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Original Article |

Here's Looking at You, Kid:  Neural Systems Underlying Face and Gaze Processing in Fragile XSyndrome FREE

Amy S. Garrett, PhD; Vinod Menon, PhD; Katie MacKenzie, BA; Allan L. Reiss, MD
[+] Author Affiliations

From the Stanford Psychiatry Neuroimaging Laboratory and BehavioralNeurogenetics Research Center, Department of Psychiatry and Behavioral Sciences,Stanford University School of Medicine, Stanford, Calif.


Arch Gen Psychiatry. 2004;61(3):281-288. doi:10.1001/archpsyc.61.3.281.
Text Size: A A A
Published online

Background  Children with fragile X syndrome (fraX) are at risk for manifesting abnormalities in social function that overlap with features of autism and social anxiety disorder. In this study, we analyzed brain activation in response to face and gaze stimuli to better understand neural functioning associated with social perception in fraX.

Methods  Eleven female subjects with fraX, aged 10 to 22 years, were compared with age-matched female control subjects. Photographs of forward-facing and angled faces, each having direct and averted gaze (4 types of stimuli), were presented in an event-related design during functional magnetic resonance imaging. Subjects were instructed to determine the direction of gaze for each photograph. Activation in brain regions known to respond to face and gaze stimuli, the fusiform gyrus (FG) and superior temporal sulcus (STS), were compared between groups to isolate neural abnormalities in the perception of directed social stimuli.

Results  The fraX subjects had decreased accuracy in determining the direction of gaze compared with controls. Region of interest analysis of the FG revealed a significant interaction between diagnostic group and face orientation. Specifically, control subjects had greater FG activation to forward than to angled faces, whereas fraX subjects had no difference in FG activation to forward and angled faces. Controls showed greater left STS activation to all stimuli compared with fraX subjects.

Conclusions  Our results suggest that gaze aversion in fraX subjects is related to decreased specialization of the FG in the perception of face orientation. Decreased STS activation in fraX suggests aberrant processing of gaze. These data suggest that gaze aversion in fraX may be related to dysfunction of neural systems underlying both face and gaze processing.

Figures in this Article

Fragile X syndrome (fraX) is an inherited neurodevelopmental disordercaused by disrupted expression of the fragile X mental retardation (FMR1) gene. In this relatively common syndrome, FMR1 gene expression is reduced, and the resulting lack of FMR1 protein(FMRP) protein leads to altered synaptic function and abnormal dendritic spinemorphology.1 Fragile X syndrome is an X-linkedcondition; therefore, female subjects have 1 affected and 1 unaffected X chromosome,resulting in FMRP levels that are reduced by approximately 50%. In addition,the level of FMRP can vary among affected male and female individuals, thuscontributing to variation in the level of impairment. As a neuropsychiatricphenotype, fraX is associated with increased risk for impairment in severaldomains, including sustained attention, working memory, visuospatial analysis,visuomotor coordination, executive function, and social function.2

Social difficulties, often associated with a subset of autistic behaviors,are one of the earliest and most maladaptive symptoms of fraX. These difficultiesmay worsen during childhood, thus having a potential long-term effect on thechild's adaptive behavior and mental health. One hallmark of fraX is the propensityto avoid eye contact and turn away during a social greeting, even while offeringa handshake or socially acceptable remark.3 Maleindividuals also show abnormalities in social play with peers and during verbaland nonverbal social communication.4 Younggirls with fraX are usually less affected than boys but also show social deficits,including withdrawal and avoidant behavior.5 Evenfemale subjects with fraX who have IQs in the normal range exhibit socialdysfunction, which may be related to reports of increased frequencies of socialanxiety and mood disorders6 in these subjects.The social avoidance seen in individuals with fraX has been attributed tohyperarousal during social situations.7,8 Together,these studies suggest that brain systems that process socially relevant stimulimay function differently in fraX than in typically developing subjects.

