metabolism—all of these systems

This is clearly established in many reports, says Guillaume Ferreira, a neurobiologist with France’s National Research Institute for Agriculture, Food, and Environment (INRAE) at the University of Bordeaux. “Even after short-term exposure—as little as one week in animals—an obesogenic diet impacts the memory,” he says, citing recent findings from his own laboratory and others. This is the case even in the absence of disease, differential weight gain, or metabolic differences, suggesting that it’s not obesity per se that is detrimental to the brain, but the obesogenic diet.

Sensitive Periods

Ferreira’s team was the first to show that adolescence is a period of vulnerability to diet-induced changes, with findings now replicated widely. “You can see in the literature that high-fat in general is detrimental for brain plasticity and for cognitive processes,” he says. “What we found is that it is even more deleterious during adolescence.”

For Spencer at RMIT, “it does seem that a high-fat, highsugar diet leads to cognitive dysfunction, and that there are periods of vulnerability throughout life.” During the prenatal and perinatal stages, dietary influences can lead to lasting changes in metabolic function, cognition, mood, and even reward processing. In animal models, exposure to a high-fat, high-sugar diet during the first few weeks of life (equivalent to early postnatal in humans) can lead to lasting damage, yet adults on the same diet can endure much longer exposures.

Recent evidence suggests the same thing happens in humans, Spencer says. For example, women who had diets high in junk food during late pregnancy were more likely to have children who subsequently went on to develop obesity. The same is true of children born to mothers who have diabetes during pregnancy.

Better Brains Through Blueberries?

Aging is another period of apparently heightened vulnerability to dietary influences. Barbara Shukitt-Hale, a United States Department of Agriculture research psychologist based at Tufts University, has spent 26 years studying how plant-derived nutrients from berries and other foods benefit the aged brain. In multiple studies, her laboratory has found that feeding older rats a diet supplemented with two percent blueberry extract—equivalent to roughly a half-cup of blueberries daily for a human—reliably and reproducibly improves performance on a battery of cognitive and motor tests. “You can prevent and even sort of reverse some of the impact of aging,” she says, if the diet is supplemented at the right time and for the right length of time (two months for the rats, or one-twelfth of their lives).

The rats are fed the supplemental blueberries at a critical period where they’re beginning to show age-related cognitive deficits, which normally progress over time. “Blueberries prevented good performers from getting worse but also helped bad performers get better,” Shukitt-Hale says. Her team has also conducted two clinical trials in humans showing similar improvements in cognitive benefits after adding blueberries to the diet.

These results are in line with a burgeoning field of research into so-called phytochemicals, including polyphenols, a large group of plant-derived compounds found in berries, nuts, dark chocolate, and other foods being investigated for brain benefits. “I think that we have some good evidence that eating foods that are high in these phytochemicals can have a positive impact on the brain and cognition,” says Shukitt-Hale.

Polyphenol-rich foods may exert a number of mechanisms at the cellular level to alter the neuronal environment in a beneficial way. Though often referred to as antioxidants, polyphenols’ actions in the brain seems to go far beyond that. “They are antioxidants, but I don’t think they’re just antioxidants. I don’t even think that’s their primary mechanism,” says Shukitt-Hale. “We think the story is much deeper than that.”

Recent evidence suggests polyphenols are involved in cellular signaling pathways that mediate inflammatory processes in the brain. Neuroinflammation is considered a primary culprit in a range of neurodegenerative disorders like Parkinson’s and Alzheimer’s disease, as well as other neurological and psychiatric disorders. Increasing evidence points to inflammatory changes as a primary mechanism by which obesity can lead to cognitive impairment or dementia, which could help explain the observed co-occurrence of dementia with diabetes, a metabolic disorder associated with obesity.

Cognitive Enhancer?

A key finding that has emerged from her own studies and others, Shukitt-Hale says, is that “these foods seem to especially impact learning and memory when the brain is taxed, in the really difficult tasks. If you’re a normal person with no deficits, it seems like these things are helping you when the cognitive load is greatest.” Moreover, she says it seems to help across the lifespan, as evidenced by recent research showing benefits in children, college students, and middle-aged adults.

Williams’ work, for example, is among the first to show short-term acute cognitive benefits of eating blueberries at different ages in humans. “We see small but meaningful cognitive benefits of polyphenol-rich foods in the period of two to six hours post consumption,” Williams says. Her time points are consistent with the peak blood levels of polyphenols. “Importantly, these effects seem to be amplified when performing tasks that are more cognitively demanding, or when participants are more cognitively fatigued.”

Williams stops well short of calling her findings evidence of a quick-fix cognitive enhancer for that upcoming exam or big deadline. “I wouldn’t go so far as to say that we’ve proved it conclusively, but the work is certainly suggestive that having a polyphenol-rich portion (or two) of fruit for breakfast can help cognitive function throughout the day,” she says.

Rescue Attempts

Given what is currently understood about the detrimental effects of high-fat diets and the beneficial effects of others, might it be possible to harness the good ones to help counteract the bad ones?

Ferreira’s team is one group that’s trying. In investigative models, his team is testing various dietary approaches as well as exercise and manipulation of sleep-wake cycles as potential strategies to protect the brain. They recently showed that supplementing animals’ high-fat diet with Omega-3 fatty acids or vitamin A prevented some of the impairment induced by a high-fat diet. “Even if you have an obesogenic diet that has very great impact on the brain and memory, you can try to rescue the effect,” he says.

