The Inverse Relationship between the Microstructural Variability of Amygdala-Prefrontal Pathways and Trait Anxiety Is Moderated by Sex

Abstract

Anxiety impacts the quality of everyday life and may facilitate the development of affective disorders, possibly through concurrent alterations in neural circuitry. Findings from multimodal neuroimaging studies suggest that trait-anxious individuals may have a reduced capacity for efficient communication between the amygdala and the ventral prefrontal cortex (vPFC). A diffusion-weighted imaging protocol with 61 directions was used to identify lateral and medial amygdala-vPFC white matter pathways. The structural integrity of both pathways was inversely correlated with self-reported levels of trait anxiety. When this mask from our first dataset was then applied to an independent validation dataset, both pathways again showed a consistent inverse relationship with trait anxiety. Importantly, a moderating effect of sex was found, demonstrating that the observed brain-anxiety relationship was stronger in females. These data reveal a potential neuroanatomical mediator of previously documented functional alterations in amygdala-prefrontal connectivity that is associated with trait anxiety, which might prove informative for future studies of psychopathology.

Neurogenetic plasticity and sex influence the link between corticolimbic structural connectivity and trait anxiety

“…Using a large multimodal dataset from the Duke Neurogenetics Study, we demonstrate that the expression of trait anxiety as a function of the microstructural integrity of a prominent pathway linking the amygdala and vPFC is moderated by sex and a functional genetic polymorphism associated with neuroplasticity. Replicating our prior work 13 , we found an inverse correlation between amygdala-vPFC FA values and self-reported trait anxiety in women but not men. Furthermore, we demonstrate that this association in women is specific to Met allele carriers of BDNF rs6265, which is associated with impaired activity-dependent plasticity as well as multiple anxiety-related phenotypes including impoverished fear extinction.…”

“…While the exact nature of the sex-specific association between amygdala-vPFC and trait anxiety remains to be determined, it is likely that both psychosocial (e.g., some young men may be more reluctant than women to report their own levels of trait anxiety 31 ) and biological (e.g., prenatal stress may lead to increased anxiety-like behaviors in female versus male rats 32 ) mechanisms contribute to the observed differences between men and women. We do note that these particular sex differences in dMRI studies of brain-anxiety associations have emerged only recently 13 , and that not all previous studies reporting an inverse correlation between trait anxiety and amygdala-vPFC structural connectivity observed moderating effects of sex 12 , 14 . Regardless, the current findings from our large sample, which had better power to detect small effects than any prior work, along with previously reported sex-specific effects buttress the link between trait anxiety and the structural connectivity of the amygdala-vPFC pathways in women but not men.…”

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Figure 1 Moderating effect of sex. ( a ) An illustration of the right (yellow) and left (cyan) amygdala-vPFC pathway masks, defined using probabilistic tractography data from an independent group of samples ( n = 71) 13 . ( b ) The association between the right amygdala-vPFC pathway strength and trait anxiety was significantly moderated by sex.

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“…Given that our goal was to first replicate the moderating effect of sex on the inverse correlation between trait anxiety and the microstructural integrity of the amygdala-vPFC pathways, we adopted a region-of-interest (ROI) approach. The bilateral amygdala-vPFC pathways from our previous dMRI study 13 were used as a priori ROI masks for the current study. These amygdala-vPFC pathways were defined using probabilistic tractography on 71 dMRI scans acquired with a higher angular sampling resolution (61 noncollinear diffusion directions), and stored in standard MNI space.…”

“…While the inverse association between amygdala-vPFC structural connectivity and anxiety is further supported by studies of clinical populations such as generalized anxiety disorder 19 , 20 and social anxiety disorder 21 , 22 , comparison of available studies examining trait anxiety in non-clinical samples has been inconsistent, possibly related to inadequate power to detect small effects as well as to explore the influence of potential moderators such as sex and age 23 – 25 . Our recent study 13 aimed to address this issue by examining these links in a relatively large sample ( n = 275) comprised of three independent datasets. In addition to observing a significant inverse association between amygdala-vPFC structural connectivity and trait anxiety, our work further revealed sex differences wherein the negative correlation was primarily driven by women.…”