In typically developing subjects, the neurofunctional correlates ofsocial cognition have been investigated by observing responses to faces andthe direction of eye gaze. Neuroimaging studies have found greater activationof the fusiform gyrus (FG) in response to faces compared with letter strings,scrambled faces, houses, or human hands.911 Also,patients with lesions in this area have difficulty recognizing faces,12 and intraoperative recordings from the FG show increasedresponses to faces.13,14 However,the specificity of FG activation remains in question. Recently, Gauthier andcolleagues15,16 suggested thatvisual expertise in general, rather than the analysis of faces in particular,recruits the capabilities of the FG. An understanding of the variables thatmodulate FG activation in response to faces is beginning to emerge. Rossionand colleagues17 showed that the left FG wasparticularly responsive to parts of faces rather than whole faces, whereasthe opposite was true for the right FG. Forward and angled faces have beenshown to evoke a greater FG response than profiles of faces.14 Attentionto faces increases FG activation,18 and reducedaccuracy at matching faces may decrease FG activation.19

The perception of gaze direction is less well studied, but neuroimagingdata suggest the involvement of the superior temporal sulci (STS)20,21 and the middle and inferior temporalgyri.22 Some studies suggested that avertedgaze activates the STS more than does direct gaze,20 whereasother studies found no differences in STS activation to averted vs directgaze.22,23 A recent parametricanalysis showed that increasing proportions of direct gaze are associatedwith increasing blood flow in the STS.24

We hypothesized that if the FG and the STS are typically activated inresponse to face and gaze stimuli, then studying activation of these regionsin individuals with fraX may help us begin to understand the nature of socialdifficulties in this condition. Several studies have shown that individualswith fraX, unlike individuals with autism, recognize and recall faces normally.2,25 Therefore, we predicted that the perceptionof faces, which is attributed to the FG, may function normally in fraX. However,because of the symptom of gaze aversion, the STS may show altered functioning,and brain regions associated with anxiety may show increased activation infraX. We addressed our hypothesis by presenting 4 types of stimuli: Forwardand angled faces with direct and averted gaze. Direct gaze and forward facessignify socially relevant stimuli. Averted gaze and angled faces are appropriatecontrol stimuli because they possess similar visual characteristics. Combinedwith the inclusion of a homogeneous patient group with an identifiable etiology,this design allowed us to provide a foundational study of social informationprocessing in fraX. To our knowledge, this study is the first to use event-relatedfunctional magnetic resonance imaging (fMRI) to examine functional brain abnormalitiesunderlying the perception of face and gaze stimuli in fraX.

SUBJECTS

Fifteen female subjects with a diagnosis of fraX (fraX subjects) wererecruited through advertisements in national and regional fraX newslettersand referrals from physicians. Fifteen typically developing female controlsubjects were recruited through advertisement within the local community.We included only female subjects because they have milder symptoms than malefraX subjects and therefore are more likely to perform the task accuratelyand tolerate the scan. Including only female subjects also removes intersubjectvariance attributable to sex.

All subjects reported that they were right-handed. All fraX subjectshad the FMR1 full mutation, as confirmed by DNA (Southernblot) analysis. Written informed consent was obtained from all participants,and the human subjects review committee at Stanford University School of Medicine,Stanford, Calif, approved all protocols.

All of the control subjects were medication free. Of the final 11 fraXsubjects included in the study, 8 were medication free. The remaining 3 fraXsubjects were taking the following medications: (1) guanfacine hydrochloride(Tenex) and venlafaxine hydrochloride (Effexor); (2) paroxetine (Paxil) andmethylphenidate hydrochloride (Ritalin Hydrochloride); and (3) paroxetine,methylphenidate, and levothyroxine sodium (Synthroid). Subjects stopped takingmethylphenidate and guanfacine for 24 hours before the scan, and continuedtaking all other medications. The fraX group consisted of 9 white, 1 Hispanic,and 1 Pacific Islander subject. The final control group consisted of 9 white,1 Hispanic, and 1 Asian American subject.

The final subject groups did not differ significantly in age (fraX group,mean age, 16.4 years [SD, 4.09 years; range, 10-22 years]; control group,mean age, 15.5 years [SD, 3.41 years; range, 10-22 years]; F1,20<1).The IQs were measured using the Wechsler Intelligence Scale for Children IIIfor subjects younger than 17 years and the Wechsler Adult Intelligence ScaleIII for subjects 17 years and older. One fraX subject was removed for havingan IQ significantly below the group mean (>2.5 SDs). To reduce the IQ disparitybetween groups, 3 control subjects were removed for having an IQ significantlygreater than the group mean (>120, or 1.33 SDs). The final Full-Scale IQ scoresfor the fraX group were in the average range of intelligence (80-111), witha mean score of 93.7 (SD, 10.4). Full-Scale IQ scores for the control groupranged from 85 to 120, with a mean score of 107.0 (SD, 11.2). A between-groups t test verified that the control group had significantlyhigher Full-Scale IQ scores than the fraX group (F1,20 = 8.24 [P<.01]).

