A new study puts a number on how dangerous such chronic tiredness can be, at least in regard to driving. For every eight additional breathing interruptions per hour, the odds of making a dangerous driving move such as speeding, braking hard or accelerating suddenly increase by 27%, according to a study by researchers at Washington University School of Medicine in St. Louis.

Older adults are more likely to develop sleep apnea. They also are more likely to be seriously injured or killed in a car accident. The findings, available online in the journal Sleep, suggest that screening older adults for sleep apnea and for treatment, if needed, may help older people continue driving safely for longer.

“The percentage of older adults with mild sleep apnea is 30% to 50%, but if such adults don’t have daytime sleepiness or other evidence of impairment, they may not come to medical attention,” said co-senior author Brendan Lucey, MD, an associate professor of neurology and director of Washington University’s Sleep Medicine Center. “However, these findings suggest that we might want a lower threshold to evaluate older adults for sleep apnea and track their breathing interruptions. If their conditions worsen by just eight interruptions an hour, that could have significant adverse effects on their driving and their risk of suffering serious injury.”

People 65 and over are the most responsible drivers on the road. They obey speed limits. They drive defensively. They avoid driving at night, in bad weather and in unfamiliar places. But the changes that often come with advancing age — such as deteriorating vision, slower reflexes and, yes, difficulty sleeping — can undermine even the safest habits.

Lucey teamed up with driving researcher Ganesh M. Babulal, PhD, OTD, an assistant professor of neurology and the paper’s co-senior author, to investigate the relationship between sleep apnea and risky driving behaviors. Participants were recruited from ongoing studies at Washington University’s Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight ADRC).

Babulal and Lucey monitored the driving and sleep habits of 96 older adults under real-world conditions. They used a commercially available take-home test to identify people with sleep apnea and measure its severity. Less than five breathing interruptions per hour is considered normal, five to 15 is mild sleep apnea, 15 to 30 is moderate, and greater than 30 is severe.

To assess driving habits, the researchers installed a chip developed by Babulal and colleagues into participants’ personal vehicles and monitored their driving for a year, focusing on episodes of hard braking, sudden acceleration and speeding. In total, they collected data on more than 100,000 trips. Participants also were evaluated by researchers at the Knight ADRC for cognitive impairments and molecular signs of early Alzheimer’s disease.

Even though all participants were cognitively normal, about a third had brain changes indicative of early Alzheimer’s disease. The researchers found that the frequency with which drivers made dangerous moves behind the wheel rose in parallel with the frequency with which their sleep was interrupted at night, regardless of whether their brains bore the marks of early Alzheimer’s.

“We didn’t have cameras in the vehicles, so we don’t know exactly what happened that caused someone to, say, brake hard suddenly,” Babulal said. “But it could be something like a stoplight that they didn’t realize was red until they got close and had to stomp on the brakes. The more tired you are, the less attention you have to deploy to the task at hand, especially if it is novel and constantly changing.”

The study helps untangle the ways aging-associated risk factors such as poor sleep and Alzheimer’s disease put older adults in danger while driving, and could aid efforts to find ways to maximize years of safe driving, the researchers said.

“Driving always carries the risk of crashing, and older adults are at risk of more severe injury than younger adults if they experience a crash,” Babulal said. “But we can’t just tell them to give up their keys. When older people stop driving, they lose a lot of their independence and mobility, which is often associated with negative health and social outcomes. What we want to understand is what puts them at a higher risk so we can intervene and help them stay behind the wheel, safely, for as long as possible.”

These nerve cells are often generated far from where they will eventually reside and function in the new brain, a migration that, while much investigated in animal models using chemical or biological tracers, has never been studied directly in humans. Until now.

In a new paper, published online April 20, 2022 in Nature, scientists at University of California San Diego School of Medicine and Rady Children’s Institute of Genomic Medicine describe novel methods for inferring the movement of human brain cells during fetal development by studying healthy adult individuals who have recently passed away from natural causes.

“Every time a cell divides into two daughter cells, by chance, there arise one or more new mutations, which leave a trail of breadcrumbs that can be read out by modern DNA sequencers,” said senior author Joseph Gleeson, MD, Rady Professor of Neuroscience at UC San Diego School of Medicine and director of neuroscience research at the Rady Children’s Institute for Genomic Medicine.

“By developing methods to read these mutations across the brain, we are able to reveal key insights into how the human brain forms, in comparison with other species.”

