How Do Axons Make Connections as the Brain Grows?

How a person’s brain grows and makes connections can determine intelligence as well as susceptibility to disorders such as epilepsy and mental illness. However, a lot of questions remain about how the process works, especially the mechanics of brain folding.

In a study recently published in the journal Nature Communications, researchers from Binghamton University propose the first dynamic model predicting the complicated mechanics of connectivity development and folding in the cerebral cortex — the outermost layer of the brain where memory and reasoning occur.

Assistant Professor Mir Jalil Razavi — a faculty member at the Thomas J. Watson College of Engineering and Applied Science’s Department of Mechanical Engineering — led the research, with contributions from PhD students Akbar Solhtalab and Ali H. Foroughi. Dr. Lana Pierotich from Harvard Medical School and Boston Children’s Hospital also contributed to the study, providing insights into the biological relevance of the proposed model.

“Our motivation,” Razavi said, “was to look at the physical interplay between the folding of the brain and connectivity development, and why if we have an alteration in one of them, there will be disruption in the other one. How are they connected?”

The researchers studied why axons — the long, slender projections of neurons that transmit electrical impulses — have a much higher density in the gyri (convex parts) then in the sulci (concave parts). Because of what they are calling axon reorientation theory, axons grow differently when exposed to tensile or compressive forces within the brain’s white matter.

“The folding brain creates a stress landscape,” Razavi said. “Where we have convex and concave patterns because of folding, we have tensile stresses and compressive stresses. When axons move or expand from the core of the brain toward the cortex or outer layer of the brain and they experience a stress created by the folding in the white matter, they just change their direction. They reorient themselves toward the tensile stresses, not compressive stresses.

“They love to be under tension rather than on compression. Although they grow faster in a stiffer medium, they tend to move toward a softer medium. The folding of the brain, which generates tensile and compressive forces, can alter the stiffness of the white matter, influencing the environment in which axons grow.”

Razavi has spent the last 10 years looking at the brain from a mechanical standpoint, since his PhD studies at the University of Georgia, and his research earned him a $587,853 grant from the National Science Foundation in 2021.

Now that he has a model for axon growth behavior, the next step would be to validate it through experimentation. He knows other researchers who are ready to collaborate — all he needs is funding from the National Institutes of Health, the NSF or elsewhere.

“This research has a lot of potential to reveal brain disorders and mechanisms, so if we have funding, we will extend this to a true scale model,” Razavi said. “We could initiate fibers in different locations and let them grow to see what happens when we have the unfolding of the brain. Can we see the same pattern that we have predicted?”

Reference: Solhtalab A, Foroughi AH, Pierotich L, Razavi MJ. Stress landscape of folding brain serves as a map for axonal pathfinding. Nat Commun. 2025;16(1):1187. doi: 10.1038/s41467-025-56362-3

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