In a new paper with implications for preventing Alzheimer’s disease and other neurological disorders, Keith Hengen, an associate professor of biology in Arts & Sciences at Washington University in St. Louis, suggests a new comprehensive approach to understanding how the brain works and the rules it must follow to reach optimal performance.
“There’s a common perception that the human brain is the most complicated thing in the universe,” Hengen said. “The brain is immensely powerful, but that power may arise from a relatively simple set of mathematical principles.”
Hengen starts with the premise that almost everything our brains do is learned or powerfully shaped by experience. In other words, we aren’t born with hard-wired circuits preprogrammed to help us read, drive cars or do anything else that we do every day. A healthy brain must be ready to learn anything and everything.
But how is a collection of neurons capable of learning? Hengen suggests that brains become learning machines only when they reach a special state called “criticality.” A concept borrowed from physics, criticality describes a complex system that is at the tipping point between order and chaos. At this razor’s edge, brains are primed to gain new information, Hengen said. “Brains need to reach criticality to think, remember and learn.”
Hengen proposed criticality as a unifying theory of brain function and disease in the prestigious journal Neuron. Woodrow Shew, a physicist at the University of Arkansas, is the co-author.
A biologist and a physicist may seem like an odd pairing, but the new unifying theory blends both realms of science. Physicists often describe criticality using the classic example of a sand pile: As sand is added, the pile will grow steeper and steeper until it eventually avalanches. Right before that final grain triggered a moment of chaos, the pile was at a critical angle, one step away from instability.
Shew explained that physicists first developed a deep understanding of criticality as a way to describe magnets and other materials. Around the turn of the 21st century, these ideas were expanded to explain a broader range of complex systems, including avalanches, earthquakes and, ultimately, living systems and the brain.
A defining aspect of critical systems is that they look the same at any scale: A sand pile on the brink of an avalanche has the same slope whether the pile is tiny or mountainous. In the brain, criticality is constant whether it’s measured in a handful of neurons or an entire region. Likewise, brain patterns that unfold in time are startlingly similar when considered in milliseconds or hours. “This matches our intuitive understanding of how brains work,” Hengen said. “Our internal experiences span milliseconds to months. They don’t have a scale.”
Hengen and Shew suggest that criticality isn’t just a theoretical concept; it’s a state that can be precisely measured and calculated through fMRI brain imaging technology. “Criticality is the optimal computational state of the brain,” Hengen said. “We’ve developed a mathematical way to measure how close the brain is to criticality, which should help us nail down the fundamental questions about how a human brain works.”
A new understanding of disease
The criticality framework offers a new perspective for understanding neurological disease. Rather than focusing on specific damaged brain regions or accumulated proteins, Hengen argues that diseases such as Alzheimer’s destroy something more basic: the brain’s ability to maintain criticality.
“Alzheimer’s and other neurodegenerative diseases don’t just damage neurons, they break the brain’s general ability to compute by slowly dissolving criticality,” Hengen explained. “As a brain moves further and further from criticality, it loses the ability to adapt and process information effectively.”
This framework explains a puzzling feature of brain diseases: Patients often appear completely normal until they’ve lost many neurons. “The brain has remarkable compensatory abilities that can mask functional problems even as criticality begins to erode,” Hengen said. “Traditional assessments miss the early stages because they focus on established endpoints that the brain tries to maintain through workarounds.”
As criticality gradually deteriorates, the brain works harder to achieve the same cognitive outcomes, Hengen said. “It’s like an engine that still runs but requires more fuel and generates more heat. By the time we notice memory problems or other symptoms, criticality has likely been compromised for years.”
Hengen’s collaboration with David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor at WashU Medicine, has revealed that tau protein buildup in Alzheimer’s directly disrupts criticality, providing a clear link between the disease’s molecular hallmarks and cognitive collapse.
This connection between criticality and Alzheimer’s opens exciting diagnostic possibilities. In theory, a simple fMRI could help detect breakdowns in criticality years before symptoms appear. “In combination with cutting-edge blood tests, we could identify people at risk and intervene before irreversible damage occurs,” Hengen said.
In another collaboration, Hengen has teamed up with Deanna Barch, the Gregory B. Couch Professor of Psychiatry at WashU Medicine and a professor of psychological and brain sciences in Arts & Sciences, for an observational study to see how criticality at birth determines cognitive development and abilities in childhood. “From the beginning, some kids are closer to criticality than others, which, based on our theory, suggests they are going to be better learners,” Hengen said. “Many outside factors can affect their success in school, but criticality can explain an impressive amount of the variability between children.”
The sleep-mind connection
In early 2024, Hengen and co-author Ralf Wessel, a professor of physics in Arts & Sciences at WashU, used the concept of criticality to revisit an age-old question: Why do we need sleep? By tracking brain activity over multiple weeks, they found that sleep restores a state of criticality. “Being awake and active moves us away from criticality, and sleep is like a reset button,” Hengen explained.
That insight could help researchers unlock the power of sleep as a therapy for Alzheimer’s and other neurological diseases that push the brain away from its optimal state. Previous studies by Holtzman and others have found that people who don’t get the sleep they need — perhaps due to shift work or chronic insomnia — are at a much higher risk for Alzheimer’s as they age. And there’s already some evidence that sleep interventions can help slow the progression of Alzheimer’s symptoms.
Hengen believes that targeted, intensive sleep-based therapy could help restore criticality and improve learning and memory in people with brain disease. Studies of mice conducted by Holtzman and James McGregor, a postdoctoral researcher in Hengen’s lab, offer a glimpse of the possibilities: Mice specifically bred to have symptoms of Alzheimer’s become faster learners after a targeted sleep intervention reinforces criticality.
Critical future
There is much work to be done, but Hengen would eventually like to understand how criticality helps explain complex features of human neurobiology. “We may find that someone who is an amazing artist, for example, might be extremely close to criticality in parts of the brain involved in creative ideation,” he said. It’s also possible that a close look at criticality could point to undiscovered tendencies or talents that just need an outlet. “Maybe they never tried art, but we can see that the potential is there.”
In the meantime, Hengen, Shew, and others are spreading the word about the importance of criticality. Hengen presented a TEDx talk on the subject in 2024 and shared his work at Arts & Sciences’ inaugural research pitch competition, where he took second place. He hopes the new Neuron paper will inspire conversations among neurologists, doctors, reporters and the general public.
A unified theory of the mind could change the world, but first, it must unify the experts. “Woody (Shew) and I really think we’re on to something here,” Hengen said. “And, perhaps slowly, others are starting to agree.”
WashU was the ideal place for a new concept of the brain to emerge, Hengen said. “We’re surrounded by brilliant people in diverse fields, including physics, biology, psychology, mathematics and neuroscience, and the community here is remarkably supportive,” he said. “Everyone is ready to help.”
