Preliminary Evidence of White Matter Abnormality in the Uncinate Fasciculus in Generalized Social Anxiety Disorder

Anxiety disorders peak in incidence during adolescence, a developmental window that is marked by dynamic changes in gene expression, endocannabinoid signaling, and frontolimbic circuitry. We tested whether genetic alterations in endocannabinoid signaling related to a common polymorphism in fatty acid amide hydrolase (FAAH), which alters endocannabinoid anandamide (AEA) levels, would impact the development of frontolimbic circuitry implicated in anxiety disorders. In a pediatric imaging sample of over 1,000 3-to 21-y-olds, we show effects of the FAAH genotype specific to frontolimbic connectivity that emerge by ∼12 y of age and are paralleled by changes in anxietyrelated behavior. Using a knock-in mouse model of the FAAH polymorphism that controls for genetic and environmental backgrounds, we confirm phenotypic differences in frontoamygdala circuitry and anxiety-related behavior by postnatal day 45 (P45), when AEA levels begin to decrease, and also, at P75 but not before. These results, which converge across species and level of analysis, highlight the importance of underlying developmental neurobiology in the emergence of genetic effects on brain circuitry and function. Moreover, the results have important implications for the identification of risk for disease and precise targeting of treatments to the biological state of the developing brain as a function of developmental changes in gene expression and neural circuit maturation.A nxiety disorders typically emerge during adolescence, when the incidence of mental illness peaks (1, 2). The developmental phase of adolescence is characterized by dynamic changes in gene expression, frontolimbic circuitry (3, 4), and overall tone of the endocannabinoid system, which are implicated in anxiety (5-7).The corticolimbic endocannabinoid system undergoes dynamic changes across development. The onset of adolescence is marked by the highest expression of type 1 cannabinoid receptor (CB1) in both cortical and subcortical brain regions, with CB1 expression declining to adult levels throughout adolescence (8, 9). Across the amygdala and prefrontal cortex, fatty acid amide hydrolase (FAAH) expression shows a transient increase from postnatal day 35 (P35) to P45 during adolescence in mice (10). Consistent with the regulatory role of FAAH, anandamide (AEA) levels show an inverse pattern of a peak at P35 and subsequent decrease during adolescence (10, 11). AEA is an endogenous ligand for the CB1 receptor, suggesting that the concurrent changes in AEA and CB1 expression reflect decreasing endocannabinoid signaling during adolescence (12), which may be associated with increasing risk for anxiety (Fig. 1).A common human polymorphism in the gene encoding FAAH (C385A; rs324420), the primary catabolic enzyme of the prototypical endocannabinoid AEA, regulates FAAH activity. The variant FAAH A385 allele destabilizes the FAAH protein, causing lower levels of FAAH enzymatic activity and/or increased levels of AEA in T lymphocytes and brain (13,14). Phenotypic expression of common polymorphism...

Previous findings suggested the role of the prefrontal cortex, hippocampus, and cingulate gyrus in major depressive disorders (MDD), but the white matter microstructural abnormalities of the fibers connecting these brain structures are not known. The purpose of this study was to test the hypothesis that white matter abnormalities are present in association fibers of the uncinate fasciculus (UF) and cingulum bundle (CB) among MDD subjects. A total of 21 MDD subjects aged between 30 and 65 years and 21 age-matched healthy controls (HC) were recruited. All subjects were right-handed and without history of diabetes or other cardiac diseases. We extracted quantitative tract-specific measures based on diffusion tensor imaging tractography to examine both diffusivity and geometric properties of the UF and CB. Significantly decreased fractional anisotropy (FA) and increased radial diffusivity of the right UF were observed in MDD patients compared with HC (po0.05), while their geometric characteristics remained relatively unchanged. Among MDD subjects, depression severity had a significant negative correlation with normalized number of fibers (NNF) in the right UF (r ¼ À0.53, p ¼ 0.02). We also found significant age effect (oldoyoung) in HC group and laterality effect (L4R) in both groups in the FA measure of the CB. Our study demonstrates novel findings of white matter microstructural abnormalities of the right UF in MDD. In the MDD group, the severity of depression is associated with reduced NNF in the right UF. These findings have implications for both clinical manifestations of depression as well as its pathophysiology.

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