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Neuroscience should take sex differences in the brain more seriously

Diseases like Alzheimer's and schizophrenia manifest differently in men and women, and that's important to know

Aarthi Gobinath

Neuroscience

As a neuroscientist who identifies as a woman, I love that there is discussion of dismantling the patriarchy and supporting diversity for those working in STEM. But, as a neuroscientist who studied the neurobiology of postpartum depression and how hormones affect the brain, there’s another layer to the issue of sexism in the field that we have to talk about: diversifying our research subject pools.

Neuroscience has historically had a problem of predominantly using male test subjects, from studies of how the brain works to what happens in brain illnesses. The field then assumes that whatever has been true for them will be true for everyone else. This assumption is dangerous.

Take the drug zolpidem (trade name: Ambien) to treat insomnia. When the medication was first released in 1992, doctors provided men and women with prescriptions of equal doses of zolpidem, and hoped that this would alleviate their sleep troubles. But, no such luck... for women. Women began reporting adverse effects ranging from hallucinations to sensory distortions because the drug was not clearing out as quickly from their bodies. In 2010, women accounted for 68% of ER visits related to zolpidem. Researchers are still not entirely sure why women are more sensitive to it; hypotheses range from differences in how men and women's liver enzymes work, body weight differences, and even testosterone levels. Nonetheless, the FDA now recommends that women should be prescribed smaller doses than men.

Similar issues have come up with different responses to antidepressants, identifying symptoms of autism, and understanding how Alzheimer's disease happens.

Some medications, like Ambien, affect men and women differently

 Photo by freestocks.org on Unsplash 

But, the bigger question is why did it take women struggling before researchers realized that sex differences exist in the first place?

Before we answer that question, we have to talk about what sex differences are. Sex refers to the biological condition of one’s sex chromosomes, with XY generally classified as male, XX as female, and expressions like XO or XXY as intersex (XX or XY individuals can be intersex as well). Gender refers to how one identifies and is influenced by societal and cultural factors. Sex differences in the brain refer to when features of the brain — like chemical levels, hormone receptors, or immune activity — are present in everyone, but biological sex influences how much they are present. For example, sex chromosomes affect production of hormones like testosterone and estrogens. Everyone has different levels of both hormones which can affect all organs of the body, including the brain. It’s not only hormone levels, either. There are sex differences in how the brain processes the stress response, activity of chemicals like dopamine and serotonin, and even how the immune system interacts with the brain.

Biological sex affects many aspects of how our brains work

 Photo by Ken Treloar on Unsplash 

And yet, neuroscience has long evaded including a diverse group of participants, members of all sexes, in experiments.

A 2017 study on sex bias in neuroscience research analyzed leading journals in the field and found that for rat and mice models, which account for approximately 50% of neuroscience research, the majority failed to use biological sex as a statistical variable or acknowledge the sex of the animal. Omitting sex as a variable in data analysis means that valuable information about whether a discovery was relevant or not to a particular sex gets lost. Failing to report the biological sex of the subjects creates chaos in trying to replicate and build upon findings. And casually discarding data should bother everyone.

Considering biological sex as a factor in research has been revelatory for understanding the brain. Neurological and psychiatric conditions such as autism, Alzheimer’s disease, schizophrenia, depression, and Parkinson’s disease are characterized by sex differences in the prevalence of the disease, how if manifests, and even how effective treatments are. In my own research, I've studied depression, an illness that affects twice as many females as males, with particular vulnerability around times of hormone shifts like puberty and pregnancy. Using a rat model of postpartum depression, I found that after the huge hormone changes of pregnancy and postpartum, traditional antidepressants weren’t as effective in the brain, a concern for the 15% of mothers struggling with postpartum depression.

But, there is understandable concern about how academic institutions and their deeply rooted misogyny will use this information. Will differences be exploited as biological proof one group is better than the other? More capable than the other? Will differences be used to categorize what’s “normal” and consequently discriminate other groups as “abnormal”?

Considering biological sex as a factor in research has been revelatory for understanding the brain

These fears have sparked a counter-argument, calling for researchers to abandon studying sex differences in the brain. Researchers like Gina Rippon, a professor in cognitive neuroscience at Aston University in the UK, claim that researching sex differences is a form of “neurosexism” and that the evidence of biological sex affecting the brain is a “myth.” Not only is this problematic because it undermines the growing body of evidence that researchers have been conducting to rectify the historical sex bias in neuroscience research, it creates confusion for how today's neuroscientists fix the problems of the past. And it does so by conflating equality with conformity, aka to treat everyone as “equal” means they must all be “identical to men.”

