Juliana Morsello
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that impacts how individuals think, learn, and behave (Cleveland Clinic, 2020). Symptoms include difficulties with social interaction, trouble understanding nonverbal communication, and having intense interests. Although we will not be discussing the process of receiving a diagnosis, it is important to note that ASD presents differently depending on the individual, with symptoms varying from “mild to severely disabling.”
One factor that can contribute to differences in the neurobiology and presentation of ASD is someone’s sex assigned at birth (Napolitano et al., 2022). However, research on ASD in females remains limited. This gap in understanding, and research on females in general, will be discussed in the following section.
In the remainder of this article, we will focus on the neurobiological aspects of sex differences in ASD. It should be noted that I am using the terms “male” and “female” to refer primarily to biological sex and not gender, although future research should continue to investigate differences in ASD related to gender.
Underrepresentation of Female Participants in Research
Females are unfortunately disproportionately underrepresented in both general research and clinical trials. This applies not only to human studies but also to nonhuman studies. For example, Beery (2018) reported that only about 20% of neuroscience rat studies include both male and female subjects, and 25% do not specify the sex of the rats at all. Even in studies that include both sexes, it is rare that researchers analyze their results based on sex.
Researchers have proposed multiple justifications for the male bias observed in mammal studies. For example, some researchers previously believed that hormonal fluctuations pertaining to female humans and nonhuman female mammals (e.g. menstrual and estrous cycles) would complicate their data collection (Zucker et al., 2021). Additionally, recruiting biases (Merone et al., 2022), personal and practical concerns (e.g. childcare), and religious or cultural norms (Subdeh & Alzoubi, 2021) may also contribute to poor female representation.
While underrepresentation is increasingly being addressed by the scientific community, it is equally important to consider the consequences of this phenomenon. For instance, clinicians may fail to diagnose female patients with particular conditions, which can leave them with unresolved treatment needs. Females may also experience adverse reactions to pharmacological treatments that were primarily studied on males (D’Mello et al., 2022).
Underrepresentation can have an impact on several research fields. For example, there are typically few female participants in ASD studies, or sometimes male-only samples (D’Mello et al., 2022). This underrepresentation is critical for us to keep in mind, especially while looking at statistics– According to the CDC, boys are four times more likely than girls to be diagnosed with ASD. If someone interprets this report without any context, they may conclude that ASD is simply more common among males. However, due to a lack of female participants in ASD studies, it is likely that ASD is more evenly prevalent across both sexes, yet there is just a lack of understanding about ASD in females that is deterring the development of more accurate diagnostic criteria. Unfortunately, researchers suggest that flawed diagnostic criteria are a contributing factor in females being undiagnosed, misdiagnosed, or diagnosed with ASD later in life (e.g., Harmens et al., 2022).
Likewise, diagnostic techniques have been shown to exclude females from ASD studies. Researchers in Dr. John Gabrieli’s lab at MIT discovered that the Autism Diagnostic Observation Schedule (ADOS), a common test for determining eligibility for ASD studies, typically screens out more females than males (D’Mello et al., 2022). So, why should this matter? Such exclusion may be limiting our understanding of how ASD affects male and female brains differently, which influences how we define ASD today and the efficacy of treatments for both sexes.
Next, we will discuss just how the neurobiology of ASD differs between males and females, and how these differences can help inform both diagnostic methods and treatment strategies.
Brain Development
There is evidence to suggest that there are neurodevelopmental sex-differences in the trajectory of ASD. For example, a team of researchers at UC Davis (Andrews et al., 2024) discovered that the brain's cortex thins at different rates in males compared to females with ASD.
Before we discuss Andrews et al.'s (2024) study, it is important to review general patterns of neurodevelopmental differences between sexes. The cortex, the outermost layer of the brain, is made up of gray matter. Gray matter is a type of tissue found in the central nervous system (brain and spinal cord) that processes information and supports higher-level brain functions such as processing sensory information, and controlling emotions, memory, and movement (Cleveland Clinic, 2023).
Andrews et al. (2024) investigated sex differences in cortical thickness in children with ASD. “Cortical thickness” is the width of our gray matter, which naturally shrinks as we age. Our cortical thickness increases during the prenatal period, is widest between 1.5-2 years of age, and then begins to thin for the remainder of our lives. Although it has been suggested that individuals with ASD experience different patterns of cortical thickness, this appears to be the first study that has longitudinally examined sex-differences in cortical width in children with ASD.
Andrews et al. (2024) analyzed neuroimaging (MRI) data from the UC Davis Mind Institute ASD Phenome Project (APP). The MRI scans were performed on male and female autistic and non-autistic children aged 3 to 11.5 years. It was found that three-year-old females with ASD had a thicker cortex compared to non-autistic females of the same age. Furthermore, females with ASD began to experience cortical thinning faster during their middle childhood compared to males with ASD.
