Sex Differences in the Human Brain

Equal ≠ The Same: Sex Differences in the Human Brain

FDA ordered Ambien dose reduction by half, but only for women, revealing overdosing for millions of women for 20 years, which raised questions about sex differences in research and medicine.
False assumption: Biological sex matters little in most areas of medicine.
Biomedical research establishment does not treat men and women equally.

Why Sex Didn’t Matter

For a long time, sex influences hardly mattered to the neuroscience mainstream for most aspects of brain function.
Neuroscientists were primarily concerned with brain regions (hypothalamus) regulating sex hormones and sexual behaviors.
They assumed that the sexes shared anything fundamental when it came to brain function and viewed sex differences as not fundamental.
Studying males almost exclusively was thought to allow researchers to understand all that was fundamental in females without hormonal complications.
Neuroscientists overwhelmingly study only male animals to this day.
Studying sex differences in the brain was considered distasteful to academia.
Sex differences research was regarded as “anti-American, crazy thinking”.
Senior colleagues advised against studying sex differences because it would “kill” careers.

Why Sex Matters

Deeply ingrained assumption that sex does not matter is wrong.
Animal research demonstrates sex influences on brain function at all levels, including the molecular level and ion-channel level.
Sex influences are often unanticipated by investigators.
Mammalian brains are filled with sex influences that cannot be explained by human culture.
The human mammalian brain must contain all manner of biologically based sex influences—from small to large—that cannot be explained simply by human culture.
Animal research has refuted the idea that it’s all human culture.
Human research has generated equally impressive findings.

Human Brain Structure

University of Pennsylvania study used diffusion tensor imaging (MRI) to measure brain white matter (axons) in men and women (428 males and 521 females, ages 8 to 22 years).
Women's brains exhibit significantly stronger patterns of interconnectivity across brain regions, including across the hemispheres.
Men's brains exhibit significantly greater average connectivity within local brain regions (modularity).
The brains of men tend to be more asymmetrically organized across the hemispheres than are those of women.
No age-by-sex interactions were found.
These results cannot be explained as simply being due to different cultural experiences between males and females.
Neda Jahanshad and colleagues found greater average interhemispheric connectivity in women compared to men.
Investigators can accurately classify brain connectivity networks based on sex with 93 percent accuracy.
Male and female brains exhibit, on average, differing patterns of structural interconnectivity, in particular between the hemispheres.
It should be mandatory to take gender into account when designing experiments or interpreting results of brain connectivity/network in health and disease.

Human Brain Genetics

David Cribbs and other researchers performed a comprehensive analysis of the patterns of expression in the brain of immune system–related genes in human aging and Alzheimer’s disease (AD).
They found sex-specific patterns of gene expression in both conditions.
The hippocampus was more prone to immune-type gene reactions in females than in males, while the superior frontal gyrus was more susceptible to immune-type gene reactions in males than in females.
The biological mechanisms of brain aging and disease cannot be assumed to be the same in men and women.

The Counter-reaction

Striking growth in sex-differences research has elicited a counter-reaction from some academic quarters, especially among non-neuroscientists.
This counter-reaction is sometimes justified, when scientists object to gross overstatements about sex differences.
Counter-reaction appears to reflect a misunderstanding of some key facts of brain biology.

