This article was first published on The Wire Science.
In early 2013, the US Food and Drug Administration (FDA) recommended that doctors lower the dose of a sedative called zolpidem for women. According to studies, the drug metabolised differently in women, leading to higher concentrations remaining in their bodies for more time.
For University of California neurobiologist Larry Cahill, the decision was a “case in point” about how crucial studying sex differences in the brain was, and is.
When Cahill began studying this topic two decades ago, he claims to have been advised by his senior colleagues to not tread on that path. “It would ‘kill’ my career,” he recalled in 2014.
He carried on anyway. In 2017, he edited an issue of the Journal of Neuroscience Research that was the first dedicated entirely to the study of sex differences in the brain. Together with 70 papers from different research groups, he called the issue’s publication a “zeitgeist shift”.
“So overpowering is the wave of research that the standard ways of dismissing sex influences … have all been swept away, at least for those cognizant of the research,” Cahill wrote.
When his colleagues warned him, they were probably erring on the side of caution.
A troubled history
In 1854, the German anatomist Emil Huschke proposed that there were structural differences between male and female brains. He contended that the frontal lobe in particular is larger in males than in females.
His idea soon gave way to remarks on women’s intelligence. Paul Broca, famous for identifying a region of the brain important for speech, also found a difference in the size of male and female brains in autopsies he performed in four hospitals in Paris. When another anatomist wondered if the comparatively smaller brains in women could be related to the fact that women have, on the whole, slightly smaller bodies than men, Broca disagreed:
“… women are, on the average, a little less intelligent than men, a difference which we should not exaggerate but which is, none the less, real. We are therefore permitted to suppose that the relatively small size of the female brain depends in part upon her physical inferiority and in part upon her intellectual inferiority.”
Women’s supposed intellectual inferiority was then supplemented with the 19th century’s most radical scientific idea: Charles Darwin’s theory of evolution. When Broca measured the cranial capacity – an indirect indicator of brain size – in prehistoric skulls from the l’Homme Mort cave in 1873, he found that the difference between prehistoric male and female skulls was far lower than that in the modern population.
Paul Topinard, Broca’s protege, used Darwin’s theory to draft an explanation: men fought in the “struggle for existence” and constantly worried about the “cares of tomorrow”. So, Topinard concluded, men needed “more brain than the women [they] must protect and nourish.”
To Topinard, women were “sedentary”, obligated to the role of raising children, to love and to “be passive”. Their brains, therefore, had to mirror this Victorian myth.
In a 1966 article in Scientific American, Seymour Levine, a neuroscientist who studied early brain development, wrote that “there is increasing evidence that mammalian behaviour patterns are basically female and that male patterns are induced by the action of the sex hormone testosterone on the brain of the newborn animal.”
He cited several studies in which researchers introduced testosterone in female mice right after birth, either by transplanting testes or by injecting testosterone, which is a hormone produced by the testes.
One of them reported that female mice treated with testosterone at birth were much less responsive to “male sexual advances” compared to their sisters who hadn’t received the hormone. This behaviour, Levine claimed, couldn’t be altered even if the “testosteronised” females were injected with large doses of “female hormones” at maturity.
According to Levine, the brain had been irreversibly changed by the action of testosterone.
Conversely, when newborn male rats had their testes surgically removed, injecting small doses of oestrogen and progesterone (a.k.a. “female hormones”, in Levine’s words) could elicit “sexual behaviour precisely like that of normal females”.
In a 2006 review, Cahill wrote that Levine’s article spearheaded the widespread belief that sex differences in the brain translated “exclusively to sex behaviours, sex hormones and the hypothalamus” (a part of the brain involved in regulating sex hormones and sexual behaviours).
By then, he continued, researchers had used new neuroscience tools – including functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) – to identify surprising sex differences “on many areas of brain and behaviour, including emotion, memory, vision, hearing, processing faces, pain perception, navigation, neurotransmitter levels, stress hormone action of the brain and disease states”.
For Cahill, then, human brains were sexually dimorphic – i.e. possessing two different forms depending on the individual’s sex. “Sex differences have been found in every brain lobe,” he added.