Shukitt-Hale’s lab has investigated a similar rescue approach in rats. They fed animals a blueberry extract along with a high-fat diet and compared them cognitively to animals on the high-fat diet without blueberries or a control group eating regular fare. By the third month, the high-fat, blueberrysupplemented group was no different than the control group that ate regular fare, suggesting a reversal to normal levels.

“The hope is that people will eat these healthy foods instead of something that is not as healthy, but we know that not everyone is going to do that all the time, so it’s interesting that if you include some healthy foods you might mitigate some of the effect of the bad foods,” Shukitt-Hale says. “We’re not advocating people eat crap, and just add a few blueberries and you’ll be fine. That’s not it.”

You Are (More Than) What You Eat

Diet is but one piece of the brain-wellness puzzle, which also includes adequate sleep, hydration, physical activity, and social connectedness. “Diet is important, but it’s not the only element that determines lifelong cognition,” Williams says.

“All of these modifiable behaviors are important for a healthy brain,” says Ruth Barrientos , a neuroscientist at Ohio State University who (with Spencer, Shukitt-Hale and others) recently reviewed the science of diet and cognition. “But in my opinion, diet is one of the cornerstones because it can affect so many systems.” The gut microbiome, the immune system, and metabolism—all of these systems signal the brain and influence its functions, from sleep and social interactions to the ability and motivation for physical activity, she says. All are impacted by diet.

Fernando Gomez-Pinilla , a neurophysiologist and head of UCLA's NeuroLife Lab who studies the role of trophic factors on plasticity, likens it to an orchestra: “you need to have all the components to have the music.” He is interested in how other modalities can contribute synergistically to a healthful diet and has found that exercise can counteract some effects of negative diet and boost the effects of a positive diet. “We need to think beyond diet,” he says. “It’s important to understand that there is a whole package.”

Science Confirms What Mom Said

As the science of dietary influences on cognition matures, what researchers are willing to say with confidence about diet and the brain turns out to be remarkably old-fashioned.

Shukitt-Hale’s advice? “I like to say just eat a variety of fruits and vegetables because they might be having different effects, and substitute some of these good snacks, if you will, for some of the bad snacks you’re eating,” Based in part on her own research on walnuts, she also advocates eating whole foods vs. isolated compounds of foods. “There’s something about the synergy of the compounds working together.”

Gomez-Pinilla echoes the sentiment that there’s no single miracle ingredient. “Our diets have so many components; we eat many different things every day, some better than others.” It’s the overall impact that matters to brain health, he says, and those effects can be different for each person depending on their genetic makeup and their personal history.

Barrientos concurs: “Nutrients in isolation may not be as effective as when they are interacting with other nutrients in whole foods.” To her, the best advice for a brain-healthy diet boils down to consuming a variety of natural foods that have undergone the fewest alterations.

Williams, whose latest work on blueberries raises the specter of a plant-based, non-drug (and really yummy) cognitive enhancer of sorts, is herself abundantly cautious: “At this stage, I don’t think I’d commit myself to saying anything other than the current dietary advice of eating a balanced diet with a wide variety of fruits and vegetables included,” she says. “A healthy balanced diet and taking regular exercise is what will make the difference for the vast majority of us.”

In other words, do what your mom told you to. Eat smart. l

A Sampler of Cerebrum Podcast Episodes

Aselection of some of Bill Glovin’s engaging and memorable interviews with top neuroscientists who discuss their Cerebrum articles, their personal stories, and how their work has the potential to make a difference in people’s lives. Subscribe to Cerebrum here or on your favorite platform.

Catherine Woolley, Ph.D., the William Deering Chair in Biological Science and professor of neurobiology and neurology at Northwestern University and the author of this issue’s cover story on sex differences in the brain.

Previous Episodes

Ilina Singh, Ph.D., Professor of Neuroscience & Society and co-director of the Wellcome Center for Ethics and Humanities at the University of Oxford, and author of last issue’s cover story on global neuroscience expansion.

Gregory Bern, M.D., Ph.D., director of the Center for Neuropolicy and Facility for Education & Research in Neuroscience at Emory University, on his Spring 2020 cover story, “Decoding the Canine Mind.”

Jerold Chun, M.D., Ph.D., senior VP of Neuroscience Drug Discovery at Sanford Burnham Prebys, on his January 2019 article, “The Gene Conundrum in Alzheimer’s Disease.”

Thomas R. Insel, M.D., former director of NIMH and co-founder and president of Mindstrong Health, on his November 2018 article, “Building the Thermometer for Mental Health.”

Vince Calhoun, Ph.D., founding director of the Center for Translational Research in Neuroimaging and Data Science and author of this issue's feature on the promise of big data neuroimaging for mental health.

Frank R. Lin, M.D., Ph.D., director of the Cochlear Center for Hearing and Public Health at Johns Hopkins University and author of the Fall 2020 feature on the link between hearing loss and dementia.

Lee Alan Dugatkin, Ph.D., a biologist at the University of Louisville and coauthor of How to Tame a Fox (and Build a Dog), on his Spring 2020 article, “Jump-Starting Evolution.”

Maheen Mausoof Adamson, Ph.D., senior scientific research director for Defense and Veterans Brain Injury Center in Palo Alto, CA, on her November 2019 article, “Rewiring the Brain: Zapping with Precision.”

Michael L. Lipton, M.D., Ph.D., associate director of the Gruss Magnetic Resonance Research Center at Einstein College of Medicine, on his September 2019 article, “Rethinking Youth Sports.”