EXPERIMENTAL TASKS
Stimuli

Color photographs of faces of 120 college-aged models with neutral facialexpressions were taken against a common, solid-color background at a distanceof about 2 m. Thirty photographs from each of the following 4 categories wereused: (1) face forward with direct gaze, (2) face forward with averted gaze,(3) face angled with direct gaze, and (4) face angled with averted gaze. Angledfaces and averted gaze were turned approximately 45° away from the camera.The photographs included 66 men and 54 women. Of these, 93 were white and27 were African American, Hispanic, Asian American, or Indian. Sex and racewere distributed similarly across stimulus categories. Examples of the stimuliare shown in Figure 1.

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Figure 1

Examples of photographs used asstimuli. Labels describe stimulus type. FD indicates forward face with directgaze; FA, forward face with averted gaze; AD, angled face with direct gaze;and AA, angled face with averted gaze.

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Task Designs

A research investigator (K.M.) practiced a training version of the taskwith each subject until confident that she understood the instructions andcould respond accurately. Subjects performed 2 tasks. The event-related taskused a jittered stimulus presentation, with a mean intertrial interval of1572 milliseconds (SD, 1805 milliseconds)26 anda range of 0.25 to 4.25 seconds. Stimuli were presented using PsyScope software,27 which also triggered the initiation of the fMRI scanby sending a transistor-transistor logic pulse to the scanning processor.Stimuli were projected onto a screen attached to the head coil. Subjects lookeddirectly upward at a mirror to view the stimuli. Each stimulus was presentedfor 1750 milliseconds, followed by a 250-millisecond duration fixation cross.Subjects were instructed to use the right index finger to press a button ifthe person in the photograph was looking at them, and to use the right seconddigit to press another adjacent button if the person was looking away fromthem. Correct and incorrect responses and reaction times were recorded ifthey occurred between 150 and 2000 milliseconds after the stimulus. Each subjectperformed 2 runs of the event-related task, with each run lasting 4 minutes32 seconds. The runs were separated by 2 to 3 minutes to prevent subject fatigue.In each run, 15 stimuli of each condition were presented, so 2 runs contained30 stimuli per condition.

The same stimuli described above were then presented in a block designto derive functional regions of interest (ROIs) defining the FG and STS. Inparticular, a block design was used to measure responses to all types of stimulicombined. This method of defining ROIs by the location of significant activationin response to related stimuli has been used in previous studies28 andis a methodologically attractive way to create subject-specific ROIs basedon functional anatomy. The task consisted of 8 alternating epochs, each lasting30 seconds and presenting 15 stimuli for 1750 milliseconds each, with a 250-millisecondinterstimulus interval. Half of the epochs contained a mix of all 4 typesof face stimuli, whereas the alternating epochs contained scrambled pictures.Subjects were asked to indicate the direction of gaze for the faces and toalternate pressing the first and second button in response to the scrambledpictures.

MRI SCANNING

Images were acquired on a 1.5-T GE scanner (General Electric Company,Milwaukee, Wis) using a custom-built whole-head coil that provides a 50% advantagein signal-to-noise ratio over that of the standard GE head coil.29 Acustom-built head holder was used to prevent head movement. Eighteen axialslices (6-mm thickness; 1-mm gap) parallel to the anterior and posterior commissuresand covering the whole brain were imaged using a T2-weighted gradient echospiral pulse sequence (repetition time [TR], 2000 milliseconds; echo time[TE], 40 milliseconds; flip angle, 89° and 1 interleave30;field of view [FOV], 240 mm; in-plane resolution, 3.75 mm). To help localizeactivation, a high-resolution T1-weighted, spoiled GRASS (gradient recalledacquisition in a steady state) image (SPGR) 3-dimensional MRI sequence (TR,24 milliseconds; echo time, 5 milliseconds; flip angle, 40°; FOV, 240mm; 124 sagittal slices; 256 × 192 matrix; resolution, 1.5 × 0.9× 1.2 mm) was also collected.

DATA ANALYSIS

A 3-way analysis of variance (ANOVA) was used to examine task accuracy(percentage correct) and response time. The factors included face orientation(forward and angled), gaze orientation (direct and averted), and group (controland fraX).

Functional images were reconstructed by means of the inverse Fouriertransform for each of the 186 time points into 64 × 64 × 18 imagematrices (voxel size, 3.75 × 3.75 × 7 mm). Functional MRI datawere analyzed using SPM99 software (Statistical Parametric Mapping 99; WellcomeDepartment of Cognitive Neurology, Institute of Neurology, University College,London, England). Images were corrected for movement using least squares minimizationwithout higher-order corrections for spin history, and normalized to stereotaxicMontreal Neurologic Institute coordinates.31 Imageswere then resampled every 2 mm using sinc interpolation and smoothed witha 4-mm gaussian kernel to decrease spatial noise.

