells are firing at the same time, and so the regions are likely to be functionally connected. “Fire together, wired together” is how connectome scientists put it. Since gray matter is where brain information processing occurs, the researchers are most interested in seeing how one patch of gray matter connects and communicates with other nearby or distant patches.

There’s gray matter distributed throughout the brain, but perhaps the most important bits of it are contained in the cerebral cortex, a sheet of gray matter tissue about 2 to 3 millimeters thick that covers the bulk of the brain. It contains one-fifth of the brain’s neurons and is believed to be responsible for most of the higher-order brain functions, like information processing, language and consciousness. Neuroscientists have discovered that certain parts of the cerebral cortex are associated with certain functions—the occipital lobe, for instance, is the visual processing center of the brain—but many of the finer details remained unmapped.

Along with constructing a connectome, the HCP also is well on its way to producing a 21st-century map of the cerebral cortex, one that is much more precise than those currently found in medical science textbooks. Van Essen’s team estimates that 150 to 200 distinct cortical areas are on each side of the brain. Some of these parcellations will match up to the older, rougher maps, but many of the regions are essentially new, explains Matthew Glasser, a doctoral student in neuroscience who worked on this aspect of the HCP. It’s as if we knew there was such a thing as Europe for years and only just discovered that it was made up of individual countries, each with its own features.

Getting an accurate map is key because, as Sebastian Seung, a computational neuroscientist at Princeton University, explains in his book, Connectome: How the Brain’s Wiring Makes Us Who We Are, carving up the brain into distinct regions “will help us understand the pathologies that so often plague [the brain], as well as its normal operation.” For example, it’s expected that a better understanding of how a healthy brain is wired will lead to greater awareness of what symptoms might occur when a brain is miswired.

Having finished the project’s primary mission of acquiring information, Van Essen and his colleagues are now analyzing the data. In particular, he is keen to compare the regional connectomes of identical twins to learn which aspects of brain circuitry are heritable and which are changed by experience. So far, they’ve seen that the folding patterns of the brain—its wrinkles—are strikingly different between identical twins and so cannot be the work of genetics alone. “My guess is that it will turn out that most of these maps are largely determined by heritability, while experience fine-tunes and helps organize the wiring between different areas,” says Van Essen. “Both [genes and experience] are extremely important.”

The National Institutes of Health intends to fund three new connectome projects that will look at young children and older adults to understand how the connectome changes over a life span. In the meantime, Van Essen’s team is sharing its information with researchers around the world. Among those who have already begun to put at least some of this warehouse of data to good use is Todd Constable, a professor of radiology, biomedical imaging and neurosurgery at Yale University. For a recently published study, he and his colleagues compiled data from 126 project participants, who underwent six scan sessions each. Based on the strength of coordinated activity across 268 separate brain regions, the researchers discovered they could identify individuals: Like fingerprints, our connectomes—or brainprints—are unique.

While performing a motor task, our connectomes look more similar, but when we are at rest, daydreaming, our brains appear much more idiosyncratic. To be clear, our brains don’t have some kind of distinctive design, like fingerprints; it’s more as if each person’s brain has its special code, a string of numbers representing the connections between different areas of the brain. These codes are unique to each individual. The most distinctive area is the fronto-parietal network, the area of the brain believed to define our personality, plan and make decisions, and manage our behavior—mental skills commonly referred to by scientists as “executive functioning.” In addition, says Constable, “evolutionarily, that’s the last thing that developed and made humans unique from other animals.”

The scientists were also able to use the brain scans to predict fluid intelligence, which measures a person’s ability to reason and think, independently of acquired knowledge. Looking at a person’s brain organization, Constable could see where it fits within the spectrum of all people imaged for the HCP and give it an accordant fluid intelligence score. Scientists want to see if other measures of behavior might also be extracted from or explained by brain organization data.

The HCP’s brain map won’t solve every neurological mystery. It “may well help you define which piece of the brain does what job and which pieces of the brain work together to do a job,” says Tony Movshon, a neurophysiologist at New York University. But the resolution is still too unrefined to allow you to look at the details of the neuronal circuit. Only a more intricate picture of the brain, a “microconnectome,” could do that, says Movshon. It would, hypothetically, map every connection, estimated at tens of thousands, for every one of the 100 billion neurons in the brain. As Seung theorizes, we might even “attempt to read memories from connectomes” once the gradient of the map becomes micro-fine. Scientists generally agree that a microconnectome like that is beyond human achievement in this lifetime.

Meanwhile, the humble macroconnectome is useful to psychologists and neurologists. Constable has already used regional connectomes to model and predict attentional disorders in children. He is exploring potential applications, striving to use the connectome to benefit patients. If symptoms of psychiatric disorders relate to functional brain organization and can be “seen” in your connectome—for example, if paranoia were visible in your connectome just as a tumor is visible on your lung—psychiatric disorders would no longer rely on subjective evaluation. Understanding “connectopathies” (miswired or damaged axons that cause illness or disease) from material provided by the HCP could be the key to unlocking the most complex of brain disorders, including schizophrenia, depression and even autism.

Presumably, a doctor could even quantitatively measure how much you suffer. Knowing the circuitry of the brain and how it relates to brain disorders, psychiatrists might also objectively monitor treatment, and give scientists new targets for treatment. When weak connections between specific brain regions are seen, there might be some new way to manipulate and strengthen them. “We don’t just want to understand the brain,” says Seung. “We want to change it.”