The researchers suggest that future studies investigate the correlation between cortical structure and changes in ASD symptoms (Andrews et al., 2024) which may not only aid in improvement of diagnostic criteria, but also result in treatments that are better-tailored to individual needs. It also may give the scientific community more insight into whether sex-specific ASD screening is beneficial, which is a research area that has yielded mixed findings (e.g., Terner et al., 2024; Mårland et al., 2022).
In the following sections, we will focus on specific aspects of brain function in autism.
Functional Brain Organization
Functional brain organization refers to how different brain regions work together as networks to perform complex functions. In a study by Supekar et al. (2022), an AI algorithm found that brain organization in ASD differs between male and female children (M = 13.2 years). For example, females had different patterns of connectivity than males in language and spatial attention systems. The algorithm was able to distinguish between these patterns in children with ASD, but it could not do the same for neurotypical children, which suggests that these sex-differences are specific to ASD.
Differences in several motor areas, such as the primary motor cortex, were found to be the most important for the algorithm’s ability to predict whether someone is a female with ASD. Interestingly, males with ASD tend to exhibit more repetitive motor behaviors (Karadaş et al., 2021), and in this study, females with similar brain patterns to males had the most prominent motor symptoms. This suggests that females who are autistic, yet just display less apparent repetitive motor behaviors, may be more likely to receive a delayed diagnosis (Digitale, 2022). We will discuss life with a late-life diagnosis in the “Significance” section of this article.
Ventromedial Prefrontal Cortex and Camouflaging
Another factor that may lead to late-life diagnosis is camouflaging, when individuals with ASD adjust their social behaviors to fit in with their neurotypical peers (Alaghband-rad et al., 2023). In other words, their outward social behavior might differ from how they represent themselves internally/neurologically (self-representation).
In a study by Lai et al. (2018), researchers examined brain activity in adults with ASD as they performed a task that tested how they see themselves. Using fMRI, the researchers found that males with ASD had a weaker response in a brain area called the ventromedial prefrontal cortex (vmPFC) compared to neurotypical males. Interestingly, for females with ASD, their brain activity in this area was similar to that of neurotypical females. It was also found that females with ASD who camouflaged more had a stronger self-representation response in the vmPFC.
What does this mean? Because females may generally face higher social pressure than males due to traditional sex/gender expectations (Kreiser & White, 2013; as cited in Lai et al., 2018), females with ASD might engage in certain mental processes to help them meet these expectations. This could explain why their activity in the vmPFC is more typical. Additionally, in order to “camouflage successfully,” females with ASD may need to be highly aware of how their own behaviors impact others and align with those of their neurotypical peers, which might explain the positive correlation between camouflaging & vmPFC response (Lai et al., 2018).
An Area for Future Research: The Hippocampal Subareas
A brain region that needs to be further studied in individuals with ASD is the hippocampus. The hippocampus plays a large role in memory, learning, and language, making it an important target for developing ASD treatments (Long et al., 2024). For instance, MRI research has shown that people with ASD have different hippocampal volume compared to neurotypical individuals, which is related to challenges with long-term memory, language skills, social communication, and emotional regulation. However, it is still not fully understood how changes in the hippocampus lead to the cognitive and behavioral challenges seen in ASD.
What is also poorly understood is the function of the hippocampal subareas, whose distinct and overlapping contributions to memory are currently under debate. The subareas include the subiculum, cornu ammonis (CA) 1-3, and dentate gyrus (DG)/C4. Li et al. (2022) chose to research these areas because prior work has shown that children with ASD experience atypical brain overgrowth, but little is known about the development of specific brain regions like the hippocampus.
The researchers conducted the first MRI study of the hippocampus subareas in infants with ASD, and found that CA1-3, but not the CA4/DG, showed abnormal increases in size in males at 6, 12, and 24 months of age when compared to neurotypical controls (Li et al., 2022). There were no significant differences found in females in ASD groups and control groups, which may be due to the smaller sample size of females. Additionally, through analyzing brain scans from the National Database for Autism Research (NDAR), the researchers found that CA1-3 overgrowth is followed by excessive reduction during adulthood. However, only males, (6 to 58 years of age) were included in this analysis because the NDAR lacks female subjects (Li et al., 2022).
To further address the lack of research on CA1-3 development in ASD, study how atypical changes in these areas manifest both cognitively and behaviorally, and continue research on the hippocampus as a target for ASD treatment, it is crucial that this work is comprehensive, and therefore includes more females. Without this, it will be more challenging for the scientific community to get closer to fully understanding how ASD presentation varies depending on the individual.