The general linear model and the theory of gaussian random fields implementedin SPM99 were used to complete statistical analyses of fMRI data.30 For each subject, activation was calculated at eachvoxel and corrected for temporal autocorrelation. Confounding effects of fluctuationsin the global mean were removed by proportional scaling. Low-frequency noisewas removed by applying a high-pass filter (0.5 cycle/min) to the fMRI timeseries at each voxel. A temporal smoothing function (gaussian kernel correspondingto dispersion of 8 seconds) was applied to the fMRI time series to enhancethe temporal signal-to-noise ratio.

For each subject, a t score image was generatedfor each contrast of interest, including (1) forward compared with angledfaces, collapsed over gaze orientation, and (2) direct compared with avertedgaze, collapsed over face orientation. Individual contrast images were combinedinto a group image using a random-effects model, which provides a strongergeneralization to the population.32 All comparisonsbetween the fraX and control groups were controlled for differences in IQby including IQ as a covariate. A mask was used to remove group differencesarising from deactivation. Voxelwise t statisticswere normalized to z scores to provide a statisticalmeasure independent of sample size. Significant clusters of activation weredetermined using the joint expected probability of height (z>1.96 [P<.05]) and extent of z scores (P<.05),33 yieldinga clusterwise significance level of P = .05, correctedfor multiple comparisons. The MNI coordinates were converted to Talairachcoordinates using procedures described by Brett.34 Activationfoci were superimposed on high-resolution T1-weighted images and localizedwith reference to the stereotaxic atlas of Talairach and Tournoux.31 Because the contrasts examined in this study werechosen a priori, activations from other contrasts are not reported.

ROI ANALYSIS

An ROI analysis was used to explore activation of the FG and STS withingroups and in response to each type of stimulus. The boundaries of anatomicalregions were drawn on each subject's spatially normalized structural MRI.These regions were further constrained by a mask constructed from each subject'sactivation during the block design task, which combined all face and gazestimuli (minus scrambled stimuli), thresholded at P<.05.When conjoined with the anatomical outline, each subject's FG and STS regionswere defined structurally and functionally. The ROI activation was calculatedas the percentage of significant voxels (z>1.67)for each of the 4 stimulus conditions. A repeated measures ANOVA was conductedfor each ROI with the factors of face orientation (forward and angled), gazeorientation (direct and averted), hemisphere (right and left), and group (fraXand control).

The anatomical boundaries of all regions were drawn on coronal slicesusing BrainImage software.35 The FG beginsat the coronal slice containing the largest cross section of the anteriorcommisure and proceeds back to the posterior transverse collateral sulcus.The medial border is the collateral sulcus, and the lateral border is theoccipitotemporal sulcus. The superior temporal region includes the STS andthe superior and middle temporal gyri. It begins at the onset of the anteriortemporal pole and terminates posteriorly at the disappearance of the inferiortemporal sulcus.

Three fraX subjects were removed from the sample for scoring below 50%on the gaze discrimination task, leaving only those subjects whose task accuracyindicated understanding and compliance with task demands. One control subjectwas removed for failure to respond to the task. Thus, the following resultsinclude 11 subjects in the fraX group and 11 subjects in the control group.

TASK ACCURACY

Group means and SDs for task accuracy are summarized in Table 1. Main effects were found for group, face orientation, andthe interaction between face and gaze orientation. Control subjects had significantlygreater accuracy compared with the fraX group (F1,19 = 13.39 [P = .002]). For all subjects, accuracy was greater forforward than for angled faces (F1,19 = 10.88 [P = .004]). The significant interaction between face and gaze orientation(F1,19 = 10.60 [P = .004]) showed thatfor forward faces, accuracy was greater for direct gaze than for averted gaze,but for angled faces, accuracy was not different for direct compared withaverted gaze conditions. This effect was driven primarily by the fact thatall subjects had greater accuracy responding to forward faces with directgaze than to any other stimulus.