In stark contrast, the title of Lise Eliot and her team’s paper, published in 2021, went: ‘Dump the ‘Dimorphism’: Comprehensive synthesis of human brain studies reveals few male-female differences beyond size’. Eliot is a neuroscientist at the Rosalind Franklin University of Medicine and Science and the study’s lead author.
1/🧵 Tweetorial on our new paper, “Dump the Dimorphism: Comprehensive synthesis of brain studies finds few male-female differences beyond size.” (https://t.co/3H2r732GtX). It's big (43K words, 616 refs) so I'll cut to the chase.
— Lise Eliot (@Lise_Eliot) March 20, 2021
In their paper, Eliot’s team examined three decades’ worth of neuroimaging studies and their meta-analyses. They concluded that other than size, sex differences in the brain were “trivial and population-specific”.
That is, to them, the human brain wasn’t sexually dimorphic.
According to their paper, “Most claims of ‘sexual dimorphism’ have not been reliably replicated.” They singled out two parts – the putamen and the amygdala – as being found to be consistently larger in men, but only by a “mere 1-3%” by volume.
The paper also refuted another claim, that the male brain displays more asymmetric functioning (‘lateralisation’, in neuroscience-speak) than the brains of women. Proponents of the theory, like psychologist Jeanette McGlone, have argued that the brain’s left hemisphere is more specialised to language-related tasks while the right is more concerned with “perception, construction and recall of stimuli that are difficult to [express in words]”, to quote from a 2010 article.
“There is an impressive accumulation of evidence suggesting that the male brain may be more asymmetrically organised in the female brain, both for verbal and nonverbal function,” McGlone added.
But when Eliot and her team considered several studies of differential lateralisation of the brain in the two sexes, they found little to set them apart. “The collective data do not support the widespread belief that males’ brains are meaningfully more lateralised than females’,” they wrote in the 2021 paper.
Then there was a final case – one that has been a knobbly bone of contention: do male and female brains process emotions differently?
fMRI proved crucial here. In an fMRI study, researchers assume that the more active a brain region is during a task, the more blood flows to that region. fMRI maps this flow.
But according to Eliot et al., while fMRI has been used “extensively” to study whether the neural basis of emotion processing differs between male and female brain, these studies have “surprisingly little consensus”.
The group found that fMRI-based studies of emotion processing in male and female brains haven’t been reproducible as a result of several confounding factors: differences in hardware, image-processing techniques, stimuli used during the experiments, the ages and the nationalities of participants, their educational backgrounds, and the cohort sizes.
“If anything can be concluded from these hundreds of fMRI studies of emotion processing,” Eliot at al. wrote, “it is that … the circuitry for emotion processing – like language and spatial cognition – appears overwhelmingly similar between men and women.”
While they admitted the possibility of “reliable male/female differences in certain populations under very specific conditions”, these differences between groups are also confounded by higher differences within each group. That is, two male brains might be processing emotion more differently than a male brain versus a female brain.
Whence the differences?
In 2005, psychologist Janet Hyde proposed a “gender similarities hypothesis” as opposed to a “gender differences model”. Per the latter, males and females are psychologically different – but according to Hyde, “males and females are similar on most, but not all, psychological variables” (emphasis added).
It appears to be true for the brain. Even if small differences exist between the brains of male and female individuals, aren’t the two similar for the most part?
How is it then that sex differences seem to be highlighted more than than sex similarities?
In March 2021, Eliot proposed that publication bias might have the answer. “Sex comparisons are super easy for researchers to conduct after an experiment is already done. If they find something, it gets another publication. If not, it gets ignored,” she told ScienceDaily.
Put another way, “only the differences that get hyped”.
In 2008, psychologist and philosopher of science Cordelia Fine coined the term “neurosexism” to refer to such research.
When Eliot was writing her book Pink Brain, Blue Brain (2010), her kids were still kids, and “some books were starting to come out about the so-called ‘hard-wired’ differences between boys and girls,” she told The Wire Science.
“I know that nothing in our forebrains is truly hard-wired, so I dove in to find out what is truly known about human brain sex differences,” she added.
Eliot argued in Pink Brain, Blue Brain that sex differences in the brains of infants are small – but become amplified over time as the baby’s parents, teachers and society at large reinforce sex and gender stereotypes.