Significance
This article mainly discusses the neuroscience of ASD in females. However, I would like to highlight qualitative behavioral studies that shed light on the ASD experience, in an effort to urge the scientific community to conduct more studies with female participants. Through interviews, Milner et al. (2019) provided a platform for females to share their personal experiences living with ASD. Many women made several comments regarding sex/gender:
“Every girl has a completely different experience with autism”
“I think it would be nice for people to realize that autism can affect girls”
“Girls are really good at, you know, masking and hiding their autism so that it’s harder to identify an autistic girl that you know needs help with the world”
“Boys are more content to be themselves and it’s like this is how I am, whereas the girls really want to fit in, um, and I think that makes them unhappier”
These comments emphasize the need for more inclusive ASD research. It is not only disheartening to see that females with ASD feel under-recognized, but also that social pressures seem to weigh heavily on their emotional-wellbeing. Ultimately, research on females must continue to be encouraged to help rectify this. While the comments above reflect the impact of camouflaging, some women in Milner et al.'s (2019) sample reported that they find it impossible to camouflage. Perhaps future research in both neuroscience and psychology is necessary to better understand how camouflaging works in both sexes.
Impact of Late-Life Diagnosis
We previously discussed certain factors that may lead to late-life diagnosis of ASD in females. So why does late-life diagnosis matter? In a study by Stagg and Belcher (2019), researchers found that individuals who received a diagnosis of ASD over the age of 50 felt extremely isolated as children. One woman described her experience with not fitting in, stating, “I thought maybe I’m a bad person, I’ve got a horrible personality, there’s something about me people don’t like, and I didn’t understand why.”
When participants finally received a diagnosis later in life, they appeared to have mixed reactions. For example, one woman said, “It really was like a sort of eureka moment … it was kind of a relief … and it wasn’t my fault, and that was one of the biggest things, that I realized it wasn’t my fault.” However, she also mentioned, “It robs me, I guess, of maybe confidence and stuff. Maybe I would have, if I hadn’t got it, I would have maybe done some different things in my life.”
While an early diagnosis may not completely eliminate the possibility of feeling isolated, giving someone a sense of knowledge or a label for their experiences might help them better understand themselves and potentially carry greater self-esteem into their adult life. I recognize that individuals who receive a late-life diagnosis may still grapple with unresolved past struggles, and may face stigma or self-doubt due to their new label. Therefore, it is important that research continues on effective ASD support systems, as these systems may help individuals address these challenges.
Concluding Statement
While neuroscience research on ASD has made significant strides, it still needs to broaden its scope to include a more diverse range of participants. For instance, beyond sex and gender, historically marginalized racial and ethnic groups remain underrepresented in ASD studies (University of North Carolina, 2022).
Specifically for females with ASD, increasing equal representation across sexes may lead to improved diagnostic criteria and more tailored treatment options. This could not only support individuals with ASD in managing daily challenges but also improve society’s understanding of ASD. By fostering a more empathetic view of ASD, increased inclusivity in research has the potential to promote a more inclusive society that celebrates individuals’ positive experiences with ASD and their unique strengths.
As research advances, we can all increase ASD awareness by educating ourselves and our peers, while also having meaningful conversations with individuals on the autism spectrum to truly understand their experiences. For readers interested in learning more about autism in females and contributing to ASD awareness, I have provided helpful resources below.
References
Al Subeh, Z. Y., & Alzoubi, K. H. (2021). Researchers’ ethical perspective about women participation in research studies in Jordan. Heliyon, 7(12), e08492. https://doi.org/10.1016/j.heliyon.2021.e08492
Alaghband-rad, J., Hajikarim-Hamedani, A., & Motamed, M. (2023). Camouflage and masking behavior in adult autism. Frontiers in Psychiatry, 14(14). https://doi.org/10.3389/fpsyt.2023.1108110
Andrews, D. S., Diers, K., Lee, J. K., Harvey, D. J., Heath, B., Cordero, D., Rogers, S. J., Reuter, M., Solomon, M., Amaral, D. G., & Nordahl, C. W. (2024). Sex differences in trajectories of cortical development in autistic children from 2–13 years of age. Molecular Psychiatry, 1–12. https://doi.org/10.1038/s41380-024-02592-8
