Study links physical activity in older adults to brain white-matter integrity

Like everything else in the body, the white-matter fibers that allow communication between brain regions also decline with age. In a new study, researchers found a strong association between the structural integrity of these white-matter tracts and an older person’s level of daily activity – not just the degree to which he or she engaged in moderate or vigorous exercise, but also whether the person was sedentary the rest of the time.

The study, reported in the journal PLOS ONE, tracked physical activity in 88 healthy but “low-fit” participants aged 60 to 78. The participants agreed to wear accelerometers during most of their waking hours over the course of a week, and also submitted to brain imaging.

“To our knowledge, this is the first study of its kind that uses an objective measure of physical activity along with multiple measures of brain structure,” said University of Illinois postdoctoral researcher Agnieszka Burzynska, who conducted the research with U. of I. Beckman Institute director Arthur Kramer and kinesiology and community health professor Edward McAuley.

Most studies ask subjects to describe how much physical activity they get, which is subjective and imprecise, Burzynska said. The accelerometer continuously tracks a person’s movement, “so it’s not what they say they do or what they think they do, but we have measured what they are actually doing,” she said.

The researchers assumed that participants’ activity levels over a week accurately reflected their overall engagement, or lack of engagement, in physical activity.

The study also relied on two types of brain imaging. The first, diffusion tensor imaging, offers insight into the structural integrity of a tissue by revealing how water is diffused in the tissue. The second method looks for age-related changes in white matter, called lesions. Roughly 95 percent of adults aged 65 and older have such lesions, Burzynska said. While they are a normal part of aging, their early onset or rapid accumulation may spell trouble, she said.

The team found that the brains of older adults who regularly engaged in moderate-to-vigorous exercise generally “showed less of the white-matter lesions,” Burzynska said.

The association between physical activity and white-matter structural integrity was region-specific, the researchers reported. Older adults who engaged more often in light physical activity had greater structural integrity in the white-matter tracts of the temporal lobes, which lie behind the ears and play a key role in memory, language, and the processing of visual and auditory information.

In contrast, those who spent more time sitting had lower structural integrity in the white-matter tracts connecting the hippocampus, “a structure crucial for learning and memory,” Burzynska said.

“This relationship between the integrity of tracts connecting the hippocampus and sedentariness is significant even when we control for age, gender and aerobic fitness,” she said. “It suggests that the physiological effect of sitting too much, even if you still exercise at the end of the day for half an hour, will have a detrimental effect on your brain.”

The findings suggest that engaging in physical activity and avoiding a sedentary lifestyle are both important for brain health in older age, Burzynska said.

“We hope that this will encourage people to take better care of their brains by being more active,” she said.

(Image caption: The hair cells of mice missing just Hey2 are neatly lined up in four rows (left) while those missing Hey1 and Hey2 are disorganized (right). The cells’ hairlike protrusions (pink) can be misoriented, too. Credit: Angelika Doetzlhofer)

Hey1 and Hey2 ensure inner ear ‘hair cells’ are made at the right time, in the right place

Two Johns Hopkins neuroscientists have discovered the “molecular brakes” that time the generation of important cells in the inner ear cochleas of mice. These “hair cells” translate sound waves into electrical signals that are carried to the brain and are interpreted as sounds. If the arrangement of the cells is disordered, hearing is impaired.

A summary of the research will be published in The Journal of Neuroscience on Sept. 16.

"The proteins Hey1 and Hey2 act as brakes to prevent hair cell generation until the time is right," says Angelika Doetzlhofer, Ph.D., an assistant professor of neuroscience. "Without them, the hair cells end up disorganized and dysfunctional."

The cochlea is a coiled, fluid-filled structure bordered by a flexible membrane that vibrates when sound waves hit it. This vibration is passed through the fluid in the cochlea and sensed by specialized hair cells that line the tissue in four precise rows. Their name comes from the cells’ hairlike protrusions that detect movement of the cochlear fluid and create electrical signals that relay the sound to the brain.

During development, “parent cells” within the cochlea gradually differentiate into hair cells in a precise sequence, starting with the cells at the base of the cochlea and progressing toward its tip. The signaling protein Sonic Hedgehog was known to be released by nearby nerve cells in a time- and space-dependent pattern that matches that of hair cell differentiation. But the mechanism of Sonic Hedgehog’s action was unclear.

