Fear-Specific Amygdala Function in Children and Adolescents on the Fragile X Spectrum: A Dosage Response of the FMR1 Gene

Abstract

Mutations of the fragile X mental retardation 1 (FMR1) gene are the genetic cause of fragile X syndrome (FXS). The presence of significant socioemotional problems has been well documented in FXS although the brain basis of those deficits remains unspecified. Here, we investigated amygdala dysfunction and its relation to socioemotional deficits and FMR1 gene expression in children and adolescents on the FX spectrum (i.e., individuals whose trinucleotide CGG repeat expansion from 55 to over 200 places them somewhere within the fragile X diagnostic range from premutation to full mutation). Participants performed an fMRI task in which they viewed fearful, happy, and scrambled faces. Neuroimaging results demonstrated that FX participants revealed significantly attenuated amygdala activation in Fearful > Scrambled and Fearful > Happy contrasts compared with their neurotypical counterparts, while showing no differences in amygdala volume. Furthermore, we found significant relationships between FMR1 gene expression, anxiety/social dysfunction scores, and reduced amygdala activation in the FX group. In conclusion, we report novel evidence regarding a dosage response of the FMR1 gene on fear-specific functions of the amygdala, which is associated with socioemotional deficits in FXS.

Hypothalamic-pituitary-adrenal axis function in Fragile X Syndrome and its relationship to behaviour: A systematic review

“…FMR1 knockout mice (an animal model of FXS) have been found to have fewer glucocorticoid receptors (GR-within neuronal dendrites which would decrease homeostatic feedback regarding levels of cortisol (Jafari, Seese, important role in fear memory formation in the amygdala (Bear, 1998;Rodrigues et al, 2002). In turn, functional neuroimaging (fMRI) research has highlighted resultant atypical fear-specific functioning of the amygdala and a possible association between these brain changes and socioemotional deficits in individuals with FXS (Kim et al, 2012). These emotional-evaluative changes may clearly have downstream implications for cortisol release.…”

Modulation of the GABAergic pathway for the treatment of fragile X syndrome

“…Socioemotional impairments are prevalent in both premutation and full mutation patients, which warrants study of the amygdala as a basis for this impairment. Numerous studies have been performed assessing amygdala volume, activation in relation to gaze processing, and facial-emotional processing, which yield contradictory and inconsistent results due to varied protocols and populations (as summarized in Kim et al) 40. Fear-specific activation of the amygdala was significantly reduced in patients with FXS compared to neurotypical controls, despite no differences in amygdala volume,40 which suggests biological impairment possibly at the synaptic level instead of altered brain size leading to emotional dysregulation.…”

“…Numerous studies have been performed assessing amygdala volume, activation in relation to gaze processing, and facial-emotional processing, which yield contradictory and inconsistent results due to varied protocols and populations (as summarized in Kim et al) 40. Fear-specific activation of the amygdala was significantly reduced in patients with FXS compared to neurotypical controls, despite no differences in amygdala volume,40 which suggests biological impairment possibly at the synaptic level instead of altered brain size leading to emotional dysregulation. The amygdala’s phasic inhibitory postsynaptic currents, tonic inhibitory currents, reduced GABA release, and inhibitory synapses are considerably reduced in frequency and amplitude in the amygdala of Fmr1 -KO mice 35.…”

Emotion Potentiated Startle in Fragile X Syndrome

“…In an fMRI study of facial processing in females with FXS, however, Hagan et al did not report any differences in amygdala activation, though significantly reduced anterior cingulate activation was documented (Hagan et al 2008). We documented reduced amygdalar activation in response to social stimuli among individuals who carry the FMR1 premutation (50 to 200 CGG repeats), females with FXS and males with mosaic expression of the FXS allele as compared to controls with normal FMR1 alleles (Hessl et al 2007; Hessl et al 2011; Kim et al 2012). This reduction in amygdalar activation to fearful faces appears to be a dose responsive effect of FMRP expression, therefore it may be particularly prominent among individuals with the FXS full mutation, in whom FMRP expression is the most dramatically reduced (Hessl et al 2011; Kim et al 2012).…”

“…We documented reduced amygdalar activation in response to social stimuli among individuals who carry the FMR1 premutation (50 to 200 CGG repeats), females with FXS and males with mosaic expression of the FXS allele as compared to controls with normal FMR1 alleles (Hessl et al 2007; Hessl et al 2011; Kim et al 2012). This reduction in amygdalar activation to fearful faces appears to be a dose responsive effect of FMRP expression, therefore it may be particularly prominent among individuals with the FXS full mutation, in whom FMRP expression is the most dramatically reduced (Hessl et al 2011; Kim et al 2012). This finding may be particularly relevant to the FXS phenotype, as clinical measures of psychiatric symptoms, autistic symptoms and anxiety have all been associated with an “FMRP mediated blunted amygdala response” (Hessl et al 2007; Hessl et al 2011; Kim et al 2012).…”