Beery, A. K. (2018). Inclusion of females does not increase variability in rodent research studies. Current Opinion in Behavioral Sciences, 23, 143–149. https://doi.org/10.1016/j.cobeha.2018.06.016
Cleveland Clinic. (2023, March 19). Grey matter. Cleveland Clinic. https://my.clevelandclinic.org/health/body/24831-grey-matter
Cleveland clinic. (2020, December 29). Autism Spectrum Disorder (ASD): Causes, Symptoms, Treatment & Outlook. Cleveland Clinic; Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/8855-autism
D’Mello, A. M., Frosch, I. R., Li, C. E., Cardinaux, A. L., & Gabrieli, J. D. E. (2022). Exclusion of females in autism research: Empirical evidence for a “leaky” recruitment‐to‐research pipeline. Autism Research, 15(10). https://doi.org/10.1002/aur.2795
Digitale, E. (2022). Study finds differences between brains of girls, boys with autism. News Center. https://med.stanford.edu/news/all-news/2022/02/autism-brain-sex-differences.html
Harmens, M., Sedgewick, F., & Hobson, H. (2022). Autistic women’s diagnostic experiences: Interactions with identity and impacts on well-being. Women’s Health, 18, 174550572211374. https://doi.org/10.1177/17455057221137477
Karadaş, C., Bakkaloğlu, H., & Demir, Ş. (2021). Exploring the effect of motor coordination on repetitive behaviours in children with autism spectrum disorder. International Journal of Developmental Disabilities, 1–10. https://doi.org/10.1080/20473869.2021.1948318
Kreiser, N. L., & White, S. W. (2013). ASD in Females: Are We Overstating the Gender Difference in Diagnosis? Clinical Child and Family Psychology Review, 17(1), 67–84. https://doi.org/10.1007/s10567-013-0148-9
Lai, M.-C., Lombardo, M. V., Chakrabarti, B., Ruigrok, A. N., Bullmore, E. T., Suckling, J., Auyeung, B., Happé, F., Szatmari, P., Baron-Cohen, S., Bailey, A. J., Bolton, P. F., Carrington, S., Catani, M., Craig, M. C., Daly, E. M., Deoni, S. C., Ecker, C., Henty, J., & Jezzard, P. (2018). Neural self-representation in autistic women and association with “compensatory camouflaging.” Autism, 23(5), 1210–1223. https://doi.org/10.1177/1362361318807159
Li, G., Chen, M.-H., Li, G., Wu, D., Lian, C., Sun, Q., Rushmore, R. J., & Wang, L. (2022). Volumetric Analysis of Amygdala and Hippocampal Subfields for Infants with Autism. Journal of Autism and Developmental Disorders. https://doi.org/10.1007/s10803-022-05535-w
Long, J., Li, H., Liu, Y., Liao, X., Tang, Z., Han, K., Chen, J., & Zhang, H. (2024). Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder. Frontiers in Psychiatry, 15. https://doi.org/10.3389/fpsyt.2024.1364858
Mårland, C., Nilsson, T., Larsson, H., Gillberg, C., Lubke, G., & Lundström, S. (2022). Measuring autism in males and females with a differential item functioning approach: Results from a nation-wide population-based study. Psychiatry Research, 314, 114674. https://doi.org/10.1016/j.psychres.2022.114674
Merone, L., Tsey, K., Russell, D., & Nagle, C. (2022). Sex Inequalities in Medical Research: A Systematic Scoping Review of the Literature. Women’s Health Reports, 3(1), 49–59. https://doi.org/10.1089/whr.2021.0083
Napolitano, A., Schiavi, S., La Rosa, P., Rossi-Espagnet, M. C., Petrillo, S., Bottino, F., Tagliente, E., Longo, D., Lupi, E., Casula, L., Valeri, G., Piemonte, F., Trezza, V., & Vicari, S. (2022). Sex Differences in Autism Spectrum Disorder: Diagnostic, Neurobiological, and Behavioral Features. Frontiers in Psychiatry, 13. https://doi.org/10.3389/fpsyt.2022.889636
Stagg, S. D., & Belcher, H. (2019). Living with autism without knowing: receiving a diagnosis in later life. Health Psychology and Behavioral Medicine, 7(1), 348–361. https://doi.org/10.1080/21642850.2019.1684920
Supekar, K., Angeles, C. de los, Ryali, S., Cao, K., Ma, T., & Menon, V. (2022). Deep learning identifies robust gender differences in functional brain organization and their dissociable links to clinical symptoms in autism. The British Journal of Psychiatry, 1–8. https://doi.org/10.1192/bjp.2022.13
Terner, M., Israel-Yaacov, S., & Golan, O. (2024). Sex differences in autism screening: An examination of the Childhood Autism Spectrum Test–Hebrew version. Autism. https://doi.org/10.1177/13623613241235053
The University of North Carolina at Chapel Hill. (2022). Study shows lack of representation across historically minoritized racial and ethnic groups in autism intervention data | Frank Porter Graham Child Development Institute. Fpg.unc.edu. https://fpg.unc.edu/news/study-shows-lack-representation-across-historically-minoritized-racial-and-ethnic-groups-autism#:~:text=White%20participants%20made%20up%2064
Zucker, I., Prendergast, B. J., & Beery, A. K. (2021). Pervasive Neglect of Sex Differences in Biomedical Research. Cold Spring Harbor Perspectives in Biology, a039156. https://doi.org/10.1101/cshperspect.a039156
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