Aberrant Neural Response During Face Processing in Girls With Fragile X Syndrome: Defining Potential Brain Biomarkers for Treatment Studies

Abstract

Background: Children and adolescents with fragile X syndrome (FXS) manifest significant symptoms of anxiety, particularly in response to face-to-face social interaction. In this study, we used functional near-infrared spectroscopy to reveal a specific pattern of brain activation and habituation in response to face stimuli in young girls with FXS, an important but understudied clinical population.

Methods: Participants were 32 girls with FXS (age: 11.8 ± 2.9 years) and a control group of 28 girls without FXS (age: 10.5 ± 2.3 years) matched for age, general cognitive function, and autism symptoms. Functional near-infrared spectroscopy was used to assess brain activation during a face habituation task including repeated upright/inverted faces and greeble (nonface) objects.

Results: Compared with the control group, girls with FXS showed significant hyperactivation in the frontopolar and dorsal lateral prefrontal cortices in response to all face stimuli (upright + inverted). Lack of neural habituation (and significant sensitization) was also observed in the FXS group in the frontopolar cortex in response to upright face stimuli. Finally, aberrant frontopolar sensitization in response to upright faces in girls with FXS was significantly correlated with notable cognitive-behavioral and social-emotional outcomes relevant to this condition, including executive function, autism symptoms, depression, and anxiety.

Conclusions: These findings strongly support a hypothesis of neural hyperactivation and accentuated sensitization during face processing in FXS, a phenomenon that could be developed as a biomarker end point for improving treatment trial evaluation in girls with this condition.

Keywords: Biomarkers; Face processing; Fragile X syndrome; Frontopolar cortex; Functional near-infrared spectroscopy; Neural habituation.

Figure 1.

Experimental design of this study. (A): The face habituation task; (B): An example of the measurement setup (a signed consent form has been obtained from the participant for the publication of this figure); (C): The location of fNIRS channels (projected from scalp to cortical surface, channels within the same ROI were assigned with the same color).

Figure 2.

Significant brain activation in response to different conditions in the FXS group. A: Upright face; B: Inverted face (this fNIRS channel covered both BA 9 and BA 10); C: Greeble object. Colored regions indicate p < 0.05 (FXS > baseline, false discovery rate corrected, see coordinates and t values in Table S1). L: left; R: right; BA: Brodmann Area; DLPFC: dorsal lateral prefrontal cortex.

Figure 3.

Significant brain activation differences between the FXS and control groups in response to each condition. A: Upright face; B: Inverted face (this fNIRS channel covered both BA 9 and BA 10); C: All faces (upright + inverted faces). Colored regions indicate p < 0.05 (FXS > Control, false discovery rate corrected, see coordinates and t values in Table S2). L: left; R: right; BA: Brodmann Area; DLPFC: dorsal lateral prefrontal cortex.

Figure 4.

(A-C): Temporal fluctuation of HbO in response to different conditions (A: Upright face; B: Inverted face; C: Greeble) at the frontopolar cortex. (D-F): Group-averaged habituation (HbO_{Block5-Block1}) analysis at the frontopolar cortex and DLPFC in response to different conditions. Note that the HbO values of channels within the same cortical regions were averaged. Asterisk indicates significant difference between two groups (p < 0.05). Note that sensitization in Y-axis equals change of activation between block 5 and block 1 (HbO_{Block5-Block1}), where value of 0 = no habituation, negative value = habituation, positive value = sensitization. A.U.: Arbitrary Unit.

Figure 5.

Correlation between frontopolar sensitization (HbO_{Block5-Block1}) induced by upright face stimuli and various cognitive-behavioral measures, including BRIEF-2-Global executive composite, CBCL-Anxiety, ADAMS-Anxiety, ADAMS-Depression and SRS-2. Solid and dash regression lines were plotted for FXS group and control group, respectively. Correlation coefficients and p values were only shown in the plots for significant correlations in FXS group (Control group: correlation coefficients ranged from −0.264 to 0.079, p values ranged from 0.174 to 0.964. Multiple correlations were controlled by FDR). Note that sensitization in X-axis equals the change of activation between block 5 and block 1 (HbO_{Block5-Block1}), where value of 0 = no habituation, negative value = habituation, positive value = sensitization.