Study identifies distinct brain organization patterns in women and men

A new study by Stanford Medicine investigators unveils a new artificial intelligence model that was more than 90% successful at determining whether scans of brain activity came from a woman or a man.

The findings, to be published Feb. 19 in the Proceedings of the National Academy of Sciences, help resolve a long-term controversy about whether reliable sex differences exist in the human brain and suggest that understanding these differences may be critical to addressing neuropsychiatric conditions that affect women and men differently.

"A key motivation for this study is that sex plays a crucial role in human brain development, in aging, and in the manifestation of psychiatric and neurological disorders," said Vinod Menon, PhD, professor of psychiatry and behavioral sciences and director of the Stanford Cognitive and Systems Neuroscience Laboratory. "Identifying consistent and replicable sex differences in the healthy adult brain is a critical step toward a deeper understanding of sex-specific vulnerabilities in psychiatric and neurological disorders."

Menon is the study's senior author. The lead authors are senior research scientist Srikanth Ryali, PhD, and academic staff researcher Yuan Zhang, PhD.

"Hotspots" that most helped the model distinguish male brains from female ones include the default mode network, a brain system that helps us process self-referential information, and the striatum and limbic network, which are involved in learning and how we respond to rewards.

The investigators noted that this work does notweigh in on whether sex-related differences arise early in life or may be driven by hormonal differences or the different societal circumstances that men and women may be more likely to encounter.

Uncovering brain differences

The extent to which a person's sex affects how their brain is organized and operates has long been a point of dispute among scientists. While we know the sex chromosomes we are born with help determine the cocktail of hormones our brains are exposed to -- particularly during early development, puberty and aging -- researchers have long struggled to connect sex to concrete differences in the human brain. Brain structures tend to look much the same in men and women, and previous research examining how brain regions work together has also largely failed to turn up consistent brain indicators of sex.

In their current study, Menon and his team took advantage of recent advances in artificial intelligence, as well as access to multiple large datasets, to pursue a more powerful analysis than has previously been employed. First, they created a deep neural network model, which learns to classify brain imaging data: As the researchers showed brain scans to the model and told it that it was looking at a male or female brain, the model started to "notice" what subtle patterns could help it tell the difference.

This model demonstrated superior performance compared with those in previous studies, in part because it used a deep neural network that analyzes dynamic MRI scans. This approach captures the intricate interplay among different brain regions. When the researchers tested the model on around 1,500 brain scans, it could almost always tell if the scan came from a woman or a man.

The model's success suggests that detectable sex differences do exist in the brain but just haven't been picked up reliably before. The fact that it worked so well in different datasets, including brain scans from multiple sites in the U.S. and Europe, make the findings especially convincing as it controls for many confounds that can plague studies of this kind.

"This is a very strong piece of evidence that sex is a robust determinant of human brain organization," Menon said.

Making predictions

Until recently, a model like the one Menon's team employed would help researchers sort brains into different groups but wouldn't provide information about how the sorting happened. Today, however, researchers have access to a tool called "explainable AI," which can sift through vast amounts of data to explain how a model's decisions are made.

Using explainable AI, Menon and his team identified the brain networks that were most important to the model's judgment of whether a brain scan came from a man or a woman. They found the model was most often looking to the default mode network, striatum, and the limbic network to make the call.

The team then wondered if they could create another model that could predict how well participants would do on certain cognitive tasks based on functional brain features that differ between women and men. They developed sex-specific models of cognitive abilities: One model effectively predicted cognitive performance in men but not women, and another in women but not men. The findings indicate that functional brain characteristics varying between sexes have significant behavioral implications.

"These models worked really well because we successfully separated brain patterns between sexes," Menon said. "That tells me that overlooking sex differences in brain organization could lead us to miss key factors underlying neuropsychiatric disorders."

While the team applied their deep neural network model to questions about sex differences, Menon says the model can be applied to answer questions regarding how just about any aspect of brain connectivity might relate to any kind of cognitive ability or behavior. He and his team plan to make their model publicly available for any researcher to use.