Table Graphic Jump LocationTable 1. Gaze Orientation Task Performance*

Full-Scale IQ scores were significantly correlated with task accuracyfor both groups combined (r = 0.56 [P = .003, 1-tailed]). However, this appeared to reflect a categorical(ie, group) effect only, since IQ and task accuracy were not significantlycorrelated within each of the groups (control group, r =0.36 [P = .14]; fraX group, r =0.35 [P = .15]). Therefore, all subsequent between-groupanalyses were covaried for IQ, which also controlled for between-group differencesin task accuracy.

RESPONSE TIME

Table 1 shows the groupmeans and SDs for response time. No group differences were found in responsetime. Main effects were found for face orientation and the interaction betweenface and gaze orientation. For all subjects, reaction time was quicker forforward than for angled faces (F1,19 = 5.07 [P<.04]). The interaction between face and gaze orientation (F1,19 = 35.03 [P<.001]) showed that for forwardfaces, response time was similar for direct and averted gaze, but for angledfaces, response time was longer for direct than for averted gaze (F1,19 = 21.2 [P<.001]).

BRAIN ACTIVATION RELATED TO FORWARD COMPARED WITH ANGLED FACES

There were no significant between-group differences in the comparisonof forward faces with angled faces (collapsed over gaze orientation). TheROI analysis was used to investigate activation of specific brain regionswithin each group and for each type of stimulus.

BRAIN ACTIVATION RELATED TO DIRECT COMPARED WITH AVERTED GAZE
Control > fraX

Three clusters of significantly greater activation were found in thecontrol group. Activation maxima included the STS, lingual gyrus, and cerebellum.Other significantly activated regions are listed in Table 2 and shown in Figure 2.

Table Graphic Jump LocationTable 2. Brain Regions Showing Significantly Greater Activation toDirect Gaze Compared With Averted Gaze After Covarying for IQ*
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Figure 2.

Location of activation that is significantly differentbetween groups for the whole brain analysis of direct gaze compared with avertedgaze, after covarying for group differences in IQ. The Talairach atlas y-coordinateis given in the lower left corner of each image. The right side of image indicatesthe right side of brain. All clusters are significant at P<.05.A, Greater activation in the control compared with the fragile X syndrome(fraX) group, including left superior temporal sulcus, middle temporal sulcus,and hippocampus. Additional significant clusters are listed in Table 2. B, Greater activation in the fraX compared with the controlgroup in the right insula, posterior thalamus, and brainstem. Additional clustersare listed in Table 2.

Graphic Jump Location
fraX > Control

Two clusters of significantly greater activation were found in the fraXgroup. Activation maxima included the right insula and cerebellum. Other significantlyactivated regions are listed in Table 2 and shown in Figure 2.

FUSIFORM GYRUS ROI

A significant interaction was detected between group and face orientation(F1,20 = 9.20 [P = .007]). Although controlsubjects had significantly greater FG activation in response to forward comparedwith angled faces (post hoc t11 = 6.42[P = .02]), fraX subjects had no difference for forwardcompared with angled faces (P = .09) (Figure 3A). Activation of the FG to angled faces was not significantlydifferent between the fraX and control groups (post hoc F1,19 =0.309 [P = .59]). A significant interaction betweengroup and hemisphere (F1,20 = 5.75 [P =.03]) showed that controls had significantly greater right than left FG activationto all stimuli, whereas fraX subjects had no hemispheric differences in FGresponse (Figure 3B). Activationof FG in the left hemisphere is not significantly different between groups(F1,19 = .55 [P = .47]).

Place holder to copy figure label and caption
Figure 3

Fusiform gyrus (FG) region ofinterest. A, Significant interaction between group and face orientation (F1,20 = 9.20 [P= .007]). Control subjects show significantlygreater FG activation for forward faces than for angled faces, and subjectswith fragile X syndrome (fraX) show no difference between forward and angledfaces. Activation of FG to angled faces is not significantly different betweengroups. B, Significant interaction between group and hemisphere (F1,20 = 5.75 [P= .03]). Control subjects have greater rightthan left hemisphere FG activation to all stimuli, whereas fraX subjects haveno significant difference in activation of the FG between hemispheres. Datapoints indicate means; error bars, SEM.

Graphic Jump Location
SUPERIOR TEMPORAL SULCUS ROI

The analysis of the STS region showed significant main effects of groupand hemisphere. Control subjects had greater STS activation than fraX subjectsin response to all stimulus conditions combined (F1,19 = 6.11 [P = .02]; Figure 4).In addition, all subjects had greater STS activation in the right hemispherecompared with the left (F1,20 = 14.61 [P =.001]).

