London’s streets are a mess. Roads bend sharply, end abruptly, and meet each other at unlikely angles. Intuitively, you might think that the cells of our brain are arranged in a similarly haphazard pattern, forming connections in random places and angles. But a new study suggests that our mental circuitry is more like Manhattan’s organised grid than London’s chaotic tangle. It consists of sheets of fibres that intersect at right angles, with no diagonals anywhere to be seen.
Van Wedeen from Massachusetts General Hospital, who led the study, says that his results came as a complete shock. “I was expecting it to be a pure mess,” he says. Instead, he found a regular criss-cross pattern like the interlocking fibres of a piece of cloth.
For years, scientists have been able to trace the outlines of individual neurons by injecting them with telltale chemicals that migrate along their lengths. But this technique can only be used in dead brains, and it’s small in scale. To get the big picture, Wedeen turned to diffusion magnetic resonance imaging (MRI), a technique that uses magnetic fields to detect the water flowing along our neurons. By tracking these streams, Wedeen mapped the brain’s white matter fibres – the tracts that carry signals from one area to another. They are the original information superhighways, and Wedeen could see huge groups of them at once.
He studied the human brain, as well as those of four primates – the rhesus macaque, owl monkey, marmoset, and galago (or bushbaby). He started with a single large white matter tract – the equivalent of a motorway. Here’s one in the macaque’s brain, coloured in blue.
Then, Wedeen looked for all the fibres coming off this main tract. Here they are in red, orange and yellow. You can see them branching off perpendicularly in a single curving sheet.
Wedeen did this over and over again, creating stunning images like these – a riot of right angles, arranged in sheet after colourful sheet. “I was astonished,” he says. “[The pattern] was present in every part of every brain of the different species. It was always there.” Wedeen has even found the same patterns in the brains of cats, rats, possums and other animals, although those data have not yet been published.
Opinion is divided on the new study. “It’s really ingenious what they’ve done,” says Tim Behrens from the University of Oxford, who is particularly impressed with the idea that the white matter forms interwoven sheets. “It’s really quite convincing,” he says. “There’s no way that the sheets are there by chance.”
David van Essen from Washington University in St Louis agrees, but he and Behrens both say that Wedeen’s technique is more sensitive at measuring right angles than other angles. They feel that the right-angled connections of the white matter remain to be proven.
Partha Mitra from Cold Spring Harbour Laboratory is more critical, describing the paper as “lots of pretty pictures, but not something that will fundamentally alter our views of how the brain is wired”. He notes that the structures of the grids don’t actually say much about how parts of the brain are connected to one another, since the origins of the fibres are still a mystery. He is also says that Wedeen didn’t “ground-truth” his maps against ones obtained from tracer studies in other animals.
It is certainly true that the maps, while beautiful, have to be interpreted carefully. For a start, diffusion MRI is an indirect technique, so the lines it produces are not really depicting specific neurons. “They’re mathematical constructs showing the most probable trajectory of the cells,” says Wedeen.
And while diffusion MRI gives a much broader view than tracer chemicals, it lacks the same resolution. It reveals the general structure of the brain’s road network, without showing where individual alleys and streets are. So each colourful line represents thousands of cells. Wedeen also cautions that, no matter what the diagrams might suggest, the white matter isn’t arranged in bundles or “discrete noodles”. The brain is full of cells running in parallel, and the lines just represent areas where they are most heavily concentrated.
Origin of the grids
Wedeen’s maps may not reveal all the details about the brain’s network, but it does show how that network is structured. “If you look at brain connections in an adult human, it’s really a massive puzzle how something so complex can emerge,” says Behrens. “If we can establish any sort of organisation, we get a clue about how these things grow. If it obeys some rules, you could start to work out how it follows those rules. You have something to hang onto.”
Wedeen thinks that the origins of the orderly sheets arise during our early embryonic days. As we grow from a featureless ball of cells, some molecules become concentrated at specific ends. These gradients set up three invisible axes that determine left from right, top from down, and front from back. And these axes, all perpendicular to one another, guide the growth of our first neurons to create neat grids.
Later, things get more complicated. Some fibres execute 90 degree turns, and some entire grids will curve and warp. But the same underlying pattern holds. This simple system can still produce a brain of staggering complexity, but it makes it easier for neurons to find one another.
Wedeen also suspects that right angles have been an important feature of in brain evolution. The simple nervous system of a flatworm, for example, looks like a ladder, with two main fibres running down its body and rungs connecting them. In fact, Wedeen speculates that such angles may have been necessary in early brains.
Our neurons are surrounded by insulation sheaths made of a substance called myelin, which shields the electric currents that run down their length. But these sheaths are a recent evolutionary innovation. “Electrical engineers have suggested to me that in some earlier brains, which don’t have myelin, neurons would have electrical problems if they crossed at anything other than a right angle,” says Wedeen. “They’d be more likely interfere with each other.”
The human brain is both larger and messier, but Wedeen is hopeful that his study will help us in our quest to understand its connections. He and van Essen are both involved in the ambitious Human Connectome Project, which is trying to “map the wiring diagram of the entire, living human brain”. “The field is just beginning,” says Michael Huerta from the National Library of Medicine. “As more data are collected… I would be astonished if additional general principles didn’t emerge regarding the way the brain is organized, functions, develops and evolves.”
Van Essen says that the grid idea “is likely to be an incomplete and imperfect representation of the fabulously complex wiring of the human brain.” But Wedeen isn’t claiming otherwise. He hopes that it will provide a valuable starting point. “Everyone knows that imaging isn’t equivalent to mapping every cell. There’s an endless expanse of potential detail that we still wish to know. But this [pattern] is a new piece on the chessboard.” He pauses. “And it really is a chessboard.”
Another pause. “And the piece is a rook.”
Reference: Wedeen, Rosene, Wang, Dai, Mortazavi, Hagmann, Kaas & Tseng. 2012. The Geometric Structure of the Brain Fiber Pathways. Science http://dx.doi.org/10.1126/science.1215280
All images courtesy of Wedeen and Science.