Brain structure, function, and behavior show independent patterns of sex differences

Men and women show distinct biological differences in how their brains activate during various tasks, the physical size of specific brain regions, and their behavioral traits. A new study published in Nature Communications reveals that while each of these factors can accurately predict a person’s sex, an individual’s degree of sex typicality in one domain is entirely unrelated to the others. These results suggest that sex differences in the human brain are highly context-dependent and operate independently across structure, function, and behavior.

Biological sex differences appear in the prevalence of various neuropsychiatric conditions, such as autism and mood disorders. They also manifest in specific aspects of cognition and physical behavior. Past neuroimaging research has attempted to map out how male and female brains differ in their physical structure and functional activity.

Functional magnetic resonance imaging, or fMRI, allows researchers to observe which brain regions activate when a person performs specific mental tasks. Structural MRI measures the physical volume and shape of brain tissue. Many previous fMRI studies on sex differences have relied on small numbers of participants completing single tasks. This reliance on limited data has led to intense debate about the true extent and relevance of sex differences in human brain function.

To address this gap, researchers Siyuan Liu and Armin Raznahan at the National Institute of Mental Health led a comprehensive analysis of brain activity, anatomy, and behavior. The research team aimed to determine if sex differences in brain function are tied to specific tasks, if they align with physical brain volume, and how they relate to behavior.

The researchers analyzed data from nearly 1,000 healthy young adults. The participants underwent fMRI scans while completing seven different tasks. These tasks were designed to measure emotion processing, gambling, relational reasoning, social cognition, language processing, working memory, and motor skills. By scanning participants during this wide array of activities, the team could observe both task-specific brain activation and general activation patterns.

The analysis revealed widespread sex differences in brain activation across 85 percent of the outer layer of the brain, known as the cerebral cortex. These differences were highly reproducible but mostly specific to individual tasks. For instance, certain brain regions showed more activation in females during a language task but more activation in males during a gambling task.

A small number of regions, particularly those involved in motor control and physical sensation, showed a general tendency for higher activation in females across all seven tasks. Across the board, the effect sizes for these functional differences were small to moderate.

Next, the researchers examined whether these functional differences matched up with anatomical differences. They used structural MRI scans from the same participants to measure the volume of gray matter, which is the tissue containing the main bodies of nerve cells. The team found reproducible sex differences in gray matter volume across various regions of the cerebral cortex.

They then mapped the areas with functional activation differences over the areas with physical volume differences. The spatial patterns did not overlap in a coordinated way. Brain regions that exhibited sex differences in volume were generally not the same regions that showed sex differences in task activation. This lack of alignment suggests that sex differences in brain structure and brain function represent distinct biological phenomena.

The team then incorporated behavioral data, analyzing participant scores across 86 different behavioral traits. These traits ranged from physical grip strength and visual judgment to tendencies toward anxiety and psychological distress. Using a machine learning framework, the researchers tested whether an individual’s combined profile of brain activity, brain volume, or behavior could predict their biological sex.

The machine learning models accurately predicted a participant’s sex based on any of the three categories alone. Task-specific brain activation predicted sex with 88 percent accuracy, regional brain volume with 86 percent accuracy, and behavior with 91 percent accuracy. The models also generated a sex typicality score for each person within each category, rating how closely their data matched the average male or female profile.

Despite the high predictive accuracy of all three categories, a participant’s sex typicality score in one domain did not correlate with their score in another. An individual might have a highly male-typical brain volume, but a strongly female-typical pattern of brain activation during a language task. Only a tiny fraction of individuals exhibited consistently male-typical or female-typical profiles across all measurements of brain and behavior.

In their final analysis, the researchers looked for interactions between sex, brain activation, and behavior. They conducted a brain-wide association study to see if variations in brain activation between individuals correlated with variations in behavior. They first confirmed that measurable links exist between task-induced brain activation and specific behavioral traits within each sex group.

When the team compared these brain-behavior associations between men and women, they found striking similarities. The overall topography of how brain activity relates to behavior is broadly consistent across both sexes. The researchers detected a few isolated instances where the relationship between brain activity and behavior diverged between males and females. However, these rare differences did not preferentially involve behaviors that were themselves heavily sex-biased.

The study relies on observational data, meaning it can only identify associations rather than establish direct biological causes. Finding a sex difference in brain activation or structure does not mean that sex directly dictates how the brain operates, nor does it guarantee that the physical difference has a functional consequence. The research is focused exclusively on the biological construct of sex based on self-identification as male or female, rather than the psychosocial concept of gender.

The findings are also limited to specific types of neuroimaging. Functional MRI during tasks and structural gray matter measurements capture only a portion of the brain’s complex organization. Other techniques, such as resting-state fMRI or imaging that tracks the brain’s white matter connections, could reveal different patterns of sex-based variation. Future research will need to explore how these independent traits develop over a person’s lifespan and whether they fluctuate during different stages of brain development and aging.

The study, “Robust but independent sex differences in human brain function, structure, and behavior,” was authored by Siyuan Liu, Bridget W. Mahony, Ethan T. Whitman, Stephen J. Gotts, Dustin Moraczewski, Adam Thomas, Alex Martin, and Armin Raznahan.