A study recently published in the American Journal of Psychiatry provides new insights into structural changes in the brain associated with anxiety disorders in preadolescent children. The research highlights marked differences in white matter alterations between boys and girls, suggesting a sex-specific aspect to these disorders that could influence future treatments.
“Anxiety disorders are among the most common psychiatric disorders in children and represent an increasingly large public health concern,” said study author Nakul Aggarwal, a PhD student at the University of Wisconsin-Madison and member of the Kalin Lab. “Current treatment options, however, are often suboptimal, as many children fail to respond or relapse after treatment. A better understanding of the neurobiology underlying childhood anxiety disorders may be able provide us with circuit and molecular targets for novel, more precise therapeutic strategies.”
The study included neuroimaging data from 295 children between the ages of 8 and 12, out of which 163 were diagnosed with anxiety disorders and 132 served as healthy controls. Those with anxiety disorders had diagnoses of generalized, separation, and/or social anxiety disorders, based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria.
Importantly, all participants were free from psychiatric treatment for at least six months prior to the study, and major exclusion criteria included the use of psychotropic medication or having other severe psychiatric conditions. For the imaging component, the participants underwent diffusion tensor imaging (DTI), a type of magnetic resonance imaging that specializes in measuring the integrity of white matter by capturing water diffusion within the brain’s neural pathways.
The research demonstrated that boys with anxiety disorders exhibited significant reductions in the fractional anisotropy (FA) of white matter in various brain regions, particularly in the uncinate fasciculus, which connects the prefrontal cortex to limbic regions. These regions are crucial for emotional regulation, suggesting that alterations in these pathways might play a role in the manifestation of anxiety disorders in boys.
Interestingly, the researchers found that these alterations were not present in girls with anxiety disorders. This suggests a sex-specific pattern in how anxiety disorders affect brain structure.
“Children with anxiety disorders show widespread reductions in the white matter microstructural integrity of their brains,” Aggarwal told PsyPost. “White matter refers in part to the fatty insulation surrounding brain cells, which supports efficient signal transmission and communication in the brain. Importantly, these anxiety-related brain changes appear most prominent in boys with anxiety disorders.”
“This finding is exciting because it suggests that improving white matter structure (including the fatty insulation around brain cells) might represent a novel treatment target for childhood anxiety. Taken together with prior work showing that white matter is modifiable and responsive to pharmacological and environmental interventions, this work paves the way for further studies exploring the therapeutic potential of targeting white matter in new treatment strategies to help children with anxiety disorders.”
The broader implications of these findings are profound, indicating that the neurobiological underpinnings of anxiety may differ significantly between sexes, potentially influencing how symptoms are expressed and how effective certain treatments might be.
“The sex-specific nature of the results was striking to us,” Aggarwal said. “While some of our previous work, both in preadolescent children with anxiety disorders and anxious nonhuman primates, suggested a similar sex-specific pattern of white matter alterations in specific brain regions, the widespread and robust anxiety-related white matter microstructural integrity reductions we observed in this large sample specifically in boys – and not girls – was surprising.”
“The reason for this discrepancy remains unclear but, as we speculate in this paper, there is some preliminary preclinical evidence to suggest that it may be related to intrinsic differences in how oligodendrocytes – the cells that generate myelin (the fatty insulation around brain cells) – respond to cellular and metabolic stress in males vs. females, and that male oligodendrocytes may be more susceptible to damage from these stress-related factors.”
The study highlights the importance of considering sex as a critical factor in the study of psychiatric disorders. But, like all research, there are some caveats to consider.
“An important point to keep in mind is that, although the current study, which is a cross- sectional analysis of a large sample of preadolescent youth, shows that anxiety-related changes in white matter structure occur only in boys, it does not preclude the possibility of white matter biology being involved in the pathophysiology of anxiety disorders in girls,” Aggarwal noted. “It is possible that anxiety-related alterations in girls with anxiety disorders are more subtle or exhibit greater inter-individual variability, which may be better captured with methods that minimize between participant variability.”
“In fact, our prior work in a longitudinal study of girls with pathological anxiety – which allowed us to examine within-participant relationships between anxiety and white matter over time – revealed a negative association between global white matter structure and anxiety symptoms, which is consistent with the idea of disruptions in white matter integrity being linked to greater anxiety.”
The research team plans to continue exploring this topic, aiming to refine treatment approaches for anxiety disorders by understanding the underlying brain changes better. They are particularly interested in how interventions like cognitive behavioral therapy can impact brain structure and alleviate symptoms.
“The ultimate goal of this line of inquiry is to inform novel, more precise treatment strategies for children with anxiety disorders,” Aggarwal explained. “In that vein, we are excited to build on the current work by leveraging the translational neuroscience approach in our lab to: 1) conduct mechanistic studies in our nonhuman primate model of anxiety exploring the utility and neural effects of different pharmacological agents targeting white matter structure (as highlighted in a recent pilot study); and 2) begin to explore the extent to which targeted behavioral and environmental interventions in children – including cognitive behavioral therapy – may improve anxiety symptoms via enhancing white matter structure, and – looking further into the future – how certain FDA-approved medications that affect white matter may be repurposed as potential adjunctive therapies for anxiety disorders.”
The study, “Sex-Specific Distributed White Matter Microarchitectural Alterations in Preadolescent Youths With Anxiety Disorders: A Mega-Analytic Study,” was authored by Nakul Aggarwal, Do P.M. Tromp, Jennifer U. Blackford, Daniel S. Pine, Patrick H. Roseboom, Lisa E. Williams, and Ned H. Kalin.
