Berkeley Scientists Target Brain Optimization Trend

"Health optimization" and "body hacking" is all the rage as people strap on wearable technology, undergo blood tests to monitor health biomarkers and commit to extreme exercise, supplements, diets and often unapproved medical therapies to maximize longevity.

Yet, while physical health is important, UC Berkeley neurologist Mark D'Esposito says the value of many of these interventions is unsubstantiated and, in the end, pointless if you don't also maximize brain health - the brain's ability to perform at its best at all ages. Unfortunately, without valid tests of brain health and proven methods to improve brain function, most health optimizers tend to ignore that three-pound mass between their ears.

D'Esposito, a professor of psychology and member of Berkeley's Helen Wills Neuroscience Institute, wants to change that focus and bring brain health front and center.

After 35 years of research using MRI scans to understand brain function in healthy people as well as those with brain disorders like Alzheimer's disease and Parkinson's disease, he is now trying to establish MRI benchmarks for brain health that everyone can use. This new focus has taken him out of the lab to proselytize, through podcasts and public talks, about the importance of brain health and what science tells us about how to improve it.

"I just think the focus needs to be on optimizing health as opposed to warding off disease," he said. "Neurology never was in the business of trying to prevent disease. It was only in the business of treating disease. But there's this kind of shift; they (neurologists) have bought into brain health now. Even the American Academy of Neurology is talking about preventive neurology. There can be a brain health revolution like a fitness revolution."

Governments are already focusing on "brain capital" and the "brain economy" as an asset to be optimized by improving skills such as resilience and creativity and addressing neurological and neurodevelopmental disorders. Even the World Health Organization is promoting "optimal brain development, cognitive health and well-being across the life course."

D'Esposito's turnaround to focus on preventive neurology came gradually during his 25-year, long-distance association with the Center for BrainHealth at the University of Texas-Dallas, which is establishing itself as a worldwide center of translational research to measure and boost brain function.

The center recently lured away one of D'Esposito's Berkeley colleagues, neuroscientist and psychologist Matthew Walker, to create the new Sleep Innovation Laboratories, with a major goal of translating "the latest neuroscience research into evidence-based strategies that can optimize your sleep."

According to Eti Ben Simon, a Berkeley postdoctoral fellow who is now associate director of the new lab, "We want to use technology to understand sleep better, but also to try and offer the latest innovations that can help people achieve better sleep. If we think about brain health, we cannot ignore sleep. And we're talking about not just keeping the brain away from disease, but actually really helping it thrive."

Earlier this year, D'Esposito and five other neuroscientists and neurologists founded the Society for Brain Health, hoping to channel an emerging trend as doctors think less defensively - How do we stave off dementia? - and go on offense: How do we bolster brain health to avoid neurodegenerative disease?

Meetings of the Society for Brain Health - the first is planned for next February - would be a place where researchers, clinicians, neurotech developers, public policy experts, educators and others present their results about which of the thousands of brain fitness games or other interventions are actually effective and what sorts of biomarkers, whether brain scans or blood analysis, correlate with brain health.

"We have to figure out how to measure brain health," he said. "If your primary care doctor doesn't know if your brain's healthy, then how are you going to know? And which interventions are actually helpful, have been vetted scientifically? That's where the Society for Brain Health comes in."

A longitudinal study of brain health

Five years ago, D'Esposito joined three other neuroscientists and neurologists to launch The BrainHealth Project within the Center for Brain Health. Through the project, they recruited like-minded neuropsychologists and cognitive neuroscientists to systematically vet new tests of brain function - from online performance-based measures to questionnaires - and correlate them with objective markers of brain health, some of which involve MRI scans. The resulting BrainHealth Index incorporates lifestyle questionnaires and online tasks - 22 separate measures in all - to assess not only cognitive but also social and emotional well-being, which have been linked to a longer healthspan. The team pairs these measures with online cognitive training, lifestyle modules and coaching to see if people can raise their BHI.

Participants take the test every six months to chart their progress and engage in training to learn strategies like "how to stop using toxic brain habits, stop multitasking; how to rest your brain, think deeply and continuously innovate," said cognitive neuroscientist Sandra Chapman, the founder and chief director of the Center for BrainHealth and a distinguished professor in the School of Behavioral and Brain Sciences at UT-Dallas.

"We've developed the first ever behavioral measure that, if you were to take it often, can show whether you've been able to maintain your holistic ability to think clearly, to synthesize, but also to connect warmly with people and to find emotional balance in the midst of struggles and chaos," she said. "We start during middle school and take a lifespan approach to optimize the human brain potential. We are finding there's no upper limit - it's you against yourself."

D'Esposito and Chapman compared the project to the monumental Framingham Heart Study, which over eight decades established the risk factors for cardiovascular disease that are now common knowledge: smoking, high cholesterol, high blood pressure, physical inactivity and obesity.

"You go to your doctor every year for your annual physical and they examine every organ in your body, right? Except your brain," D'Esposito said. "The BrainHealth Project has the lofty goal of enrolling 100,000 people, following them, and not only trying to develop biomarkers for brain health but also developing intervention."

Their most recent report, published in May in the journal Scientific Reports, was an analysis of three years of data on nearly 4,000 people enrolled in the project between the ages of 19 and 94. Participants of all ages reported sustained improvements in brain health as measured by the Brain Health Index, showing that cognitive decline is not an inevitable result of aging.

