Aberrant Brain Activation During Gaze Processing in Boys With Fragile X Syndrome

Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Rd, Stanford, CA 94305-5795, USA.
Archives of general psychiatry (Impact Factor: 14.48). 12/2008; 65(11):1315-23. DOI: 10.1001/archpsyc.65.11.1315
Source: PubMed


Eye contact is a fundamental component of human social behavior. Individuals with fragile X syndrome (fraX), particularly male subjects, avoid eye contact and display other social deficits. To date (to our knowledge), this behavior in fraX has been studied only in female subjects, who show lesser degrees of gaze aversion.
To determine the neural correlates of the perception of direct eye gaze in adolescent boys with fraX using functional magnetic resonance imaging.
Cross-sectional study.
Academic medical center.
Thirteen adolescent boys with fraX, 10 boys with developmental delay, and 13 typically developing control subjects.
Behavioral performance and brain activation during functional magnetic resonance imaging were evaluated during the presentation of faces with eye gaze directed to or averted away from subjects and during successive presentations of stimuli with eye gaze directed toward the subject. Whole-brain and region of interest analyses and regression analyses with task performance were performed.
Significantly greater activation was observed in prefrontal cortices in controls compared with boys having fraX, who (in contrast) demonstrated elevated left insula activation to direct eye gaze stimuli. Furthermore, compared with controls, boys with fraX showed greater sensitization in the left amygdala with successive exposure to direct gaze.
Compared with controls, boys with fraX display distinct patterns of brain activation in response to direct eye gaze. These results suggest that aberrant neural processing of direct eye gaze in subjects with fraX may be related to the associated avoidant response.

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    • "Recent optogenetic studies in mice show that elevation of the E:I ratio results in the impairment of social behaviors, and that subsequent augmentation of inhibitory neurotransmission can reduce this impairment .(Yizhar et al. 2011) In patients with syndromic and idiopathic ASD, abnormally high E:I ratios may be reflected in seizure susceptibility, sensory hyper-responsiveness, anxiety, and increases in cortical activation, especially in the amygdala, when confronted with social stimuli (Watson et al. 2008; Rubenstein and Merzenich 2003). Another potential therapeutic agent that is being tested in FXS and ASD is STX209 (arbaclofen), a specific GABA-B receptor agonist. "
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    • "The fact that hyper-reactivity to direct-gaze emotional faces was found more so for negative emotional expressions (disgusted, sad and angry) is also consistent with emerging evidence of amygdala dysfunction in the FXS population (e.g., Hessl et al., 2007, 2011; Suvrathan and Chattarji, 2011). Structural and functional amygdala abnormalities have been reported in animal models of FXS (Suvrathan and Chattarji, 2011; Suvrathan et al., 2010); as well as FXS toddlers (Hazlett et al., 2009), FXS adolescents (Gothelf et al., 2008; Watson et al., 2008), and males with the FXS premutation (Hessl et al., 2007, 2011). Overall, we suggest that these findings provide support for the hypothesis that within the FXS population socially evoked hyper-reactivity may lead to an avoidance of, or withdrawal from, social stimuli. "
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    ABSTRACT: Fragile X syndrome (FXS) is characterized by hyper-reactivity, autistic tendencies and social anxiety. It has been hypothesized that the FXS social phenotype is secondary to a generalized hyper-reactivity that leads to social avoidance. No study, however, has investigated whether hyperarousal in FXS is generalized or more specific to socially salient information. We recorded skin conductance responses (SCRs) while females with FXS, as well as chronological age- (CA-) and mental age- (MA-) matched controls, viewed two sets of visual images: direct-gaze emotional faces and affectively arousing scenes. Explicit emotion recognition and subjective ratings of emotions aroused by images were also recorded. Overall, females with FXS displayed hyper-reactivity only when viewing the more socially salient stimuli (emotional faces), compared to CA-matched controls, but not MA-matched controls. Moreover, females with FXS also displayed atypical emotion recognition abilities and subjective ratings of their own emotional states. These findings suggest that any hyper-reactivity observed in FXS may be more specific to socially salient stimuli, rather than generalized.
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    • "It has been shown that while performing simple arithmetic tasks individuals with FXS do not show typical increases in neural activity in the intraparietal sulcus that scale with task difficulty, suggesting abnormal cortical function in FXS (Rivera et al., 2002). There are also reduced levels of task-related hippocampus and basal forebrain activation during memory tasks (Greicius, 2008; Greicius et al., 2003, 2004), and reduced amygdala activation to emotionally salient stimuli (Watson et al., 2008). There have also been reports of abnormal fronto-striatal white matter pathways that may participate in cognitive control processes as well as abnormal white matter pathways in the parietal-sensory-motor tracts (Barnea-Goraly et al., 2003; Haas et al., 2009). "
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