"Our AI models have very broad applicability," Menon said. "A researcher could use our models to look for brain differences linked to learning impairments or social functioning differences, for instance -- aspects we are keen to understand better to aid individuals in adapting to and surmounting these challenges."

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Research highlights gender bias persistence over centuries

New research from Washington University in St. Louis provides evidence that modern gender norms and biases in Europe have deep historical roots dating back to the Middle Ages and beyond, suggesting that DNA is not the only thing we inherit from our ancestors.

The findings -- published on March 13, 2023 in the Proceedings of the National Academy of Sciences (PNAS) -- highlight why gender norms have remained stubbornly persistent in many parts of the world despite significant strides made by the international women's rights movement over the last 100-150 years.

Using dental records of more than 10,000 people from 139 archaeological sites throughout Europe, researchers found that individuals who live in areas that historically favored men over women display more pro-male bias today than those who live in places where gender relations were more egalitarian centuries ago -- evidence that gender attitudes are "transmitted" or handed down from generation to generation.

These biases outlasted monumental socioeconomic and political changes such as industrialization and world wars. Researchers found one exception to the rule, however: In regions that experienced abrupt, large-scale population replacement -- such as a pandemic or natural disaster -- transmission of these values was interrupted.

"The median age of the skeletons in this study is about 1,000 years dating back to the medieval era. It is therefore remarkable that the patterns of gender bias that existed during those times and earlier are still replicated in contemporary attitudes," said Margit Tavits, the Dr. William Taussig Professor in Arts & Sciences at WashU.

"Given the enormous social, economic and political changes that have taken place in Europe during this time, our findings speak to the power of cultural transmission of gender norms."

The incredible stability of these norms over hundreds, if not thousands, of years also explains why it has been difficult in some regions to move the needle toward gender equality.

"There has been a widespread belief that gender norms are a byproduct of structural and institutional factors like religion and agricultural practices. Our findings draw attention to the fact that gender-equal norms passed down from one generation to the next can persist even if institutions or structures incentivize inequality, and vice versa," Tavits said.

"For those working to foster gender equality, the message from our research is that rules and policies are not going to be enough to undermine deeply rooted sexist beliefs and sustain equal ones. We must also address the cultural forces channeling these beliefs."

Taylor Damann and Jeremy Siow -- doctoral students in the Department of Political Science at WashU -- conducted research and co-authored the paper with Tavits.

About the research

Previous archaeological research has used linear enamel hypoplasias -- permanent lesions on the teeth caused by trauma, malnutrition or disease -- to analyze prehistoric gender equality. Because the lesions form exclusively in cases of sustained bodily stress, their presence or absence can tell researchers a great deal about the person's health and living conditions. Further, differences between male and female teeth at the same location are an indication of which sex received preferential treatment in terms of health care and dietary resources at the time.

According to Tavits, studying gender norms in Europe is advantageous given the relative similarity of various institutional and environmental conditions across the region. This allowed researchers to control for factors that could affect modern gender attitudes, such as religion and political institutions.

Because differences in gender attitudes are fairly small across the continent, compared with the rest of the world, this setting also set a higher bar for detecting significant associations between historical and contemporary attitudes. Yet, time and time again, researchers found evidence of this association. For example, individuals living in an area that was historically egalitarian were 20% more likely to have pro-female attitudes than people living in areas that were historically the most pro-male.

Additional tests showed that historical gender bias failed to predict modern gender attitudes for immigrant populations. Researchers also found no evidence of historical gender bias impacting contemporary attitudes in areas hardest hit by the bubonic plague of the 14th century. Finally, they looked to the United States, where the arrival of European settlers in the 16th century led to large-scale displacement of Native Americans. Once again, they found no association between historical and current gender norms.

"Together, these findings provide further support for the idea that historical biases persist because they are passed down from one generation to the next and occur only when the transmission across generations is not interrupted. We were surprised that such a clear relationship emerged," Tavits said.

