By Tom Ulrich
At the most basic level, the brain is a collection of wires, albeit a really complex one.
But how during development do nerve fibers thread their way through the growing brain and make the right connections?
The answer to that question could reveal more about the nature of conditions like autism spectrum disorders – which, as we reported about a year and a half ago, seem to have their roots in structurally altered brain pathways.
"We know very little about what’s happening in the developing brain in three dimensions," says Emi Takahashi, PhD, a researcher in the Fetal-Neonatal Neuroimaging & Developmental Science Center (FNNDSC) at Boston Children’s Hospital. "With histology techniques, we can achieve a two-dimensional view over small areas, but it’s hard to know which fiber bundles are growing in which ways during different stages of development in the whole brain."
But new MRI-based technologies are quickly closing that knowledge gap, giving us our first high-resolution peek into how the developing brain wires itself up.
Using something called high angular resolution diffusion imaging (HARDI) MRI, Takahashi and her colleagues (including neuroradiologist and FNNDSC director P. Ellen Grant, MD) can trace the three-dimensional pathways within the growing brain via stunning images like these:
Courtesy Cerebral Cortex (Takahashi et al., 2012)
The "diffusion" part of HARDI’s name refers to the movement of water up and down the long fiber of a neuron (nerve cell) or glial cell (cells that provide scaffolding and other kinds of support for neurons). The assumption behind HARDI is that water moves along a nerve or glial cell fiber in the same direction the fiber is growing. (The fibers constitute the brain’s white matter, while gray matter comprises the neurons’ cell bodies and connections to other neurons.
Building a scaffold, one tract at a time
The HARDI images show that glial cell scaffolds grow within the white matter of the cerebrum (the largest portion of the brain) early during development. Those glial scaffolds are then replaced weeks later with an intricate network of nerve fibers that rise from deeper reaches of the brain to connect with the cortex at the surface.
The changing structure of the fetal brain through development. Courtesy Cerebral Cortex (Takahashi et al., 2012)
They also show changes that encourage the gray matter on the cerebrum’s surface (the cortex) to fold in on itself into gyri and sulci. The folding allows our brains to pack in as much gray matter – and cognitive power – as possible within the confined space of our skulls (just see what it did for Albert Einstein).
The curly-Qs of nerve tracts at the top of this image (labeled with a ‘t’) mark the beginnings of brain folding. Courtesy Cerebral Cortex (Takahashi et al., 2012)
"You can see where and when gyri form during development by looking at where U-shaped axonal fibers develop," says Takahashi. "And we could see how the folding starts at the back of the brain somewhere between 20 and 31 weeks of gestation. By the time of full term, the folding reaches the front of the brain."
Takahashi teamed up with pathologists Rebecca Folkerth, MD, and Hannah Kinney, MD, and neurologist Joseph Volpe, MD, to correlate the HARDI data with changes in cell types and tissue structure. Sure enough, the match was one-to-one. They recently published their data in Cerebral Cortex.
The same brain area seen in HARDI (left) and with cell staining for glia (center) and neurons (right). At this point – full gestational term – glial fibers have been alomst completely replaced wtih nerve fibers. Courtesy Cerebral Cortex (Xu, Takahashi et al., 2012)
Down to the cerebellum
Takahashi and another collaborator, Jeremy Schmahmann, MD, recently widened her scope to include the cerebellum, the back part of the brain responsible for coordination and movement. In a study published inNeuroImage, she and her collaborators have highlighted pathways that were recognized in anatomic studies nearly 130 years ago, but had never before been accurately seen with modern imaging in three dimensions.
The blue and green fibers above tell us that the cerebellum may do more than we’ve previously realized. Courtesy NeuroImage (Takahashi et al., 2013)
Their images reveal a tapestry of nerve fibers weaving through the cerebellum, connecting it to other parts of the brain and the body. They also illuminate new pathways that suggest it’s time to expand the cerebellum’s job description – supporting recent studies by neurologists and anatomists.
The cerebellum contains nerve fibers woven together into an intricate tapestry of inputs and outputs. Courtesy NeuroImage (Takahashi et al., 2013)
"It’s like we’re drawing a new wiring schematic for the cerebellum, one that links this part of the brain to emotion, language, and other cognitive functions beyond motion," Takahashi says. "It’s quite exciting."
To see more groundbreaking imagery of the early brain, visit the FNNDSC website.
Tom Ulrich is a senior science writer in the Children’s Hospital Boston Department of Public Affairs, covering laboratory and clinical research innovations across the hospital. Over the last ten years, Tom has parlayed his curiosity about science and passion for science writing and communications into a number of roles, including development writer at Dana-Farber Cancer Institute, marketing writer at AIR Worldwide, and editorial & account director at Feinstein Kean Healthcare. Most recently, he was the communications manager at Harvard Catalyst | The Harvard Clinical and Translational Science Center. Tom earned a master’s degree in molecular microbiology and immunology from the Bloomberg School of Public Health at Johns Hopkins University, and is an amateur photographer.
