Women's brains appear three years younger than men's

May explain why women more likely to stay mentally sharp in later years.

Time wears differently on women's and men's brains. While the brain tends to shrink with age, men's diminish faster than women's. The brain's metabolism slows as people grow older, and this, too, may differ between men and women.

A new study from Washington University School of Medicine in St. Louis finds that women's brains appear to be about three years younger than men's of the same chronological age, metabolically speaking. The findings, available online the week of Feb. 4 in Proceedings of the National Academy of Sciences, could be one clue to why women tend to stay mentally sharp longer than men.

"We're just starting to understand how various sex-related factors might affect the trajectory of brain aging and how that might influence the vulnerability of the brain to neurodegenerative diseases," said senior author Manu Goyal, MD, an assistant professor of radiology at the university's Mallinckrodt Institute of Radiology. "Brain metabolism might help us understand some of the differences we see between men and women as they age."

The brain runs on sugar, but how the brain uses sugar changes as people grow and age. Babies and children use some of their brain fuel in a process called aerobic glycolysis that sustains brain development and maturation. The rest of the sugar is burned to power the day-to-day tasks of thinking and doing. In adolescents and young adults, a considerable portion of brain sugar also is devoted to aerobic glycolysis, but the fraction drops steadily with age, leveling off at very low amounts by the time people are in their 60s.

But researchers have understood little about how brain metabolism differs between men and women. So Goyal and colleagues, including Marcus Raichle, MD, the Alan A. and Edith L. Wolff Distinguished Professor of Medicine and a professor of radiology, and Andrei Vlassenko, MD, PhD, an associate professor of radiology, studied 205 people to figure out how their brains use sugar.

The study participants -- 121 women and 84 men, ranging in age from 20 to 82 years -- underwent PET scans to measure the flow of oxygen and glucose in their brains. For each person, the researchers determined the fraction of sugar committed to aerobic glycolysis in various regions of the brain. They trained a machine-learning algorithm to find a relationship between age and brain metabolism by feeding it the men's ages and brain metabolism data. Then, the researchers entered women's brain metabolism data into the algorithm and directed the program to calculate each woman's brain age from its metabolism. The algorithm yielded brain ages an average of 3.8 years younger than the women's chronological ages.

The researchers also performed the analysis in reverse: They trained the algorithm on women's data and applied it to men's. This time, the algorithm reported that men's brains were 2.4 years older than their true ages.

"The average difference in calculated brain age between men and women is significant and reproducible, but it is only a fraction of the difference between any two individuals," Goyal said. "It is stronger than many sex differences that have been reported, but it's nowhere near as big a difference as some sex differences, such as height."

The relative youthfulness of women's brains was detectable even among the youngest participants, who were in their 20s.

"It's not that men's brains age faster -- they start adulthood about three years older than women, and that persists throughout life," said Goyal, who is also an assistant professor of neurology and of neuroscience. "What we don't know is what it means. I think this could mean that the reason women don't experience as much cognitive decline in later years is because their brains are effectively younger, and we're currently working on a study to confirm that."

Older women tend to score better than men of the same age on tests of reason, memory and problem solving. Goyal, Raichle, Vlassenko and colleagues are now following a cohort of adults over time to see whether people with younger-looking brains are less likely to develop cognitive problems.

