Aberrant face and gaze habituation in fragile x syndrome

Abstract

Objective: The authors sought to investigate neural system habituation to face and eye gaze in fragile X syndrome, a disorder characterized by eye-gaze aversion, among other social and cognitive deficits.

Method: Participants (ages 15-25 years) were 30 individuals with fragile X syndrome (females, N=14) and a comparison group of 25 individuals without fragile X syndrome (females, N=12) matched for general cognitive ability and autism symptoms. Functional MRI (fMRI) was used to assess brain activation during a gaze habituation task. Participants viewed repeated presentations of four unique faces with either direct or averted eye gaze and judged the direction of eye gaze.

Results: Four participants (males, N=4/4; fragile X syndrome, N=3) were excluded because of excessive head motion during fMRI scanning. Behavioral performance did not differ between the groups. Less neural habituation (and significant sensitization) in the fragile X syndrome group was found in the cingulate gyrus, fusiform gyrus, and frontal cortex in response to all faces (direct and averted gaze). Left fusiform habituation in female participants was directly correlated with higher, more typical levels of the fragile X mental retardation protein and inversely correlated with autism symptoms. There was no evidence for differential habituation to direct gaze compared with averted gaze within or between groups.

Conclusions: Impaired habituation and accentuated sensitization in response to face/eye gaze was distributed across multiple levels of neural processing. These results could help inform interventions, such as desensitization therapy, which may help patients with fragile X syndrome modulate anxiety and arousal associated with eye gaze, thereby improving social functioning.

Figure 1

Group difference in Habituation to direct and averted gaze stimuli combined. Yellow/orange indicates regions for which individuals with fragile X syndrome demonstrate less habituation (T values, p<0.01, FWE corrected) for both conditions combined. Left side of image = right side of brain

Figure 2

Habituation of dorsal anterior cingulate activation by group and condition. Habituation of dorsal anterior cingulate cortex is shown graphically as change in activation from run 1 to run2. Activation by group is for averted and direct gaze stimuli, for a for a 5mm sphere around the peak voxel in the dorsal anterior cingulate. Activation values are in arbitrary units and vertical bars represent standard error. * Within group difference between run 1 and run 2 is significant (p<0.05). For Direct gaze within the comparison group difference is marginally significant (p = 0.09).

Figure 3

Relationship between fusiform habituation and individual differences in level of FMRP and social functioning. A. Relationship between fusiform habituation and FMRP percentage in the FXS group. B. Relationship between fusiform habituation and ADOS scores in FXS and comparison groups. Fusiform habituation is defined as run 2 activation minus run 1 activation. Values greater than 0 indicate habituation (decreasing activation from run 1 to run 2) and values less than zero indicate sensitization (increasing activation from run 1 to run 2). The r, rs and p values refer to FXS female only scores. FMRP = Fragile X mental retardation protein, higher percentage is associated with higher levels of cognitive and neurobiological functioning. ADOS = Autism Diagnostic Observation Schedule, higher scores indicate greater symptom severity.