Doetzlhofer and postdoctoral fellow Ana Benito Gonzalez bred mice whose inner ear cells were missing Hey1 and Hey2, two genes known to be active in the parent cells but turned off in hair cells. They found that, without those genes, the cells were generated too early and were abnormally patterned: Rows of hair cells were either too many or too few, and their hairlike protrusions were often deformed and pointing in the wrong direction.

"While these mice didn’t live long enough for us to test their hearing, we know from other studies that mice with disorganized hair cell patterns have serious hearing problems," says Doetzlhofer.

Further experiments demonstrated the role of Sonic Hedgehog in regulating the two key genes.

"Hey1 and Hey2 stop the parent cells from turning into hair cells until the time is right," explains Doetzlhofer. "Sonic Hedgehog applies those ‘brakes,’ then slowly releases pressure on them as the cochlea develops. If the brakes stop working, the hair cells are generated too early and end up misaligned."

She adds that Sonic Hedgehog, Hey1 and Hey2 are found in many other parent cell types throughout the developing nervous system and may play similar roles in timing the generation of other cell types.

Brain Structure of Kidney Donors May Make Them More Altruistic

That’s the finding of a study published in today’s Proceedings of the National Academy of Sciences (PNAS) by Georgetown researchers.

Georgetown College psychology professor Abigail Marsh worked with John VanMeter, director of Center for Functional and Molecular Imaging at Georgetown University Medical Center, to scan the brains of 19 altruistic kidney donors.

More Sensitive to Distress

“The results of brain scans and behavioral testing suggests that these donors have some structural and functional brain differences that may make them more sensitive, on average, to other people’s distress,” Marsh explains.

The Georgetown researchers used functional MRI to record the neural activity of the kidney donors and 20 control subjects who had never donated an organ as they viewed faces with fearful, angry or neutral expressions.

Underlying Neural Basis

In the right amygdala, an emotion-sensitive brain region, altruists displayed greater neural activity while viewing fearful expressions than did control subjects.

When asked to identify the emotional expressions presented in the face images, altruists recognized fearful facial expressions relatively more accurately than the control subjects.

“The brain scans revealed that the right amygdala volume of altruists is larger than that of non-altruists,” Marsh says. “The findings suggest that individual differences in altruism may have an underlying neural basis.”

Opposite From Psychopaths?

These findings dovetail with previous research by the professor showing  structural and functional brain differences that appear to make people with psychopathic traits less sensitive to others’ fear and distress.

These differences include amygdalas that are smaller and less responsive to fearful expressions. People who are unusually altruistic may therefore be the opposite in some ways from people who are psychopathic.

To find kidney donors, the researchers reached out to the Washington Regional Transplant Community (WRTC), a federally designated organ procurement organizations.

A Donor’s Story

Harold Mintz, former northern Virginian who volunteered with WRTC and agreed to participate in the Georgetown study, donated a kidney to an anonymous stranger he later learned was an Ethiopian refugee who had settled in Washington, D.C.

Mintz, who now lives in California and speaks to high school students about his 2000 donation, says a series of events over time led him to supply the kidney, including his father dying of cancer diagnosed too late at the age of 56.

One Valentine’s Day in 1988, Mintz and his wife were shopping separately for presents and Mintz noticed parents in a mall with a sign saying “Please Save Our Daughter’s Life.” He walked past them, then turned around and asked what they needed. It turned out the daughter had leukemia and needed a bone marrow transplant.

The couple decided to forget about the holiday and donated blood to see if either of them were a match. But no match was found and Mintz later noticed the daughter’s obituary in the newspaper.

Stories Taken to Heart

Mintz also was surprised to hear that although the couple’s daughter had just died, they thanked everyone who tried to help and expressed hope that they might help someone else.

“All these stories just kind of stuck inside my head and every time I’d see a story about a medical story of distress, it would just kind of get put away in a file inside my heart,” Mintz says.

Marsh notes that kidney disease is now the eighth-leading cause of death in the U.S., and that living kidney donations are the best hope for restoring people to health who have kidney disease.

“Dr. Marsh’s work is a great example of how fMRI can be used to provide insight into how differences in the brain’s response can lead individuals to perform such magnanimous acts,” VanMeter says.