I understand why their fears exist. Oppressors have long distorted neuroscience to fit their claims of superiority and use it as means to justify oppression. And shamefully, it’s not even that old of a problem. The infamous 2017 Google memo claimed that sex differences in the brain meant women were biologically incapable of being equal to men in performing in the technology sector. Only last year, a professor from the European Organization for Nuclear Research, or CERN, argued that women’s brains were fundamentally inferior in studying physics as an explanation for why there are fewer women physicists relative to men. They brushed off gender inequality in their fields as the nature of the oppressed rather than systematic barriers nurtured by the oppressors.

This fear is also relevant to the LGBTQIA+ community. Sex and gender are more complex than “male” and “female” (check out this infographic from Scientific American). Biological sex is often assigned based on what the gonads look like at birth, not necessarily based on genetics. So, intersex conditions may not become apparent until later in life. Neuroscience research has been informative for sensory function during gender confirmation surgeries. But, biomedical research has historically been conducted to further marginalize those who don’t identify with their sex assigned at birth or conform to heteronormative conditions. Fear that neuroscience research will be used to further isolate them, or worse, treat their identities as deviations from a false dichotomy of “male” or “female” is anti-scientific.

The questions that plague neuroscience research — How can we cure neurological and psychiatric disease? Why aren’t the current drugs working? — are questions that demand more data. Turning a blind eye to how sex and gender affect the brain as a solution to sexist interpretations of data is akin to pretending to not see people of color as a solution to racism. Does it conveniently allow for those in power to sweep marginalized groups under the rug and call it equality? Yep. Does it actually fix the problem of inequitable research? Nope.

Studying the brain is a messy, but necessary, endeavor

 Photo by jesse orrico on Unsplash 

There also is an argument that researchers should abandon studying sex differences because gender is more influential than biological sex in the human brain, stemming from confusion about “nature” vs. “nurture” in the brain. Nature refers to things that are usually present before we’re born, like sex chromosomes, whereas nurture refers to things we encounter as we grow up, like sociocultural influences around gender. The brain is tremendously plastic, with connections rewiring moment to moment. Both biology and environment influence how plasticity happens in the brain, not simply one or the other.

Here’s the truth: studying the brain is messy. It’s messy because literally everything — from DNA to culture to gender to your childhood — affects how it works. Parsing out these differences seems messy but actually provides a more nuanced and accurate understanding of the brain. As feminists and neuroscientists, we must work towards the ideal of equitable research so that everyone benefits from neuroscience. Studying sex differences isn’t the magical last step to solving the mysteries of the brain, but it is a part of the puzzle that is valuable.  

We’re all different. And those differences aren’t going away by blindfolding the data to those differences.

Comment Peer Commentary

We ask other scientists from our Consortium to respond to articles with commentary from their expert perspective.

Laetitia Meyrueix

Nutrition and Epigenetics

University of North Carolina - Chapel Hill

Great piece Aarthi! Super appreciate the external link that you provided from Scientific American.

The issue you bring up is a general issue within a lot of scientific research right now. The NIH thankfully makes it a requirement now that you include both sexes in all preclinical studies. I am super intrigued by the point you brought  up with regards to the sex differences in neurological and psychiatric  conditions. It really seems that the sex differences in these conditions have been the main driving point to really start considering sex differences in other health conditions. I recently reviewed the literature with regards to the sexual dimorphism of the placenta, and many of the papers I came  upon had as their rationale the sex differences in neurological and psychiatric conditions in humans. It seems that even in the case of placental development and function, sex differences are KEY. The literature was supporting the idea that the placenta produces sexually dimorphic responses to intrauterine stress exposure which leads to differences in neurodevelopment in the fetus. And thus, possibly explaining the differences in disease prevalence. Thanks for this! 

Thanks for writing this piece. I think it is an extremely important point to  make not just to the neuroscience research community but to the general public. I was actually unaware that some researchers have equated sex differences in the brain as a form of ‘neurosexism’.  It’s an interesting argument because while as a woman in STEM I understand the need to combat sexism in the workplace, I also know that sex differences  do play an important role in many neurological diseases and neuropsychiatric conditions. For example, in pre-clinical stroke research there is a huge push to start incorporating male and female animals in studies in order to examine sex differences in post stroke recovery. This push is based on the fact that women over the age of 60 who have strokes are more likely to die or have worse functional  impairments compared to men over 60. These statistics clearly point to sex differences in brain responses to stroke, therefore validating the need to address sex differences in neuroscience research. 

Jenna Sternberg

Neuroscience

As Laetitia said, the NIH has begun to address the issue of including male and female subjects in clinical studies due to clear differences in responses to drug treatments.