“By appreciating how sex differences emerge, rather than assuming them to be fixed biological facts, we can help all children reach their fullest potential, close the troubling gaps between boys and girls, and ultimately end the gender wars that currently divide us,” the blurb of Pink Brain, Blue Brain read.
At the heart of her argument was the idea of neuroplasticity: that neuronal networks in the brain change in response to the environment.
Researchers know well today that infants’ brains are far more neuroplastic than those of adults, although the latter are still significantly plastic.
To The Wire Science, Eliot used the example of how gendered social behaviours lead to sex differences in the brain.
In early language development, female infants lead male infants by a “tiny amount – that of a month,” she said. But by the time they’re about six years old, the gap becomes much wider. According to Eliot, “Girls can be 6-12 months ahead in mastering the phonemic skills necessary to learn to read.”
By the time they’re 17, one of the largest cognitive gaps between a female and a male is the former’s advantage in writing.
But this isn’t because female brains are ‘hard-wired’ to be better at language, according to Eliot. Instead, she said the difference is a result of “parents talking more to girls, girls talking more to each other, girls reading more than boys, and girls writing a lot more than boys (e.g. journaling).”
For Eliot, then, the brain’s gender development is “analogous to language learning”. “Boys and girls are essentially immersed in different languages – male or female-typical words, gestures, eye contact, topics of conversation – which becomes as deeply and automatically learned as one’s native tongue,” she told The Wire Science.
Biologist and gender studies scholar Anne Fausto-Sterling has also written similarly about the popular belief that male infants are more active than female infants. Using detailed video-recordings of caretakers interacting with infants at home, Fausto-Sterling found that “mothers interact with the boys in a more physically active way. They move boy infants, help them sit up, and touch them more often than they do girls.”
“The impact of the mothers’ behaviour may go much deeper than just setting cultural expectations – it could actually have biological consequences,” she inferred.
The implications of Eliot’s and Fausto-Sterling’s observations are profound – and not just for neuroscience. They imply that the gendered ways of society and culture can directly affect an individual’s biology, which has been traditionally believed to be outside the realm of culture.
If they are right, sex differences in the brain are not naturally there. They’re created.
Neuroplasticity – which could explain how sex differences in the brain are socially and culturally produced – also offers ways in which neurodevelopment can be “rerouted” to ameliorate undesirable behaviours like aggression.
Eliot, for example, wrote about male aggression in a February 2021 paper. While researchers have blamed testosterone for male aggression, Eliot asked if it could be the product of parents being “more accepting of anger in sons than daughters”.
This, she said, could influence “boys’ and girls’ differential success at repressing aggression as they grow”.
Fortunately, she added, early interventions could dramatically lower incidents of aggression in young boys. She used the example of a Canadian programme called ‘Roots of Empathy’, where an infant and its parent join an elementary classroom once a month to “teach” emotions.
“Children in the class – boys and girls alike – develop a genuine bond and protective affection for their infant teacher,” Eliot said.
“Rigorous assessments of ‘Roots of Empathy’ have found several benefits in reducing bullying and aggression … within classrooms. Importantly, the benefits are equally great for boys as girls, contrary to teachers’ initial expectations,”
However, Cahill – who supported the sexual dimorphism of human brains – was critical in a 2014 article of the view that the brain’s plastic nature can “work against inborn masculine or feminine predisposition”.
In that article, he used the example of handedness, arguing that while it is possible to “force a child with a slight tendency to use her left hand to become a right-handed adult,” it might not be a good idea.
According to him, in similar vein, it might not be a good idea to use the brain’s plasticity to “work against inborn masculine or feminine predispositions in the brains of children”.
An androgynous brain
In 1974, psychologist Sandra Bem proposed the concept of “psychological androgyny”: the same individual exhibiting both stereotypically masculine and stereotypically feminine attributes.
A year later, Bem argued that psychologically androgynous people had better mental health, contradicting the traditional idea that masculine men and feminine women were mentally better off.
Over the years, researchers developed on Bem’s work to argue that psychologically androgynous individuals were also more creative and had higher cognitive flexibility. But the neurological basis of psychological androgyny was not investigated until last year, when researchers used fMRI to check whether psychological androgyny showed up as “brain androgyny”.