A tale of two cities

In the paper, Tavits, Damann and Siow highlight two archaeological sites to illustrate how the contrasting historical treatment of women relative to men is reflected in current gender attitudes.

At the first site in Istria, a small urban Greek settlement on the Black Sea in the modern Dobruja region of Romania, researchers found evidence of a pro-male bias in historical dental records dating back to around 550 A.D. Out of the 49 skeletons for whom sex and dental information could be extracted, 58% of females show signs of malnutrition and trauma in their teeth, while only 25% of males do.

According to the authors, the status of men and women in society today has remained relatively unequal in the southeastern region of Romania, based on modern indicators of gender equality. For example, they note, only 52.5% of women participate in the labor market compared with 78% of men, and only 18% of the representatives in the modern municipal council are women.

The population's beliefs about gender norms are similarly unequal, they write. More than half of the residents believe that men have more of a right to jobs than women and there is near consensus (89%) that a woman must have children to be fulfilled.

Contrast this with Plinkaigalis, a rural community in modern-day western Lithuania made up of a population of Balts. Unlike Istria, Plinkaigalis favored women's health. Of the 157 skeletons at this site -- also dating back to 550 A.D. -- 56% of males show dental signals of trauma and malnutrition whereas only 46% of females do. Separate studies have also found evidence that gender norms here were favorable to women.

In the modern era, this location, now called Ke ?dainiai, remains relatively gender equal. Employment levels in western Lithuanian do not vary strongly by gender: 76% men vs. 72.7% women. And women are nearly proportionally represented in local politics (48%). Likewise, less than a quarter of residents of the modern location believe men have more of a right to a job than women, and 56% believe women need children to be fulfilled.

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Study reveals average age at conception for men versus women over past 250,000 years

The length of a specific generation can tell us a lot about the biology and social organization of humans. Now, researchers at Indiana University can determine the average age that women and men had children throughout human evolutionary history with a new method they developed using DNA mutations.

The researchers said this work can help us understand the environmental challenges experienced by our ancestors and may also help us in predicting the effects of future environmental change on human societies.

"Through our research on modern humans, we noticed that we could predict the age at which people had children from the types of DNA mutations they left to their children," said study co-author Matthew Hahn, Distinguished Professor of biology in the College of Arts and Sciences and of computer science in the Luddy School of Informatics, Computing and Engineering at IU Bloomington. "We then applied this model to our human ancestors to determine what age our ancestors procreated."

According to the study, published today in Science Advances and co-authored by IU post-doctoral researcher Richard Wang, the average age that humans had children throughout the past 250,000 years is 26.9. Furthermore, fathers were consistently older, at 30.7 years on average, than mothers, at 23.2 years on average, but the age gap has shrunk in the past 5,000 years, with the study's most recent estimates of maternal age averaging 26.4 years. The shrinking gap seems to largely be due to mothers having children at older ages.

Other than the recent uptick in maternal age at childbirth, the researchers found that parental age has not increased steadily from the past and may have dipped around 10,000 years ago because of population growth coinciding with the rise of civilization.

"These mutations from the past accumulate with every generation and exist in humans today," Wang said. "We can now identify these mutations, see how they differ between male and female parents, and how they change as a function of parental age."

Children's DNA inherited from their parents contains roughly 25 to 75 new mutations, which allows scientists to compare the parents and offspring, and then to classify the kind of mutation that occurred. When looking at mutations in thousands of children, IU researchers noticed a pattern: The kinds of mutations that children get depend on the ages of the mother and the father.

Previous genetic approaches to determining historical generation times relied on the compounding effects of either recombination or mutation of modern human DNA sequence divergence from ancient samples. But the results were averaged across both males and females and across the past 40,000 to 45,000 years.

Hahn, Wang and their co-authors built a model that uses de novo mutations -- a genetic alteration that is present for the first time in one family member as a result of a variant or mutation in a germ cell of one of the parents or that arises in the fertilized egg during early embryogenesis -- to separately estimate the male and female generation times at many different points throughout the past 250,000 years.

