A new study, published in the journal Proceedings of the National Academy of Sciences, has uncovered significant sex-related differences in the brain’s subcortical gray matter. These differences were found in areas like the hippocampus, thalamus, and amygdala — regions critical to functions such as memory, emotion regulation, and sensory processing. The findings not only contribute to our understanding of brain anatomy but also hint at possible connections between these structural differences and varying susceptibility to mental health disorders.
Sex differences in mental health are well-documented: women are more likely to experience anxiety and mood disorders, while men are more frequently diagnosed with conditions like autism, attention deficit hyperactivity disorder, and antisocial behavior. Despite these known patterns, the underlying reasons for these differences remain poorly understood. Some researchers have speculated that these disparities could be rooted in the brain’s structure, but previous studies have primarily focused on larger, more visible aspects of brain anatomy, such as overall brain volume.
The current study aimed to explore whether more subtle, microscopic differences in brain structure could explain these observed mental health disparities. Specifically, the researchers wanted to determine if these microstructural differences could be linked to the neural mechanisms that might predispose individuals to certain psychiatric conditions.
“We know that mental health issues affect men and women differently; women are more likely to suffer from depression or anxiety, while men are more susceptible to attention problems or aggression. If we can understand the reason for these differences, this might help us to diagnose and treat these important issues,” explained study author Diliana Pecheva, an assistant project scientist at the Center for Multimodal Imaging and Genetics at the University of California, San Diego.
For their new study, the researchers leveraged data from the Human Connectome Project, which provided a large sample of 1,065 young adults, including 575 females and 490 males. These participants underwent a specialized form of brain imaging known as diffusion-weighted magnetic resonance imaging (MRI). Unlike traditional MRI, which captures static images of the brain, diffusion MRI measures the movement of water molecules within brain tissues. This movement, or diffusion, is influenced by the surrounding cellular environment, allowing researchers to infer details about the microstructure of the brain, such as cell density and the orientation of fibers.
The study focused on the brain’s subcortical gray matter, a region that includes structures like the hippocampus, amygdala, and thalamus. These areas were selected because they play crucial roles in emotional and cognitive processes and have been implicated in various psychiatric disorders. The researchers used an advanced analysis technique called restriction spectrum imaging (RSI), which provides detailed information about the different cellular environments in these brain regions.
In addition to the imaging data, the researchers analyzed self-reported measures of psychiatric symptoms from the participants, including symptoms of depression, anxiety, attention deficit hyperactivity, and antisocial behavior. This allowed them to examine whether the observed microstructural differences were related to these mental health symptoms.
The researchers found significant sex differences in the microstructure of several subcortical regions. For example, males showed a higher restricted isotropic signal — a measure related to cell density and complexity — in the hippocampus and amygdala. In contrast, females exhibited higher hindered isotropic signals in the thalamus.
These microstructural differences were not just statistically significant but also substantial in size. In fact, the effect sizes observed in this study were much larger than those typically seen in studies of brain volume.
“Given the large the effect sizes we observe, it is surprising that these have not been described previously,” Pecheva told PsyPost. “This challenges the idea that once individual brain size is accounted for, sex differences in the brain are small.”
Furthermore, the researchers found that these microstructural differences were linked to psychiatric symptoms. For instance, greater restricted isotropic signal in the amygdala — a region involved in processing fear emotions — was associated with higher levels of depression and antisocial behavior. Similarly, alterations in the microstructure of the thalamus were associated with symptoms of anxiety and attention deficit hyperactivity. These findings suggest that the microstructural differences observed in the study could underlie the sex differences in mental health disorders.
“Previous research has mainly concentrated on the sizes of brain structures, and have found only subtle differences between men and women, which may simply reflect the fact that men’s bodies and brains are generally larger than women’s. We have discovered much larger differences on a microscopic scale in structures deep within the brain,” Pecheva summarized.
“The structures that show the largest differences, such as the amygdala, the hippocampus, and the thalamus, are involved in things like emotions, memory, learning, and attention, and have been found to be associated with mental health problems. While our study was based on data from healthy young adults – so did not specifically recruit participants with mental health problems – we did find that our MRI measures were associated with depression, anxiety, attention deficit, and antisocial behavior.”
But the study, like all research, has some limitations to consider. One significant limitation is the nature of diffusion MRI itself. While this imaging technique provides valuable insights into the microstructure of the brain, it does not offer a clear picture of the specific cellular changes that underlie the observed differences.
“The type of MRI scan used is very sensitive to changes in the average microscopic environment, but it’s not like a microscope where we can see individual cells,” Pecheva explained. “Differences in the types of cells, their size, density, shapes, and connections will all impact the signal that we measure, but it’s difficult to attribute the changes we see to a particular feature.
“Also, from our analyses, it is not possible to say exactly what is the cause (or causes) of the differences we see. It is most likely to be a combination of biological factors, such as hormones and genetics, and environmental factors, such as gendered experiences and societal pressures and expectations.”
Future research could address these limitations by using complementary imaging techniques that provide a clearer view of the cellular basis of these differences. Additionally, studies that track these brain changes over time could help determine whether these microstructural differences emerge early in life or develop later, potentially offering insights into how sex differences in mental health disorders evolve.
“In the longer term, investigating sex differences may allow us to better understand the biological origins of mental health disorders,” Pecheva said. “This could lead to earlier diagnosis, and more effective treatments through personalized medicine, in which the treatment is tailored to the individual, rather than just the diagnosis. For example, antipsychotic drugs seem to work differently in men and women, as well as having different side effects. Our work might also provide objective measures of the effectiveness of new and existing treatments.”
The study, “Sex and mental health are related to subcortical brain microstructure,” was authored by Diliana Pecheva, Diana M. Smitha, B. J. Casey, Lianne J. Woodward, Anders M. Dalea, Christopher G. Filippi, and Richard Watts.