Christelle Langley, one of the authors of the study and a neuroscientist at Cambridge University, told The Wire Science that they found “subtle differences” in the functional connectivity in male and female brains. ‘Functional connectivity’ is a measure of how different parts of the brain work together during a task.
The researchers used a machine learning algorithm to evaluate this measure of the approximately 10,000 brains in their cohort on a scale of 1.0 to 0.0. 1.0 represented a predominantly male brain and 0.0 represented a predominantly female brain. An androgynous brain was in the middle. This, according to the researchers, was the “brain gender continuum”.
Per their paper published in 2021, the team found a surprisingly large number of brains clustered around the middle. These brains also had “fewer mental health symptoms, such as depression and anxiety, compared with those at two extreme ends,” Langley told The Wire Science.
“Men who conform to typical masculine norms – for example, never relying on others and exercising power over women – suffered more psychiatric symptoms than others, including depression, loneliness and substance abuse,” she added.
On the other hand, women who tried to conform were “perhaps opting out of their dream job because the industry is dominated by men, or were taking on the majority of tedious household chores.”
Either way, conforming to social and cultural expectations of masculinity and femininity weren’t working out for their mental well-being.
An androgynous person, however, perhaps fared better because they are not influenced by gender norms to the same extent, Langley added.
She also said that since the brain is plastic to an extent, a person’s location on the brain gender continuum could change over time. So, she recommended, “for optimal performance in school, work and for better well-being throughout life, we need to avoid extreme stereotypes and offer children well-balanced opportunities as they grow up.”
Eliot called this study “one of a growing series of papers” that take a non-binary approach to gender-brain correlates. “Since the behavioural differences (e.g., verbal skill, spatial skills, emotional style) vary in a continuous manner between sexes, you would hardly expect the brain to differ in a binary way,” she said.
The brain as a mosaic
In 2015, Daphna Joel, a neuroscientist at Tel-Aviv University, and her colleagues investigated 300 brain scans to understand whether human brains could be neatly categorised as ‘male’ or ‘female’.
They divided the scans of each individual into 112 sections and measured the size of each section for every individual. Then they recorded the data on a spreadsheet, where each row represented an individual and the columns indicated a region of the brain.
Finally, the team coded each cell of the sheet depending on whether a particular region in an individual was relatively larger or smaller than in other individuals. If a region was found to be relatively larger, the corresponding cell was coloured green. If the region was found to be relatively smaller, the cell was coloured yellow.
When they disaggregated the spreadsheet based on whether an individual was male or female, they found something striking: on a group level, the brains of female individuals were slightly more green than yellow – but there were almost no brains that showed up as being entirely yellow or entirely green. Instead, each brain was a unique “mosaic”.
So Joel’s work offered a radically different, non-binary way to conceptualise sex in the brain. “Human brains are best described as residing in a multi-dimensional space, with the brain architectures typical of women also typical of men, and vice versa,” she told The Wire Science.
As she said in a recent TED Talk, there are no ‘male’ and ‘female’ brains.
Since describing the brain’s architecture as a multidimensional mosaic, Joel has also found that the same is true for the mind. Her website, called ‘The Gender Mosaic’, offers visitors a questionnaire to help one probe their individual mosaic. It has several questions about a participant’s behaviours, preferences and attitudes, and which participants are asked to answer on a Likert scale.
(A Likert scale allows people to answer on an arbitrary numerical scale – e.g. you can come up with a Likert scale where 0 equals a ‘strong liking’ and 5 equals a ‘strong disliking’.)
In her TED Talk, for example, Joel used the following example: “When choosing a romantic partner, how important is it for you that your partner is rich?” Participants could respond on a scale of 0-4, where 0 stood for ‘unimportant’ and 4 was ‘indispensable’.
Once a large number of participants had responded to the questionnaire, she analysed their responses to each question to determine whether there was a significant difference between men’s and women’s responses. For instance, if a significantly large number of women had responded to the question with 2, 3 or 4, these positions on the Likert scale were considered “feminine traits”. Similarly, there were masculine and gender-neutral traits.