No sedative necessary: Scientists discover new “sleep node” in the brain

A sleep-promoting circuit located deep in the primitive brainstem has revealed how we fall into deep sleep. Discovered by researchers at Harvard School of Medicine and the University at Buffalo School of Medicine and Biomedical Sciences, this is only the second “sleep node” identified in the mammalian brain whose activity appears to be both necessary and sufficient to produce deep sleep.

Published online in August in Nature Neuroscience, the study demonstrates that fully half of all of the brain’s sleep-promoting activity originates from the parafacial zone (PZ) in the brainstem. The brainstem is a primordial part of the brain that regulates basic functions necessary for survival, such as breathing, blood pressure, heart rate and body temperature.

“The close association of a sleep center with other regions that are critical for life highlights the evolutionary importance of sleep in the brain,” says Caroline E. Bass, assistant professor of Pharmacology and Toxicology in the UB School of Medicine and Biomedical Sciences and a co-author on the paper.

The researchers found that a specific type of neuron in the PZ that makes the neurotransmitter gamma-aminobutyric acid (GABA) is responsible for deep sleep. They used a set of innovative tools to precisely control these neurons remotely, in essence giving them the ability to turn the neurons on and off at will.

 “These new molecular approaches allow unprecedented control over brain function at the cellular level,” says Christelle Ancelet, postdoctoral fellow at Harvard School of Medicine. “Before these tools were developed, we often used ‘electrical stimulation’ to activate a region, but the problem is that doing so stimulates everything the electrode touches and even surrounding areas it didn’t. It was a sledgehammer approach, when what we needed was a scalpel.”

“To get the precision required for these experiments, we introduced a virus into the PZ that expressed a ‘designer’ receptor on GABA neurons only but didn’t otherwise alter brain function,” explains Patrick Fuller, assistant professor at Harvard and senior author on the paper. “When we turned on the GABA neurons in the PZ, the animals quickly fell into a deep sleep without the use of sedatives or sleep aids.”

How these neurons interact in the brain with other sleep and wake-promoting brain regions still need to be studied, the researchers say, but eventually these findings may translate into new medications for treating sleep disorders, including insomnia, and the development of better and safer anesthetics.

“We are at a truly transformative point in neuroscience,” says Bass, “where the use of designer genes gives us unprecedented ability to control the brain. We can now answer fundamental questions of brain function, which have traditionally been beyond our reach, including the ‘why’ of sleep, one of the more enduring mysteries in the neurosciences.”

Researcher Develops and Proves Effectiveness of New Drug for Spinal Muscular Atrophy

According to recent studies, approximately one out of every 40 individuals in the United States is a carrier of the gene responsible for spinal muscular atrophy (SMA), a neurodegenerative disease that causes muscles to weaken over time. Now, researchers at the University of Missouri have made a recent breakthrough with the development of a new compound found to be highly effective in animal models of the disease. In April, a patent was filed for the compound for use in SMA.

“The strategy our lab is using to fight SMA is to ‘repress the repressor,’” said Chris Lorson, a researcher in the Bond Life Sciences Center and professor in the MU Department of Veterinary Pathobiology. “It’s a lot like reading a book, but in this case, the final chapter of the book—or the final exon of the genetic sequence—is omitted. The exciting part is that the important chapter is still there—and can be tricked into being read correctly, if you know how. The new SMA therapeutic compound, an antisense oligonucleotide, repairs expression of the gene affected by the disease.”

In individuals affected by SMA, the spinal motor neuron-1 (SMN1) gene is mutated and lacks the ability to process a key protein that helps muscle neurons function. Muscles in the lower extremities are usually affected first, followed by muscles in the upper extremities, including areas around the neck and spine.

Fortunately, humans have a nearly identical copy gene called SMN2. Lorson’s drug targets that specific genetic sequence and allows proper “editing” of the SMN2 gene. The drug allows the SMN2 gene to bypass the defective gene and process the protein that helps the muscle neurons function.

Lorson’s breakthrough therapeutic compound was patented in April. His research found that the earlier the treatment can be administered in mice with SMA, the better the outcome. In mice studies, the drug improved the survival rate by 500 to 700 percent, with a 90 percent improvement demonstrated in severe SMA cases, according to the study.

Although there is no cure for SMA currently, the National Institutes of Health (NIH) has listed SMA as the neurological disease closest to finding a cure, due in part to effective drugs like the one developed in Lorson’s lab.