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Articles   |    
Aberrant Face and Gaze Habituation in Fragile X Syndrome
Jennifer Lynn Bruno, Ph.D.; Amy S. Garrett, Ph.D.; Eve-Marie Quintin, Ph.D.; Paul K. Mazaika, Ph.D.; Allan L. Reiss, M.D.
Am J Psychiatry 2014;171:1099-1106. doi:10.1176/appi.ajp.2014.13111464
View Author and Article Information

Dr. Reiss has served as a consultant to Genentech (regarding biomarkers for clinical trials in fragile X syndrome) and Novartis. All other authors report no financial relationships with commercial interests.

Supported by NIH grants 5R01-MH50047 (to Dr. Reiss) and T32-MH-19908 (to Drs. Reiss and Bruno) and a postdoctoral grant from the Fonds de Recherche Société et Culture Québec (to Dr. Quintin).

From the Center for Interdisciplinary Brain Sciences Research, Stanford University, Stanford, Calif.; the Departments of Radiology and Pediatrics, Stanford University; and the Center for Advanced Brain Imaging, Georgia Institute of Technology, Atlanta.

Previously presented in part at the 20th Annual Meeting of the Cognitive Neuroscience Society, April 13–16, 2013, San Francisco.

Address correspondence to Dr. Reiss (areiss1@stanford.edu).

Copyright © 2014 by the American Psychiatric Association

Received November 06, 2013; Revised March 20, 2014; Accepted April 10, 2014.

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.

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FIGURE 1. Group Differences in Habituation to Direct and Averted Gaze Stimuli Combineda

a Functional MRI results demonstrate regions of less habituation in the fragile X syndrome group relative to the comparison group in both gaze conditions combined. Colored regions indicate p<0.01, family-wise error corrected. Left side of image=right side of brain.

FIGURE 2. Habituation of Dorsal Anterior Cingulate Activation by Group and Conditiona

a Habituation of the dorsal anterior cingulate cortex is shown graphically as the change in activation from run 1 to run 2. Activation by group (fragile X syndrome [FXS] and comparison) is for averted and direct gaze stimuli, for a 5-mm sphere around the peak voxel in the dorsal anterior cingulate. Activation values are presented 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 the difference is marginally significant (p=0.09).

FIGURE 3. Relationship Between Fusiform Habituation and Clinical Measuresa

a Panel A shows the relationship between fusiform habituation and fragile X mental retardation protein (FMRP) percentage (higher percentage is associated with higher levels of cognitive and neurobiological functioning) in the fragile X syndrome (FXS) group. Panel B shows the relationship between fusiform habituation and scores on the Autism Diagnostic Observation Schedule (ADOS) in the FXS and comparison groups (higher scores indicate greater symptom severity). 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 0 indicate sensitization (increasing activation from run 1 to run 2). The r, rs, and p values refer to scores for female participants in the FXS group.

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TABLE 1.Descriptive Statistics and Clinical Characteristics for the Fragile X Syndrome and Comparison Groupsa
Table Footer Note

a Group comparisons of IQ, scores on the Autism Diagnostic Observation Schedule and Vineland Adaptive Behavior Scales, fMRI accuracy, and fMRI reaction time include age as a covariate.

Table Footer Note

b IQ was determined using the Wechsler intelligence quotient (standard scores are reported).

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c The Autism Diagnostic Observation Schedule social + communication composite; higher scores indicate more social/communication deficits; scores ≥7 are in the autism spectrum disorder range (12 individuals in the fragile X syndrome group and nine in the comparison group met or exceeded this threshold); all participants were administered module 3 or 4.

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d For the Vineland Adaptive Behavior Scales, standard scores are reported; higher scores indicate greater adaptive functioning.

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e Fisher’s correction for chi-square was used because there were counts fewer than 5.

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f Other medications include neuroleptics, atypical antipsychotics, and other drugs known to affect neurological functioning.

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TABLE 2.Significant Clusters Showing Group Differences in Habituation to Eye Gaze (Direct + Averted Gaze Combined)a
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a Data indicate peak coordinates in MNI space for significant clusters (p<0.01, family-wise error corrected) and >20 voxels, for all participants who were included in the analyses (N=51).

Table Footer Note

b Follow up t tests refer to within-group comparison of change in activation from run 1 to run 2; sensitization indicates a significant increase in activation from run 1 to run 2 (p<0.05); habituation indicates a significant decrease in activation from run 1 to run 2 (p<0.05); n.s.=no significant change in activation from run 1 to run 2.

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