The researchers were not originally seeking to understand the relationship of gender and age at conception over time; they were conducting a broader investigation about the number of mutations passed from parents to children. They only noticed the age-based mutation patterns while seeking to understand differences and similarities between these pattens in humans versus other mammals, such as cats, bears and macaques.

"The story of human history is pieced together from a diverse set of sources: written records, archaeological findings, fossils, etc.," Wang said. "Our genomes, the DNA found in every one of our cells, offer a kind of manuscript of human evolutionary history. The findings from our genetic analysis confirm some things we knew from other sources (such as the recent rise in parental age), but also offer a richer understanding of the demography of ancient humans. These findings contribute to a better understanding of our shared history."

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Men may not 'perceive' domestic tasks as needing doing in the same way as women, philosophers argue

Philosophers seeking to answer questions around inequality in household labour and the invisibility of women's work in the home have proposed a new theory -- that men and women are trained by society to see different possibilities for action in the same domestic environment.

They say a view called "affordance theory" -- that we experience objects and situations as having actions implicitly attached -- underwrites the age-old gender disparity when it comes to the myriad mundane tasks of daily home maintenance.

For example, women may look at a surface and see an implied action -- 'to be wiped' -- whereas men may just observe a crumb-covered countertop.

The philosophers believe these deep-seated gender divides in domestic perception can be altered through societal interventions such as extended paternal leave, which will encourage men to build up mental associations for household tasks.

Writing in the journal Philosophy and Phenomenological Research, they argue that available data -- particularly data gathered during the pandemic -- suggest two questions require explanation.

One is "disparity": despite economic and cultural gains, why do women continue to shoulder the vast majority of housework and childcare? The other is "invisibility": why do so many men believe domestic work to be more equally distributed than in fact it is?

"Many point to the performance of traditional gender roles, along with various economic factors such as women taking flexible work for childcare reasons," said Dr Tom McClelland, from Cambridge University's Department of History and Philosophy of Science.

"Yet the fact that stark inequalities in domestic tasks persisted during the pandemic, when most couples were trapped inside, and that many men continued to be oblivious of this imbalance, means this is not the full story."

McClelland and co-author Prof Paulina Sliwa argue that unequal divisions of labour in the home -- and the inability of men to identify said labour -- is best explained through the psychological notion of "affordances": the idea that we perceive things as inviting or "affording" particular actions.

"This is not just looking at the shape and size of a tree and then surmising you can climb it, but actually seeing a particular tree as climbable, or seeing a cup as drink-from-able," said Sliwa, recently of Cambridge's philosophy faculty and now at the University of Vienna.

"Neuroscience has shown that perceiving an affordance can trigger neural processes preparing you for physical action. This can range from a slight urge to overwhelming compulsion, but it often takes mental effort not to act on an affordance."

There are dramatic differences in "affordance perception" between individuals. One person sees a tree as climbable where another does not. Objects offer a vast array of affordances -- one could see a spatula as an egg-frying tool or a rhythmic instrument -- and a spectrum of sensitivity towards them.

"If we apply affordance perception to the domestic environment and assume it is gendered, it goes a long way to answering both questions of disparity and invisibility," said McClelland.

According to the philosophers, when a woman enters a kitchen she is more likely to perceive the "affordances" for particular domestic tasks -- she sees the dishes as 'to be washed' or a fridge as 'to be stocked'.

A man may simply observe dishes in a sink, or a half-empty fridge, but without perceiving the affordance or experiencing the corresponding mental "tug." Over time, these little differences add up to significant disparities in who does what.

"Affordances pull on your attention," said Sliwa. "Tasks may irritate the perceiver until done, or distract them from other plans. If resisted, it can create a felt tension."

"This puts women in a catch-22 situation: either inequality of labour or inequality of cognitive load."

This gender-based split in affordance perception could have a number of root causes, say philosophers. Social cues encourage actions in certain environments, often given by adults when we are very young children. Our visual systems update based on what we encounter most frequently.