Although there are 3 billion DNA bases — and more than 30 trillion cells in the human body — Gleeson and colleagues focused their efforts on just a few hundred DNA mutations that likely arose during the first few cell divisions after fertilization of the embryo or during early development of the brain. By tracking these mutations throughout the brain in deceased individuals, they were able to reconstruct development of the human brain for the first time.

To understand the type of cells displaying these breadcrumb mutations, they developed methods to isolate each of the major cell types in the brain. For instance, by profiling the mutations in excitatory neurons compared with inhibitory neurons, they confirmed the long-held suspicion that these two cell types are generated in different germinal zones of the brain, and then later mix together in the cerebral cortex, the outermost layer of the organ.

However, they also discovered that the mutations found in the left and right sides of the brain were different from one another, suggesting that — at least in humans — the two cerebral hemispheres separate during development much earlier than previously suspected.

The results have implications for certain human diseases, like intractable epilepsies, where patients show spontaneous convulsive seizures and require surgery to remove an epileptic brain focus, said Martin W. Breuss, PhD, former project scientist at UC San Diego and now an assistant professor at the University of Colorado School of Medicine.

Breuss is co-first author with Xiaoxu Yang, PhD, postdoctoral scholar and Johannes C. M. Schlachetzki, MD, project scientist, both at UC San Diego; and Danny Antaki, PhD, a former postdoctoral scholar at UC San Diego, now at Twist Biosciences.

“This study,” the authors said, “solves the mystery as to why these foci are almost always restricted to one hemisphere of the brain. Applying these results to other neurological conditions could help scientists understand more mysteries of the brain.”

Co-authors include: Xin Xu, Changuk Chung, Guoliang Chai, Valentina Stanley, Qiong Song, Traci F. Newmeyer, An Nguyen, Beibei Cao, Jennifer McEvoy-Venneri and Brett R. Copeland, all at UC San Diego and Rady Children’s Institute for Genomic Medicine; Addison J. Lana, Sydney O’Brien, Marten A. Hoeksema, Alexi Nott, Martina P. Pasilla, Scott T. Barton, and Christopher K. Glass, all at UC San Diego; Shareef Nahas, Lucitia Van Der Kraan and Yan Ding, Rady Children’s Institute for Genomic Medicine and the NIMH Brain Somatic Mosaicism Network.

Funding for this research came, in part, from the Howard Hughes Medical Institute, the National Institute of Mental Health (grants MH108898, RO1 MH124890, R21 AG070462), the National Institute on Aging (grants RF1 AGO6106-02, R01 AGO56511-02, R01 NS096170-04) and the UC San Diego IGM Genomics Center (S10 OD026929).

Video: https://youtu.be/WfrvSYi9M6A

The results, published April 20 in Nature, may aid the development of a new generation of more effective neurological and psychiatric therapies with fewer side effects.

The new research takes a close look at glutamate, the most prevalent neurotransmitter in the brain. Glutamate binds to receptors on brain cells, which opens a channel into the cell, allowing ions to pass through to propagate an electrical signal.

“The way the brain works is through communication between neurons, and these are the main receptors which allow this communication,” says Alexander Sobolevsky, PhD, associate professor of biochemistry and molecular biophysics at Columbia and senior author on the paper.

Each receptor can bind up to four molecules of glutamate and produce four different levels of conductivity. Previous studies had linked binding to conductivity in a simple stepwise fashion, in which binding each additional glutamate molecule increased the conductivity another step.

While that explanation made sense, nobody had looked closely enough to confirm it. In the new work, the investigators combined a technique called cryo-electron microscopy with sophisticated data analysis to reveal the first detailed pictures of glutamate binding to its receptors.

“We actually carried out experiments in the conditions where we see all these intermediates, one glutamate and then two glutamates, three glutamates, and then it binds all four,” says Sobolevsky.

These images reveal that glutamate binds to the subunits of its receptor only in specific patterns. That overturns the prevailing view that each subunit binds glutamate independently and points toward new levels of complexity in neuronal signaling and drug responses.

Instead of straightforward stepwise transitions, Sobolevsky and his colleagues found that a glutamate molecule must bind to one of two specific receptor subunits before any glutamates can bind to the other two subunits. In addition, the conductivity levels of the receptor didn’t correlate directly to the number of glutamates bound to it; a receptor could have two or more glutamates attached but still only reach the first level of conductivity.

The results open an entirely new line of investigation, and the team is now probing how different accessory molecules on neurons affect the interaction. Learning more about the glutamate receptors’ specific activation states may aid the development of better drugs for conditions that involve glutamate receptors, such as depression, dementia, Parkinson’s disease, epilepsy, and stroke.