Nearly 40,000 people are now enrolled in the study, which is one reason Walker and Ben Simon have joined the project team. While the BHI already includes an assessment of sleep quality, they hope to add more measures to assess other aspects of sleep that have been linked to a healthy brain.

"We want to try and think about the four core domains of sleep: duration, quality, regularity and timing," she said. While questionnaires can gather good subjective data on some of these, the researchers are introducing wearables to measure other markers, such as the sleeping heart rate and the duration of specific sleep stages. Ben Simon herself wears an Oura ring to record when she falls asleep and when she awakens.

"It's an opportunity to integrate sleep into the notion of 24-hour brain health," she said.

The brain's connectedness

D'Esposito has helped establish that one MRI measure, of the brain's modularity or connectedness, is associated with better functioning, such as improved attention, working memory and multitasking. It can be measured during a 10-minute resting fMRI scan performed repeatedly over time to track brain health.

"The brain network is a lot like an airline network," he said. "Some hubs are critically important - like Chicago - while others, like Milwaukee, play a much smaller role. If there are delays in Chicago, the disruption spreads across the entire country. Even a direct flight from New York to San Francisco can be affected because so many routes depend on that major hub. But delays in a smaller hub like Milwaukee usually don't have the same nationwide impact."

"Similarly, major network hubs in the brain are gathering information from many other areas,'" he added. "And it turns out that these major hubs are the most vulnerable areas of the brain for disease. If you look at neurological disorders and psychiatric disorders, it's actually the major hubs that have the most pathology. Think about diseases as network failures, as opposed to just one brain area failing."

D'Esposito and his colleagues found that brain modularity predicts whether someone is going to respond well to cognitive therapies, transcranial brain stimulation, aerobic exercise and other interventions. A highly modular brain predicts likely benefits across age groups and types of therapies, he said, leading neurologists to home in on this as a biomarker for intervention success.

D'Esposito's colleague in Berkeley's psychology and neuroscience departments, associate professor Kevin Weiner, is focused on another possible measure of brain health: the prominence of grooves in the brain called tertiary sulci. He has shown with Berkeley professor Silvia Bunge that the depths of some small grooves in children and adolescents are correlated with increased connectivity between regions of the brain involved in reasoning and other high-level cognitive functions.

For Weiner, who specializes in brain anatomy, the BrainHealth Project's database is a unique opportunity to analyze people's MRI brain scans over time and identify the anatomical markers, specifically brain folds, associated with brain health and how they change with age. During human evolution, these folds were the last to appear as the brain grew and got compressed inside the skull - they're literally shaped by the human trend toward higher-level thinking. That developmental timeline is recapitulated during development in the fetus, with the tertiary sulci the last folds to form.

Because the depth and shape of these sulci vary from individual to individual, mapping them could provide a measure of brain health. Other structures, such as the brain's ridges, or gyri, and the depth of larger grooves may also be correlated with cognition and resilience, Weiner said.

He and Berkeley neuroscientist William Jagust have already shown that variability in one specific tertiary sulcus is related to cognitive resilience in superagers. These brain folds are painstaking to identify, but Weiner eventually hopes to train a computer algorithm to automatically identify these tertiary folds in MRI images so he can more thoroughly study their correlation with brain function.

"There's a retrogenesis hypothesis on the table, the idea that regions of the brain that are the last in - tertiary sulci emerge last in gestation - are proposed to be the first out as you age. So they're most vulnerable in aging," he said. "If we could identify certain features of these tertiary sulci in the parts of the brain that are most vulnerable in aging that are correlated with the brain health index, that would be awesome."

D'Esposito and Weiner both are focusing on what can be learned from MRI scans, but the BrainHealth Project's real goal is to find a way to assess brain health without expensive and time-consuming tests.

"We're not proposing that everyone get an MRI scan during their annual physical," D'Esposito said. "We're trying to develop a marker for brain health by first using the MRI data and then hopefully it'll be a biomarker that can be measured at home, either through physiological monitoring or through an ear EEG - something simple and easy. It's not going to be any single marker in the brain that tracks brain health. It's going to be some combination."

He and his colleagues are collaborating with a company called NeuroScouting, founded by one of his doctoral students at Berkeley, to employ technology developed for athletes to pick up physiological biomarkers like these.

"It's remarkable that brain modularity, as measured by fMRI, may be inferred from physiological signals such as heart rate and respiration - metrics that could potentially be monitored by a smartwatch or an in-ear device." he said.

Right now, his colleagues at the Center for BrainHealth are focused on extending the reach of their BrainHealth Index and training strategies beyond the study at UT-Dallas. The U.S. military has already shown interest as a way to bolster fitness and reslience for active and retired service members. Two former Navy SEALS, including retired Admiral William McRaven, former commander of the United States Special Operations Command, are big boosters of the program. The hope is that major hospitals and healthcare providers incorporate this into their wellness programs.

The center is also investigating how the brain health program can help treat those with addiction, traumatic brain injury, PTSD, frontotemporal dementia and other brain disorders.

"My goal from the very beginning, more than three decades ago, was to turn discoveries made in my lab into knowledge that could meaningfully improve people's lives," D'Esposito said. "Through my work at the Northern California VA Health Care System and UCSF, we have done a number of cognitive interventions with traumatic brain injury patients and healthy elderly, but The BrainHealth Project is an opportunity really to go all in and hopefully make a worldwide impact. I've completely refocused on translational work."