Psychologists solve mystery of songbird learning

Scientists rely on animal models to gain insight into how humans learn language, but it turns out that one of their favorite models, the zebra finch, has been entirely misunderstood.
New research reveals that these birds don't simply learn their songs by imitating adults: They learn by watching their mothers' reactions to their immature songs.
In "Female Social Feedback Reveals Non-Imitative Mechanisms of Vocal Learning in Zebra Finches," published Jan. 31 in Current Biology, co-authors Michael Goldstein, associate professor of psychology, and doctoral candidate Samantha Carouso-Peck solve the mystery of why juvenile male zebra finches learn to sing better when females are around, even though the females don't sing.
The researchers found that the adult females guide juveniles' song development through specific interactions, similar to how human babies learn to talk. This study brings the number of species known to engage in socially guided vocal learning to four: zebra finches, humans, marmosets and cowbirds.
The researchers' clue to the zebra finch mystery came when they considered that birds see the world at several times the "critical flicker fusion rate" of humans. Simply put, birds can perceive events that happen much too fast for a human to see, and most previous research on social learning has not taken into account such rapid "bird time," in which tiny behaviors can have large social effects.
Using slowed-down video, the Cornell researchers were able to identify tiny movements, imperceptible to the human eye, made by the female zebra finches to encourage the baby songbirds. These included wing gestures and "fluff-ups," an arousal behavior in which the bird fluffs up its feathers.
"Over time, the female guides the baby's song toward her favorite version. There's nothing imitative about it," said Carouso-Peck.
The study included nine pairs of zebra finches, genetic brothers raised for the first 35 days by their respective parents. When they reached the age at which they begin to produce practice song (subsong), the siblings were split up, moved into individual soundproof containers and randomly assigned to one of two conditions: "contingent" or "yoked."
Contingent birds were monitored by Carouso-Peck, and each time they sang in a way that matched their fathers' song, she triggered a video playback of a female performing a fluff-up. The yoked bird saw the same fluff-up video at the same time as his contingent brother, but from his perspective the fluff-ups happened at random times unrelated to his song production.
After the birds' songs "crystallized" into the final version, the researchers compared them to the songs of the juveniles' fathers. They found that the birds in the contingent group learned significantly more accurate songs than their yoked brothers. Had the traditional model of song learning as pure imitation been correct, both birds would have learned the same song, because they had the same opportunity to memorize it early and practice it, according to Goldstein.
One possible reason for the zebra finch learning style, according to the researchers, is that because zebra finches use their songs to attract mates rather than defend territory, integrating female preferences into song is "a highly adaptive strategy for future reproductive success," they wrote.
"Historically we've been studying these birds in isolation. That means we've been missing out on the entire social aspect of song learning," Goldstein said.
Similarly, he said, most labs study human babies more or less in isolation.
"But what babies -- zebra finch or human -- are good at is exploiting social information in their environment," Goldstein said. "These immature behaviors are not mindless practice and noise. Their function is to motivate the adults in the room to provide information."
Zebra finches are widely used in research of vocal learning and production as well as research on Parkinson's disease, autism, stuttering and genetic disorders of speech. "Incorporating social factors into studies of zebra finch learning will strengthen the species as a model system," the paper's authors write, "as it will uncover new possibilities for drawing parallels with human speech acquisition."
The research was supported by the National Science Foundation and Cornell's Institute for the Social Sciences.

Laughter may be best medicine - for brain surgery!

Neuroscientists at Emory University School of Medicine have discovered a focal pathway in the brain that when electrically stimulated causes immediate laughter, followed by a sense of calm and happiness, even during awake brain surgery. The effects of stimulation were observed in an epilepsy patient undergoing diagnostic monitoring for seizure diagnosis. These effects were then harnessed to help her complete a separate awake brain surgery two days later.
The behavioral effects of direct electrical stimulation of the cingulum bundle, a white matter tract in the brain, were confirmed in two other epilepsy patients undergoing diagnostic monitoring. The findings are scheduled for publication in the Journal of Clinical Investigation. Videos of the effects of cingulum bundle stimulation are available, with the patient's identity obscured.
Emory neurosurgeons see the technique as a "potentially transformative" way to calm some patients during awake brain surgery, even for