Arguments Made by “Anti–Sex Difference” Authors

There are few (if any) meaningful behavioral differences between men and women.
Rely on meta-analyses—studies that analyze patterns across many published studies.
These meta-analyses examine the literature for the size of sex differences on isolated factors.
Meta-analyses suggest that only very small differences exist in the behavior of men and women, with a few exceptions.
- It is simply incorrect to conclude that because an average difference between men and women is quantitatively small, that difference will have few meaningful practical consequences.
- Claiming that there are no reliable sex differences on the basis of analyzing isolated functions is problematic.
Marco Del Giudice and his colleagues did a study using a form of statistical analysis called multigroup latent variable modeling, which assessed the size of sex differences by combining numerous isolated factors and found very large sex differences in behavior with as little as a 10 percent overlap between the distributions of men and women.
The idea that there are only minor differences between the personality profiles of males and females should be rejected as based on inadequate methodology.
Bobbi Carothers and Harry Reis analyzed the size of sex differences in a variety of stereotypically gender-driven behaviors.
They report extremely large, bimodal sex differences that say absolutely nothing about the degree to which those taxonic behaviors result from biological or environmental factors.
Male and female stereotypical occupational preferences are strikingly consistent across 53 countries, ranging from Pakistan to Norway, under hugely variable cultural conditions.
A complete, fully-agreed-upon-by-all lack of a sex difference in a particular behavior means absolutely nothing about whether or not sex differences exist in the neural substrates of that behavior.
Sex differences in the mammalian brain often exist to prevent behavioral level sex differences (by compensating for underlying neural or hormonal differences) rather than to create behavioral level sex differences.
Understanding these compensatory sex differences is every bit as important to properly treating brain dysfunction in men and women as is understanding sex differences that induce behavioral differences.
There really aren’t male and female brains; rather, men and women have a single “intersex” brain.
Both males and females are exposed to both masculinizing and feminizing influences.
Both male and female brains are “mosaics” of such influences.
The fallacy: zero evidence supports the view that, through the normal course of development, male and female mammals, including humans, possess brains that have on average the same combination of masculine and feminine traits—that they possess a single unisex mosaic brain.
The unisex view fails to accommodate a host of facts, such as the remarkable hemisphere differences in X inactivation seen only in female brains, the consequences of incomplete X inactivation (again, only in female brains), direct Y-chromosome-linked effects on brain function in males, or dyslexia’s incidence in up to 10 times as many males as females. $(25-28)$
The brain is plastic—that is, molded by experience.
Small sex differences in human brains at birth are increased by culture’s influence on the brain’s plasticity.
It is false to conclude that because a particular behavior starts small in children and grows, that behavior has little or no biological basis.
This argument presupposes that human “cultural” influences are somehow formed independent of the existing biological predispositions of the human brain.
The key fallacy in the plasticity argument: the implication that the brain is perfectly plastic. It is not.
The brain is plastic only within the limits set by biology.
Biological limits to plasticity—and hence the presence of limits to how much experiences can affect the brain.
Udry examines the interaction between two factors—how much a mother encouraged her daughter to behave in “feminine” ways, and how much the daughter had been exposed to masculinizing hormonal influences in the womb—on how “feminine” the daughter behaved when she was older.
The more mothers encouraged “femininity” in their daughters, the more feminine the daughters behaved as adults, but only in those daughters exposed to little masculinizing hormone in utero.
The greater the exposure to masculinizing hormonal effects in utero, the less effective was the mother’s encouragement, to the point where encouragement either did not work at all or even tended toward producing the opposite effect on the daughters’ behavior.
Brains are plastic, but only within the limits set by biology.
It is decidedly not the case that environmental experience can turn anything into anything, and equally easily, in the brain.
The specious plasticity argument invoked by anti–sex difference authors appears to be just a modern incarnation of the long-debunked “blank slate” view of human brain function, the idea that all people’s brains start out as blank slates, thus are equally mold-able to become anything through experience. $(32)$

What Darwin Actually Said

The brains of men and women are a complex mix of similarities and differences, at least if we believed in evolution as Charles Darwin described it.
Evolution proceeded largely through two distinct mechanisms: natural selection and sexual selection.
Natural selection acted on the basis of whether an organism survived; the latter acted on whether it made a baby.
The beneficial effects of sexual selection must at times outweigh the negative effects of natural selection.
Sexual selection is a force that, by definition, often acts male on male or female on female.
It is therefore a force that must produce sex differences of many sorts in brain and mind, as Darwin discussed in great detail.
Evolution produced in men and women bodies and brains that are a complex mix of similarities and differences, small to large—exactly what it appears to have produced.
Evolution also has produced in men and women bodies that are filled with similarities and differences, including in the heart, liver, lungs, immune system, and even knees. $(34)$
To insist that somehow—magically—evolution did not produce biologically based sex influences of all sizes and sorts in the human brain, or that these influences somehow—magically—produce little or no appreciable effect on the brain’s function (behavior) is tantamount to denying that evolution applies to the human brain.

False Assumptions

At the root of the resistance to sex-influences research is a deeply ingrained, implicit, false assumption that if men and women are equal, then men and women must be the same.
Men and women are equal (all human beings are equal), but this does not mean that they are, on average, the same.
$2 + 3 = 10 – 5$ , but these expressions are not the same.
If two groups really are different on average in some respect, but they are being treated the same, then they are not being treated equally on average.
Women and men are not being treated equally, because by and large women are being treated as if they were the same as men.
To make real progress in improving both men’s and women’s health, and to avoid more Ambiens or worse, we need neuroscientist and non-neuroscientist alike to determine whether they too operate on the false assumption that “equal” means “the same.”
True equality for the sexes demands it.