Basic science falls further behind in dealing with sex and gender differences. Female mice are traditionally excluded from behavioral research because people believed the estrous cycle might cause uncontrollable variability. This belief may be based on erroneous anecdotal evidence, and recent research shows that variability may even be higher for males.

Classic work in pain processing performed in male mice has turned out to only apply to males. By excluding females, we fail to recognize possible sex differences in unexpected places that may also extend to humans.

Clear sex-specific differences in responses to drug treatments have fueled a response to the problem of focusing on men for research studies. However, ignoring the problem at the basic science level creates a dangerous situation in which a lack of knowledge can perpetuate misunderstandings about how the female nervous system works.

Thanks for this great article on a major social issue that impacts neuroscience and biology research every day.

Katherine Basil

Neuroscience

Maastricht University

Great piece Aarthi!

I was particularly interested in the part where you mention how results from studies investigating sex differences in the brain might have implications in academic institutions! This is definitely something that is worth pondering over. My concern is that these might not only have implications in academia but in society as a whole. For instance, how will this influence the pay gap? How will this translate in courtrooms? Are women more or less accountable for a crime because of the effects of female hormones on emotions and behaviour? Research involving female and male participants will definitely move the field of neuroscience forward in many ways but we must acknowledge that it might also carry several implications on gender inequality.

Aarthi Gobinath

Neuroscience

Thanks so much everyone for the supportive words! I wanted to share my thoughts to some of the thoughtful points raised here:

I love the point raised by Jenna about sex differences in pain responses. Stories from women experiencing distress and poor medical treatment because their doctors dismissed their pain or did not treat the pain as serious red flags of underlying physiological problems are gaining more visibility. But, if we believe women’s pain only to treat them with drugs that were optimized for the male nervous system, then we are still failing to provide good medical treatment for female patients. Addressing sex and gender differences is important for preclinical and clinical perspectives.

And thank you for bringing up that point about the estrous cycle–the estrous cycle does not make data more variable! I get frustrated when I hear scientists try to justify excluding females for that reason because it seems rooted in a misogynistic belief that hormones make females problematic–even though everyone has hormones! Conflating hormone cycles with unpredictability or treating them as a frivolous complication seems like a way to undermine women, both in data sets and in real life.

I also agree with the point raised by Katherine - I think the implications of sex differences in the brain have broad impacts well outside academia, and I’m fascinated by how neuroscience in general will intersect with the law. As the field of neuroethics grows, I hope it paves the way for better communication between researchers and public audiences.

Alison Koontz

Neurobiology

Caltech

Love this piece. An article recently came out in Science directly discussing this topic. My biggest takeaway from this article was the general bias against female mice for “hormonal problems” that could make their behavior too erratic for study. This bias can be dangerous, as scientific results that lead to drug or treatment development are inherently skewed to favor men (as discussed in the article). However, a metadata analysis of almost 300 different articles shows the opposite: females are not significantly more variable than males in various behavioral, physiological, and morphological traits.

It is important to remember that these biases stem from trends in the basic research and the structure of the research experiments themselves. Male mice are preferentially used in basic science experiments. This trend has been present in neuroscience research since the 1950s, and many landmark findings were made exclusively in male models (i.e. aspirin). In 2016, the NIH and CIHR both required science produced under their grants to consider sex as a biological variable for reporting, which has remained controversial.

Not only do we need to focus on the using the results of sex differences in the brain for treatment more seriously, but there also needs to be a serious overhaul in the current basic experimental procedure to even create more female-oriented data!

Alyssa DiLeo

Neuroscience

Tufts University

Wonderful piece! I was just thinking/hoping to see a piece about sex differences in the brain as the FDA just approved it’s first drug for post partum depression recently from Sage Therapeutics. As great as this breakthrough is, it really highlights how behind we are; that in 2019, the first treatment for a disorder affecting 15% of births is only just now being approved.

Additionally, sex differences in alcohol drinking in females is widely reported in the alcohol field and recent research shows increases in binge drinking in women (Breslow, Castle, Chen, & Graubard, 2017) further highlighting the need to include females in basic animal research on alcohol drinking to better understand how alcohol affects females as well.

Also, snaps to Jenna for bringing up the excuse of many researchers to exclude female mice from their research because of their estrous cycle as if males do not also have sex hormones!

Great piece Aarthi Thank you for bringing up the social impact neuroscience research has on marginalized groups as well. It makes platforms like this all the more important for scientists to be able to communicate their science accurately and easily to avoid data being used in the wrong way.