European scientists have historically defaulted to male subjects for research. This was true even for those studying disorders more common in women such as post-traumatic stress disorder and depression.
Limited knowledge about the female brain motivated Rebecca Shansky, a neuroscientist and group leader at Northeastern University in the United States (US), to study both sexes in rat and mouse models to explore how stress and fear change the brain structure and function. She works with male and female animal models to explore stress and fear effects on the brain.
“Male and female brains really are wired differently, a new study suggests“
By excluding female subjects, we rule out half of what’s possible. That’s going to slow down science — Rebecca Shansky, neuroscientist USA
Female brains are organised differently. They have different mechanisms for executing fundamental biological processes. If neuroscientists aim to provide knowledge to be translated into human health, it is necessary to understand that by excluding female subjects, half of what’s possible, is ruled out and that is going to slow down science.
In the study referred to above, research involved imaging the brains of nearly 1,000 adolescent male brains. It found that male brains had more connections within hemispheres, whereas female brains were more connected between hemispheres. The results, which apply to the population as a whole and not individuals, suggest that male brains may be optimised for motor skills, and female brains for combining analytical and intuitive thinking.
“On average, men connect front to back [parts of the brain] more strongly than women,” whereas “women have stronger connections left to right,” said study leader Ragini Verma, an associate professor of radiology at the University of Pennsylvania medical school. But, Verma cautioned against making sweeping generalisations about men and women based on the results.
Previous studies found behavioural differences between men and women. For example, women may have better verbal memory and social cognition whereas men, on average, may have better motor and spatial skills. Brain imaging showed that women have a higher percentage of gray matter, the computational tissue of the brain, while men have a higher percentage of white matter, the connective cables of the brain. However, few studies have shown that men’s and women’s brains are connected differently.
In the study, researchers scanned the brains of 949 young people ages 8 to 22 (428 males and 521 females), using a form of magnetic resonance imaging (MRI) known as diffusion tensor imaging, which maps the diffusion of water molecules within brain tissue. The researchers analysed participants as a single group and as three separate groups split up by age.
As a whole, the young men had stronger connections within cerebral hemispheres while the young women had stronger connections between hemispheres. The study was published in the journal Proceedings of the National Academy of Sciences. However, the cerebellum, a brain section below the cerebrum, plays a role in coordinating muscle movement. It showed the opposite pattern, with males having stronger connections between hemispheres.
Roughly speaking, the back of the brain handles perception and the front handles action. The left hemisphere of the brain is the seat of logical thinking while the right side is responsible with intuitive thinking. These findings support views that males may excel at motor skills, while women may be better at integrating analysis and intuitive thinking.
“It is fascinating that we can see some of functional differences in men and women structurally,” Verma told LiveScience. However, the results do not apply to individual men and women, she said. “Every individual could have part of both men and women in them,” she said, referring to the connectivity patterns her team observed.
When researchers compared young people by age group, they saw the most pronounced brain differences among adolescents (13.4 to 17 years old), suggesting the sexes begin to diverge in the teen years. Males and females showed the greatest differences in inter-hemisphere brain connectivity during this time, with females having more connections between hemispheres primarily in the frontal lobe. These differences got smaller with age with older females showing more widely distributed connections throughout the brain rather than just in the frontal lobe.
Currently, scientists cannot quantify how much an individual has male- or female-like patterns of brain connectivity. Another lingering question is whether the structural differences result in differences in brain function or whether differences in function result in structural changes. These findings could however assist scientists to understand why certain diseases, such as autism, are more prevalent in males.
Scientific challenges in studying both sexes
Some behaviour tests do not work as well in female animals and better investigational metrics are needed. There is also a trend in academic publishing favouring studies with sophisticated techniques only in male models over more careful, but less flashy work, using both sexes, making it difficult for researchers to take sex as a biological variable (SABV) seriously. This needs to change for the goals of the US NIH’s SABV policy and the goals of scientists to better align.
Women now account for roughly half of all participants in US NIH-supported clinical research. However, more often than not, basic and pre-clinical biomedical research focused on male animals and cells. An over-reliance on male models may obscure understanding of key sex influences on health processes and outcomes.
Accounting for sex as a biological variable begins with the development of research questions and study design. It also includes data collection and analysis of results and reporting of findings. Consideration of sex may be critical to the interpretation, validation and generalisability of research findings. Adequate consideration of both sexes in experiments and disaggregation of data by sex allows for sex-based comparisons and may inform clinical interventions. Appropriate analysis and transparent reporting of data by sex may therefore enhance the rigour and applicability of pre-clinical biomedical research.
The NIH now expects that sex as a biological variable will be factored into research designs, analyses and reporting in vertebrate animal and human studies. Strong justification from scientific literature, preliminary data or other relevant considerations must be provided for applications proposing to study only one sex.
In June 2020, the Journal of Women’s Health published “Sex as a Biological Variable: A 5-Year Progress Report and Call to Action,” an article commenting on the development and implementation of the US NIH’s SABV policy, which went into effect in January 2016.
What cannot be denied is the fact that ruling out 50% of humanity’s abilities because of biological sex, would not only be extremely foolish, but deny the world of the optimum benefits of applying the skills of all members of society. Men need women and vice versa to make sense of the world we live in and to create a future with equal opportunities to benefit all.