"Social norms shape the affordances we perceive, so it would be surprising if gender norms do not do the same," said McClelland.

"Some skills are explicitly gendered, such cleaning or grooming, and girls are expected to do more domestic chores than boys. This trains their ways of seeing the domestic environment, to see a counter as 'to be wiped'."

The "gendered affordance perception hypothesis" is not about absolving men say Sliwa and McClelland. Despite a deficit in affordance perception in the home, a man can easily notice what needs doing by thinking rather than seeing. Nor should sensitivity to domestic affordances in women be equated with natural affinity for housework.

"We can change how we perceive the world through continued conscious effort and habit cultivation," said McClelland. "Men should be encouraged to resist gendered norms by improving their sensitivity to domestic task affordances.

"A man might adopt a resolution to sweep for crumbs every time he waits for the kettle to boil, for example. Not only would this help them to do the tasks they don't see, it would gradually retrain their perception so they start to see the affordance in the future."

Collective efforts to change social norms require policy-level interventions, argue the philosophers. For example, shared parental leave gives fathers the opportunity to become more sensitive to caring-task affordances.

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Do benefits of physical, mental activity on thinking differ for men and women?

Studies have shown that physical and mental activity help preserve thinking skills and delay dementia. A new study suggests that these benefits may vary for men and women. The study is published in the July 20, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology.

The study looked at the effects of physical and mental activities, such as reading, going to classes, or playing cards or games, on cognitive reserve in the areas of thinking speed and memory. Cognitive reserve is the buffer that occurs when people have strong thinking skills even when their brains show signs of the underlying changes associated with cognitive impairment and dementia.

"We found that greater physical activity was associated with greater thinking speed reserve in women, but not in men," said study author Judy Pa, PhD, of the University of California, San Diego. "Taking part in more mental activities was associated with greater thinking speed reserve for both men and women."

Greater physical activity was not associated with memory reserve in men or women.

The study involved 758 people with an average age of 76. Some had no thinking or memory problems, some had mild cognitive impairment, and some had dementia. The participants had brain scans and took thinking speed and memory tests. To calculate cognitive reserve, people's thinking tests scores were compared against the changes in the brain associated with dementia, such as the total volume of the hippocampus, a key brain region impacted by Alzheimer's disease.

People were also asked about their usual weekly physical activity. For mental activity, they were asked whether they participated in three types of activities in the past 13 months: reading magazines, newspapers or books; going to classes; and playing cards, games or bingo. They were given one point for each type of activity, for a maximum of three points.

For mental activity, participants averaged 1.4 points. For physical activity, participants took part in an average of at least 15 minutes per week of activities that elevate heart rates such as brisk walking and biking.

Pa said that each additional mental activity people participated in corresponded to 13 fewer years of aging in their processing speed in their thinking skills -- 17 years among men and 10 years among women.

"As we have arguably few-to-no effective treatments for Alzheimer's disease, prevention is crucial. An ounce of prevention is worth a pound of treatment," Pa said. "To know that people could potentially improve their cognitive reserve by taking simple steps such as going to classes at the community center, playing bingo with their friends or spending more time walking or gardening is very exciting."

Pa said that based on the effect sizes seen in the study, a doubling of the amount of physical activity would be equivalent to an estimated 2.75 fewer years of aging when it comes to women's processing speed in their thinking skills.

Researchers also looked at whether the relationship between physical and mental activities and cognitive reserve was affected by the gene that carries the strongest risk for Alzheimer's, called APOE e4. They found that for women, having the gene lessens the effects of the beneficial relationship between physical and mental activities and cognitive reserve.

The study does not prove that physical and mental activities help improve cognitive reserve. It only shows an association.

A limitation of the study was that people reported their own physical and mental activity, so they may not have remembered correctly. Also, structural and societal factors that affect cognitive reserve, such as education, were not measured in the study.

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Loss of male sex chromosome leads to earlier death for men

The loss of the male sex chromosome as many men age causes the heart muscle to scar and can lead to deadly heart failure, new research from the University of Virginia School of Medicine shows. The finding may help explain why men die, on average, several years younger than women.

