04 Nov 2016

The width and thickness of the mammalian cortex determine how tightly it has to scrunch up to fit inside the skull, forming the characteristic folds and gyri that wend back and forth across the surface. Scientists wonder if the simple law that governs that folding holds in both men and women, and when the brain shrinks later in life. A paper from the labs of Yujiang Wang, Newcastle University, U.K., and Bruno Mota, Universidade Federal do Rio de Janeiro, suggest not always. They found that among young, healthy volunteers, the brain follows the same folding rules in both men and women. Even as people age and tensile forces in the thinning gray matter start to weaken, the same general guidelines apply. However, in people with Alzheimer’s disease (AD), the rules seem to go out the window as the folds loosen and crevices widen unpredictably. While these results are preliminary, they suggest that forces that shape the cortex in healthy brains may break down in different ways in aging and disease.

Folding Progression. The cortex is thick (orange) and tightly folded in young people (left), but it thins with age (blue, middle) and its creases widen. AD exaggerates these aging effects (right).

“This work tells us that something happens in dementia that affects the process by which gyrification occurs, probably by causing changes in the overall structural integrity of gray matter,” said Ashish Raj, Weill Cornell Medical College, New York. It is unclear how the disease process leads to these changes or if they will inform our understanding of Alzheimer’s. This may emerge in future research, Raj said. “Such knowledge might lead to new [structural] biomarkers that can distinguish healthy from diseased brain,” he suggested.

According to a previous paper co-authored by Mota, animals’ brains fold according to a set of rules that can be summed up in a simple equation. The formula relates the degree of folding to the total cortical surface area and its thickness, and relies on a constant, k. In simplest terms, the equation states that the wider the cortex, the more it has to contort to fit inside the skull, while the thicker it is, the fewer furrows it can make. The layers of the cortex basically fold like sheets of paper. A thin piece of tissue easily crumples, forming many small folds, while a stack is more resistant (Jul 2015 news).

Mota’s previous paper reported that this basic “scaling” principle—where the degree of folding changed proportionately to cortical thickness and area—held across mammalian brains, from rodents to whales. However, would it explain the variation seen within just one species, across different genders and even different ages? Take people, for instance. Their brains vary in size and shape depending on age, sex, and disease. Do the same constraints govern how a given person’s brain folds, or do other forces come into play?

To answer that question, the researchers examined MRI data from more than 1,000 healthy volunteers in three databases—the Human Connectome Project, the Open Access Series of Imaging Studies project (OASIS), and a database from the Nathan Kline Institute. Male and female volunteers ranged in age from 4 to 94. After calculating the surface area of the cortex and how thick it was, the authors ran the numbers to see if the scaling law still applied.

When it came to sex, the answer was a resounding yes. Women’s brains tended to be smaller and less wrinkled than their male counterparts’, but both followed the same law of folding. In other words, the cortical surface area and thickness had the same relationship to the degree of folding.

The equation also mostly held true for age. As it gets older, the human brain shrinks slightly and unfolds a bit. Once again, the scaling between surface area, depth, and folding held true. However, the equation only worked if the constant k was smaller. The authors think k reflects a mix of axonal tension—the pulling force between brain areas—and pressure from cerebrospinal fluid. With rising age, these forces declined steadily and so did folding. Sulci became wider and shallower, while the brain’s folds loosened (see image above). The authors are unsure what causes the cortex to become less taut, but they hypothesize that axonal pulling eases and CSF pressure decreases over time.

What about Alzheimer’s disease? There, the cortex is known to thin out considerably. Wang and colleagues analyzed MRI scans from 199 affected people and 235 controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Whereas gradually smaller k values predicted folding in healthy aging brains, k values for AD brains were already low—on par with 90-year-olds’—and stayed there as patients aged. This suggests the cortex ages prematurely in AD, said Wang. In people with AD, sulci began to widen and gyri became even shallower than they did in normal aging, and the association between surface area/thickness and folding started to break down. “This indicates there are things we don’t understand yet about the shape of the brain in AD,” said Wang. It is unclear if cortical unfolding affects circuitry, or whether it might even exacerbate part of AD pathology.

She and Mota’s group are now trying to identify measurable, tangible factors that contribute to the tension on the cortex. They are also analyzing folding by brain region. It is possible that since the AD cortex thins differently in select areas, analyzing the whole brain obscures local changes, the authors wrote. By taking a region-by-region approach, they think they may discover influences on folding that differ by area. Uncovering those could lead to new clues about the mechanism of disease, said Wang.—Gwyneth Dickey Zakaib

Cortical Folds Loosen in Aging and Disease, but Not in the Same Way

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