How do you build a brain? In the March 30 issue of Science a team of investigators presents a surprising answer, reporting their discovery of a remarkably simple organizational structure in the brains of humans and other primates. Employing sophisticated mathematical analysis of advanced imaging data, they found that the pathways carrying neural signals through the brain are arranged not in a disorganized tangle but in a curved, three-dimensional grid.

"We found the brain is built from parallel and perpendicular fibers that cross each other in an orderly fashion. Finding this kind of simple organization in the forebrain of higher animals was completely unsuspected," says Van Wedeen, MD, of the Martinos Center for Biomedical Imaging at Massachusetts General Hospital, who led the study. "Knowing there is a simple plan that, modified by evolution and development, gives rise to all brains has implications for researchers working to build an atlas of brain connections, for pursuing investigation of how the brain develops and for expanding theories of how the brain works."

It is well known that neural pathways in the spinal cord and brain stem are organized in three principal directions -- head to tail, side to side, and front to back -- all of which are either parallel or perpendicular to each other and reflect the basic patterns of embryonic development. But following those pathways into the brains of higher animals -- particularly into the cerebral cortex -- has been challenging because each pathway crosses many others within a small space. Previous studies that followed the movement of tracer chemicals injected into specific brain regions could track the progress of single pathways only and could not be used in human participants.

In the current study, Wedeen and his colleagues used diffusion spectrum MR imaging -- a technology he developed that reveals the orientation of all fibers that cross a particular point on a pathway -- coupled with mathematical analysis of all crossing or adjacent pathways in the brains of four species of non-human primates and in human volunteers. Wedeen's previous studies of animal brains had revealed parallel crossing pathways that appeared to form sheet-like structures, but it was not clear whether those structures were pervasive or only characterized a few brain systems.

The analysis revealed that all crossing or adjacent fibers were either perpendicular or parallel to the original pathway. Each of the crossing fibers was, in turn, crossed by its own perpendicular fibers, interwoven like the threads in a sheet of fabric, that defined box-like, three-dimensional curved grid structures. The same grid-like pattern was seen throughout the white matter of the brains of all four studied non-human primates -- rhesus monkeys, owl monkeys, marmosets and galagos -- and the human volunteers.

"I don't think anyone suspected the brain would have this sort of pervasive geometric pattern," Wedeen says. "Although our findings could be described as a new longitude and latitude for the brain, they're also leading us to an entirely new understanding of how and why the brain is organized the way it is. The old image of the brain as a tangle of thousands of discrete, unconnected wires didn't make sense from an evolutionary standpoint. How could natural selection guide each of those wires into more efficient, advantageous configurations?

"The very simplicity of this grid structure is the reason why it can accomodate the random, gradual changes of evolution," he continues. "It's easier for a simple structure to change and adapt, whether we're talking about the big changes that occur across evolution or the changes that can occur during an individual's lifetime -- both the normal neuroplasticity associated with development and learning or the damage that results from injury or disease. A simple grid structure makes both evolutionary and develomental sense." Wedeen is an associate professor of Radiology at Harvard Medical School and on the faculty of the Harvard-MIT Health Sciences and Technology Program.

Additional co-authors of the Science article are Ruopeng Wang and Guangping Dai of the Martinos Center; Douglas Rosene and Farzad Mortazavi, Boston University Medical Center; Patric Hagmann, University of Lausanne, Switzerland; Jon Kaas, Vanderbilt University; and Wen-Yih Tseng, National Taiwan University College of Medicine. The study was supported by grants from the National Science Foundation, the National Institutes of Health and the Human Connectome Project of the NIH.