UVA researcher Kenneth Walsh, PhD, says the new discovery suggests that men who suffer Y chromosome loss -- estimated to include 40% of 70-year-olds -- may particularly benefit from an existing drug that targets dangerous tissue scarring. The drug, he suspects, may help counteract the harmful effects of the chromosome loss -- effects that may manifest not just in the heart but in other parts of the body as well.

On average, women live five years longer than men in the United States. The new finding, Walsh estimates, may explain nearly four of the five-year difference.

"Particularly past age 60, men die more rapidly than women. It's as if they biologically age more quickly," said Walsh, the director of UVA's Hematovascular Biology Center. "There are more than 160 million males in the United States alone. The years of life lost due to the survival disadvantage of maleness is staggering. This new research provides clues as to why men have shorter lifespans than women."

Chromosome Loss and Heart Health

While women have two X chromosomes, men have an X and a Y. But many men begin to lose their Y chromosome in a fraction of their cells as they age. This appears to be particularly true for smokers. The loss occurs predominantly in cells that undergo rapid turnover, such as blood cells. (Loss of the Y chromosome does not occur in male reproductive cells, so it is not inherited by the children of men who exhibit Y chromosome loss.) Scientists previously observed that men who suffer Y chromosome loss are more likely to die at a younger age and suffer age-associated maladies such as Alzheimer's disease. Walsh's new research, however, is believed to be the first hard evidence that the chromosome loss directly causes harmful effects on men's health.

Walsh, of UVA's Division of Cardiovascular Medicine and the Robert M. Berne Cardiovascular Research Center, and his team used cutting-edge CRISPR gene-editing technology to develop a special mouse model to better understand the effects of Y chromosome loss in the blood. They found that the loss accelerated age-related diseases, made the mice more prone to heart scarring and led to earlier death. This wasn't the result of just inflammation, the scientists determined. Instead, the mice suffered a complex series of responses in the immune system, leading to a process referred to as fibrosis throughout the body. This tug-of-war within the immune system, the researchers believe, may accelerate disease development.

The scientists also looked at the effects of Y chromosome loss in human men. They conducted three analyses of data compiled from the UK Biobank, a massive biomedical database, and found that Y chromosome loss was associated with cardiovascular disease and heart failure. As chromosome loss increased, the scientists found, so did the risk of death.

Potential Treatment

The findings suggest that targeting the effects of Y chromosome loss could help men live longer, healthier lives. Walsh notes that one potential treatment option might be a drug, pirfenidone, that has already been approved by the federal Food and Drug Administration for the treatment of idiopathic pulmonary fibrosis, a form of lung scarring. The drug is also being tested for the treatment of heart failure and chronic kidney disease, two conditions for which tissue scarring is a hallmark. Based on his research, Walsh believes that men with Y chromosome loss could respond particularly well to this drug, and other classes of antifibrotic drugs that are being developed, though more research will be needed to determine that.

At the moment, doctors have no easy way to determine which men suffer Y chromosome loss. Walsh's collaborator Lars A. Forsberg, of Uppsala University in Sweden, has developed an inexpensive polymerase chain reaction (PCR) test, like those used for COVID-19 testing, that can detect Y chromosome loss, but the test is largely confined to his and Walsh's labs. Walsh, however, can foresee that changing: "If interest in this continues and it's shown to have utility in terms of being prognostic for men's disease and can lead to personalized therapy, maybe this becomes a routine diagnostic test," he said.

"The DNA of all our cells inevitably accumulate mutations as we age. This includes the loss of the entire Y chromosome within a subset of cells within men. Understanding that the body is a mosaic of acquired mutations provides clues about age-related diseases and the aging process itself," said Walsh, a member of UVA's Department of Biochemistry and Molecular Genetics. "Studies that examine Y chromosome loss and other acquired mutations have great promise for the development of personalized medicines that are tailored to these specific mutations."

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