people who are not especially anxious. For optimal protection of critical brain functions during surgery, patients may need to be awake and not sedated, so that doctors can talk with them, assess their language skills, and detect impairments that may arise from resection.
"Even well-prepared patients may panic during awake surgery, which can be dangerous," says lead author Kelly Bijanki, PhD, assistant professor of neurosurgery. "This particular patient was especially prone to it because of moderate baseline anxiety. And upon waking from global anesthesia, she did indeed begin to panic. When we turned on her cingulum stimulation, she immediately reported feeling happy and relaxed, told jokes about her family, and was able to tolerate the awake procedure successfully."
Outside of use during awake surgery, understanding how cingulum bundle stimulation works could also inform efforts to better treat depression, anxiety disorders, or chronic pain via deep brain stimulation.
Previous investigators have reported that direct electrical stimulation of other parts of the brain can trigger laughter, but the demonstration that anti-anxiety effects observed with cingulum bundle stimulation can provide meaningful clinical benefits make this study distinct, says senior author Jon T, Willie, MD, PhD, who performed the surgeries reported in the paper. He is assistant professor of neurosurgery and neurology at Emory University School of Medicine.
Additional Emory authors include Joseph Manns, PhD, Cory Inman, PhD, graduate student Sahar Harati , Nigel Pedersen, MD, Daniel Drane, PhD, and Rebecca Fasano, MD. Authors who are now at Mount Sinai in New York City are Ki Sueng Choi, PhD, Allison Waters, PhD and Helen Mayberg, MD, all previously at Emory.
Lying under the cortex and curving around the midbrain, the cingulum bundle has a shape resembling a girdle or belt -- hence its Latin name. The area that was a key to laughter and relaxation lies at the top and front of the bundle. The bundle is a logical target because of its many connections among brain regions coordinating complex emotional responses, Willie says.
The location of cingulum bundle stimulation is distinct from other brain locations that process reward, such as ventral striatum, which has been targeted for the treatment of depression and addiction. Because the cingulum bundle is a crossroads for white matter connecting several lobes, Willie and his team may be affecting widespread networks throughout the brain.
Willie says the locations of initial electrode placement were chosen in order to record brain activity and locate the onset of the first patient's seizures. The electrode initially used to stimulate the cingulum bundle was inserted into the brain in a way that was different than standard, he says. The unique trajectory was necessary because of the first patient's previous surgeries; the approach was from the rear (see illustration), leading to a broader extent of cingulum bundle being sampled and therefore accessible for electrical stimulation.
The JCI paper says that cingulum bundle stimulation "immediately elicited mirthful behavior, including smiling and laughing, and reports of positive emotional experience."
"The patient described the experience as pleasant and relaxing and completely unlike any component of her typical seizure or aura," the authors write. "She reported an involuntary urge to laugh that began at the onset of stimulation and evolved into a pleasant, relaxed feeling over the course of a few seconds of stimulation."
As a test of her mood and thought processes, the researchers tested how the first patient viewed faces and whether she interpreted them as happy, sad or neutral. Cingulum bundle stimulation shifted her view of faces so that they were interpreted as happier. This effect, called "affective bias" is known to correspond with the reduction of depressive symptoms, and suggests a potential use of cingulum stimulation in treating depression.
The two other patients that underwent cingulum stimulation and behavioral testing did not undergo awake surgery for epilepsy treatment. Upon stimulation, they both also smiled and reported mood elevation and pain relief, and at higher levels of current, experienced laughter. During stimulation, one of the later patients took tests of attention, memory and language and performed normally, except for delayed verbal recall on a list-learning task.
The researchers envision cingulum bundle stimulation as potentially applicable to surgery for brain tumors, as well as epilepsy.
"We could be surer of safe boundaries for removal of pathological tissue and preservation of tissue encoding critical human functions such as language, emotional, or sensory functions, which can't be evaluated with the patient sedated," Bijanki says. "In addition, although substantial further study is necessary in this area, the cingulum bundle could become a new target for chronic deep brain stimulation therapies for anxiety, mood, and pain disorders."
The research was supported by the American Foundation for Suicide Prevention (YIG-727 0-015-13), the National Center for Advancing Translational Sciences (UL1TR002378, KL2TR002381), the National Institute of Neurological Disease and Stroke (R21NS104953, K08NS105929, R01NS088748, K02NS070960) and the National Institute of Mental Health (K01MH116364).