Primate brains seem to be arranged in woven grids (Image: Van Wedeen, Martinos Center and Dept. of Radiology, Massachusetts General Hospital and Harvard University Medical School)

The human brain has been described as “the most complex object in the known universe”, comprising tens of billions of connecting nerve fibres seemingly tangled like a huge bowl of spaghetti.

But if a team led by Van Wedeen of Massachusetts General Hospital in Boston is correct, this staggering complexity arises from a seductively simple underlying structure, revealed using magnetic resonance imaging (MRI). If you straighten out its folds, Wedeen argues, the brain consists of a three-dimensional grid of fibres.

It is a big idea that could help unravel mysteries of brain development and evolution, and help link neurological and psychiatric disorders to abnormalities in brain structure. “I was immediately intrigued by the idea as an organising principle for brain connectivity,” says Olaf Sporns, a cognitive neuroscientist at Indiana University in Bloomington.


So have Wedeen and his colleagues uncovered the brain’s fundamental organising principle, or is their grid just part of a more complex geometry? “To me the jury is out,” says David Van Essen of Washington University in St Louis, Missouri, one of the leaders of the Human Connectome Project, which is working to produce a comprehensive map of the brain’s neural connections.

Follow the water

For years, brain-mappers have used a technique called diffusion tensor imaging, which tracks the diffusion of water through biological tissues, to follow fibres through the brain, seeing how one region connects to another.

Wedeen’s research used a related method called diffusion spectrum MRI which also maps nerve fibres by tracking the movement of water molecules but is good at highlighting where fibres cross.

In studies on people and other primates, this revealed sheets of parallel fibres running at 90 degrees to each another, much like a woven fabric. These sheets are in turn arranged at right angles to one another, giving a three-dimensional grid.

The grid is most obvious in lower primates such as the Galago bushbaby. Moving up the primate tree, there are progressively more folds and curves, but the underlying grid structure remains.

Evolutionary directions

This would help explain how brains wire themselves together. The orientations of the grid correspond to up-down, right-left and front-back body axes laid down in the earliest stages of embryonic development, Wedeen argues. This allows nerve fibres to grow in the right direction by following simple developmental rules controlled by biochemical signals – in a similar way to how the grid of New York City’s streets makes it easy to give someone directions to a specific destination.

The grid may also help to solve the puzzle of how complex brains evolved. If the brain were organised like a tangle of spaghetti, says Wedeen, it would be difficult to see how mutations could lead to incremental changes in connectivity on which natural selection could act.

“Try going into your basement and randomly rewiring your house,” Wedeen says. “In a grid structure, it’s much easier to imagine changes in the developmental code producing adaptive changes in behaviour.” Similarly, a readily rewired grid helps to explain how people are able to recover from brain injuries by making new connections to regain lost functions.

Such a three-dimensional grid would provide a coordinate system to standardise studies linking abnormalities in brain anatomy to neurological and psychiatric disorders. These studies are hampered by large natural variation from person to person, which makes it hard to align brain scans to reveal key differences in specific structures.

In the long run, it may also aid researchers striving to grow tissue grafts to repair brain injuries or treat neurodegenerative conditions. In theory, growing tissue on scaffolds that mimic the grid structure should help it to form connections with the brain after being engrafted.

Spaghetti junction

The grid is an attractive idea to many neuroscientists, but some doubt that it is the whole story. “My concern is that they may have oversimplified and overgeneralised in their optimism that this will apply brain-wide,” says Van Essen. He thinks that the brain also contains fibres criss-crossing in other orientations.

The problem is that diffusion MRI can’t detect nerve fibres directly. “This is not a microscope,” says Marsel Mesulam of Northwestern University in Chicago, who studies how neural networks are affected by dementia and other cognitive disorders.

“We’re looking at reconstructed images based on the movement of water molecules in a magnetic field.” This means that changes in machine set-up or data analysis could alter what is seen.

Marco Catani, a specialist in diffusion MRI at the King’s College London Institute of Psychiatry, argues that Wedeen’s method is likely to miss fibres crossing at angles less than about 70 degrees. Catani says his team has seen such fibres using a different diffusion imaging technique.

Wedeen is adamant that his own team would have seen fibres crossing at shallower angles if they were common. He adds that a second diffusion imaging technique gave similar results.

Who is right? Expect a wave of follow-up studies using different methods – including painstaking examination of the brain’s microscopic anatomy – as neuroscientists try to answer that question.

Journal reference: Science, DOI: 10.1126/science.1215280