Video: https://youtu.be/IeQZTFMz5ek

The study was supported by the National Institutes of Health (R01 CA206573, R01 NS083660, R01 NS107253, R01 AR078814, R01 GM128195, and R01 AG065594) and the National Science Foundation (1818086, 1818213, and 1563291).

The study, published in npj Digital Medicine, analyzed sensor data on sleep, activity and heart rate from over 5,600 individuals. Among the findings, the team showed that the average resting heart rate of participants significantly increased the day following vaccination. The effect appeared to be stronger after the second dose of the Moderna vaccine, compared to the Pfizer-BioNTech vaccine, and more pronounced in younger individuals.

According to lead author Giorgio Quer, PhD, director of Artificial Intelligence at the Scripps Research Translational Institute, this study is a first step toward quantifying the physiological response to vaccination in individuals using commercial sensors.

“Investigating the physiological signals in the period around vaccination can help us better understand the variability of vaccine response between people, as well as the changes from an individual norm due to vaccination,” Quer says. “As these individual changes are due to a person’s initial immune response to the vaccine, they can potentially help guide future vaccine development to optimize their efficacy and safety, and allow for more precise, individualized vaccine regimens.”

The researchers drew their data from a larger project, called Digital Engagement and Tracking for Early Control and Treatment (DETECT) launched in March 2020, in response to the emergence and rapid spread of SARS-CoV-2, the virus that causes COVID-19. DETECT is a mobile-app research platform that allows participants to share physiological and behavioral data gathered through a fitness band or smartwatch, as well as manually entered symptoms, test results and vaccination status.

To determine whether consumer wearables could unearth digital biomarkers of vaccine-induced immune response, the scientists analyzed DETECT sensor data from two weeks before and after each vaccination dose. They compared post-vaccination changes to the participants’ resting heart rate, sleep and activity levels, to their baselines.

The analysis showed that the average resting heart rate of study participants increased significantly the day following vaccination, peaking two days post-vaccination, and returning to normal four days after the first dose and six days after the second. In addition to increases in resting heart rate being higher after the second dose of the Moderna versus the Pfizer-BioNTech vaccine, the study suggests that prior COVID-19 infection was linked with a significantly higher resting heart rate increase after the first vaccine dose relative to those without prior infection. This increase is consistent with an expected greater immune response for these individuals.

Findings also show that women experienced greater changes than men in resting heart rate in the five days following vaccination after the first dose, and that individuals under the age of 40 had higher changes in resting heart rate than older individuals, but only after the second dose.

Activity and sleep patterns appeared to be minimally affected by the first dose, but a significant decrease in activity and an increase in sleep relative to baseline were observed immediately after the second vaccine dose.

“While the link between physiological response and immune response still requires further investigation, digital tracking could provide a novel way to identify individuals who may not be responding optimally to the vaccine,” says Steven Steinhubl, MD, associate professor at Scripps Research and senior author of the study.

“DETECT really shows the power of wearable sensor data in furthering our understanding of multiple facets of COVID-19,” Quer says. “We hope to continue to expand this research by growing our study cohort further, which will allow us to delve into important questions regarding breakthrough infections and other areas that are currently poorly understood.”

The npj Digital Medicine article, “Inter-individual variation in objective measure of reactogenicity following COVID-19 vaccination via smartwatches and fitness bands” is authored by Giorgio Quer, Matteo Gadaleta, Jennifer Radin, Kristian Andersen, Katie-Baca-Motes, Edward Ramos, Eric Topol and Steven Steinhubl.

Funding for the research was provided by the National Center for Advancing Translational Sciences at the National Institutes of Health [UL1TR002550] and the National Institute of Allergy and Infectious Diseases [U19AI135995].

About DETECT

Since its launch, the DETECT (Digital Engagement and Tracking for Early Control and Treatment) study has enrolled over 40,000 participants nationwide. The data that has been shared has enabled scientists to gain valuable insights into various aspects of COVID-19 infection. Already, DETECT has led to several peer-reviewed publications that: show how wearable devices are capable of detecting COVID-19 infection; give valuable insights into long COVID; demonstrate how machine learning techniques can predict COVID-19 infection; and more. The team aims to develop tools to complement traditional public health interventions and bolster the ability to prevent and contain future pandemics. The DETECT study is ongoing. Visit detect.scripps.edu to learn more.