For each question, she defined five score ranges: highly feminine (red), slightly feminine (pink), neutral (yellow), slightly masculine (light blue), and highly masculine (blue).
Once a person completed the questionnaire, she and her colleagues constructed a ‘gender mosaic’ by comparing each response against that of the reference, and putting them together in a grid where each square represented a trait.
Using the example above, if one person responded to a question with 2, then in their mosaic, the corresponding square would be marked as a feminine trait. Whether it was ‘highly’ or ‘slightly’ feminine depended on how many women in the reference group also responded with 2s to the same question.
Joel’s conception of the brain and the mind as a gender mosaic is interesting because it doesn’t imagine the brain to be binarily sexed or gendered. Instead, it offers a possibility that each individual is a unique combination of features that people have deemed to be ‘masculine’ or ‘feminine’ in specific cultural contexts.
Because the survey doesn’t begin by assuming which traits are ‘masculine’ or ‘feminine’ – they’re assigned based on participants’ responses – we can compare the resulting mosaics across multiple reference groups. This is a convincing way to show that ideas of masculinity or femininity are culturally constructed as well as that an individual’s ‘gender mosaic’ changes when the cultural context changes.
Consider the responses to the question in the example above: the data from a reference group in Japan took 0 to be more masculine, 1 to be gender-neutral and 2, 3 and 4 as more feminine; the data from a group in the US construed all responses to be gender-neutral. So if you picked 2 on the scale, your response would be ‘feminine’ in Japan and ‘gender-neutral’ in the US.
“See how wonderfully different we all are,” Joel said towards the end of her TED Talk, pointing to an image of the mosaics of different people. “And to think that we live in a culture that attempts to put us all into two boxes: boys and girls; men and women.”
“Doesn’t this make you too wish that we were living in a world without gender?”
Three authors of the 2013 study that reported that women have a lower clearance of and “intrinsic sensitivity” towards zolpidem – David Greenblatt, Jerold Harmatz and Thomas Roth – publishedanother paper in 2019.
Here, they reported that while women indeed retained more residual zolpidem in the blood for longer, studies to check impairment in daily functioning as a result of the drug showed “no evidence of driving impairment in men or women at eight hours after 10 mg of oral immediate-release zolpidem”.
The authors also wrote in their paper that “no clinical trial demonstrated a gender-related difference in clinical efficacy or adverse reactions, and there was no evidence of a particular risk to women”.
So contrary to what the FDA believed, the authors argued that reducing the dose among women was “not supported by available scientific evidence” as a reasonable response – and could “in fact lead to underdosing and the consequent hazard of inadequately treated insomnia”.
In 2014, Cahill told CBS News that the 2013 FDA recommendation on zolpidem was an example of what could go wrong if people neglected “fundamental” differences between men and women.
Thanks to most neuroscientists not accounting for differences in brain structure and function between men and women, they have predominantly conducted their experiments on male model animals with the assumption that their findings can be generalised to the whole population – but Cahill didn’t think this was always true.
“If you’re clumping men and women together in your study and there truly is a sex difference, you’re not just harming the women; you’re harming the men,” he told CBS News. “You’re muddling up the understanding of what’s going on, you’re muddling up the path to clear treatment, not just for the women, but for the men as well.”
Where do researchers like Cordelia Fine and Daphna Joel – whom Cahill has previously called “anti-sex differences researchers” – stand vis-à-vis the idea that studying sex differences is important for more reliable medicine? The duo, along with three others, clarified as much in a 2014 article:
“Like Cahill and many others, we welcome more active research on females in basic animal neuroscience. We strongly believe that this is necessary to ensure that basic research is relevant to all humans. We are concerned, though, that one mistake, treating males as the norm, will be replaced with another; namely, treating males and females as two distinct entities.”
Dubbing the focus on either sex similarities or differences “misleading”, they added, “We need to develop a new framework for thinking of the relation between sex, brain, and gender that better fits current knowledge, and that takes into account distributions, changes, overlap, variance, and most of all, context.”
Sayantan Datta (they/them) are a queer-trans science writer, communicator and journalist. They currently work with the feminist multimedia science collective TheLifeofScience.com, and tweet at @queersprings.
Featured illustration: Simon Lee