Amygdala Dysfunction In Children and Adolescents with Fragile X Syndrome

Background: Mutations of the fragile X mental retardation 1 (FMR1) gene are the genetic cause of fragile X syndrome (FXS), the most common inherited form of mental retardation. Hypermethylation of the FMR1 promoter region, along with CGG repeat expansion, results in deficiency or absence of the FMR1 protein (FMRP), ultimately causing cognitive and behavioral impairments. Patients with partial methylation or patients with a mixture of full and premutation cells may have some FMRP expression, resulting in a less severe phenotype (i.e. FX mosaicism). Although the mutation of the FMR1 gene is not a direct cause of autistic spectrum disorder (ASD), FXS is the most common known genetic cause of autism. In fact, prevalence of ASD in FXS is relatively high (about 15-33%), and the two disorders share similar behavioral and social deficits, such as high social anxiety, withdrawal, and gaze aversion. In the current study, we used functional magnetic resonance imaging (fMRI) to examine amygdala dysfunction in children and adolescents with FXS, as they passively evaluated social-emotional stimuli.

Objectives: Using emotion face stimuli (NimStim Face Stimulus Set, Tottenham et al., 2002), we investigated neuroanatomical and functional aspects of amygdala dysfunction in children and adolescents on the FX spectrum, including females with FXS and males and females with FX mosaicism. In particular, we examined whether the emotional deficits associated with amygdala function is sensitive to FMRP level in children with FXS.

Methods: Sixteen children and adolescents on the FX spectrum and 16 neurotypical (NT) age-matched controls participated in an fMRI task in which they passively viewed grayscale fearful and happy faces, as well as scrambled versions of calm faces. Structural MRI scans were also obtained in the same session. The functional data were analyzed using SPM5 and the volume of amygdala was manually traced for each participant.

Results: The structural analysis revealed no significant difference in the size of amygdala between the two groups. In the functional analysis, however, significant differences in amygdala activation were observed between NT and FX groups. Specifically, the NT group revealed well-established, fear-specific effects of amygdala activation (i.e., greater activation to fearful faces than to scrambled or happy faces) while fear-specific effects in amygdala activation were significantly reduced in the FX group, suggesting deficits in amygdala function in the FX group. Furthermore, a multiple regression analysis performed on data from girls with full mutation or mosaicism, using activation ratio (AR) as a regressor, showed a positive relationship between AR and fear-specific amygdala activation.

Conclusions: The difference in amygdala activation to the fear-related stimuli between the FX spectrum and the NT group suggests abnormal amygdala function in fragile X. Furthermore, the regression result with AR implies a dosage response of FMR1 gene expression on the fear-specific function of the amygdala in FXS.