Place holder to copy figure label and caption
Figure 4

Superior temporal sulcus (STS)region of interest. A, The control group has significantly greater STS activationoverall compared with the fragile X syndrome (fraX) group (F1,19 =6.11 [P= .02]). B, All subjects had greater right than left hemisphereSTS activation (F1,20 = 14.61 [P= .001]).Post hoc comparisons show that this effect is carried by control subjects,who had greater right than left hemisphere STS activation (F1,20 =13.93 [P= .001]). AA indicates angled face with averted gaze;AD, angled face with direct gaze; FA, forward face with averted gaze; FD,forward face with direct gaze; data points, means; and error bars, SEM.

Graphic Jump Location

We examined abnormalities in neural responses to face and gaze stimulito investigate the basis of alterations in social behavior, such as gaze aversion,in fraX individuals. Although all subjects had IQ scores within the averagerange of intelligence, the fraX group had lower IQ scores and decreased accuracyin determining gaze direction compared with controls. The ROI analysis ofthe FG showed a significant interaction between group and face orientation.Control subjects had greater FG activation to forward than to angled faces,whereas subjects with fraX had no difference in activation to forward comparedwith angled faces. Controls had significantly greater STS activation to allstimuli compared with fraX individuals. Therefore, our results suggest thatgaze avoidance in fraX individuals may be related to reduced ability to perceivegaze and decreased specialization in the perception of face orientation.

The results of the whole brain analysis of the FG could be interpretedas contradictory to the results of the ROI analysis of the same region. TheROI analysis showed that controls had significantly greater activation toforward than to angled faces, but the fraX group had no difference for forwardvs angled faces. Therefore, for the whole brain analysis, we would expectcontrol subjects to have greater FG activation than the fraX subjects forthe group comparison of forward minus angled faces. However, the whole brainanalysis showed no group differences. We believe that intersubject variabilityin the location of peak FG activation was responsible for this disparity.Group differences in FG activation in the whole brain analysis were in thesame direction as the ROI-based results (control > fraX) but did not reachthe significance threshold (z = 3.69 [P = .001 uncorrected; P = .21 corrected]).This indicates how the ROI analysis was helpful in controlling for individualvariation in neuroanatomy, as intended.

Activation of FG is reliably found in response to faces, and is typicallygreater for forward than for angled faces,911 perhapsbecause forward faces are perceived as more socially relevant. Lack of fusiformspecialization may be associated with a relatively greater tendency of fraXindividuals to look at faces when the faces are looking away.36,37 Thus,they may develop a normal ability to process faces, but no preference forforward faces. On the other hand, fraX individuals avoid social gaze altogether,and therefore may not develop a normal ability to process gaze.

Another possibility is that the FG finding indicates difficulty processingangled faces, since subjects with fraX had significantly lower accuracy whenresponding to angled faces compared with forward faces. Decreased accuracyhas been associated with increased activation of other visual cortical regions.38 However, decreased accuracy also has been associatedwith decreased FG activation in previous studies involving control subjects.16,19 Our data do not suggest that FG activationis related to accuracy in the current study. A post hoc analysis showed thatthere was no correlation between FG activation and accuracy for both groupscombined or considered separately (combined, Pearson r =−0.10 for left FG and r = 0.09 for right FG;fraX subjects, r = 0.15 for left FG and r = 0.06 for right FG; control subjects, r =−0.05 for left FG and r = 0.03 for right FG).

Our results suggest that social abnormalities in fraX individuals arealso related to a reduced ability to perceive social gaze, as evidenced bydecreased STS activation to all categories of stimuli. Anatomical abnormalitiesin the STS have previously been reported in fraX.39 Activationof this region has been associated with the perception of social gaze in controlsubjects.20,21 Since fraX individualstypically avoid social gaze, they may not develop a normal ability to processgaze. Of course, we cannot determine whether alterations in the STS causegaze aversion behavior, or whether gaze aversion behavior results in changesin these brain regions.

An alternative explanation for these findings is that fraX subjectslooked away from the photographs. Although we cannot rule this out, becausewe did not measure eye movements, we did not find different activity in thefrontal eye fields (Brodmann areas 6/8) of fraX subjects compared with controls.Also, fraX subjects did not have decreased accuracy in response to forwardgaze stimuli. Finally, the participants in this study were chosen to be mildlyaffected patients with less severe gaze aversion behavior.

Social problems in fraX have been attributed to hyperarousal and anxiety.7,8 Although our study did not directlyassess the role of anxiety in social gaze perception, we did not see increasedactivation of the amygdala to direct gaze in fraX subjects. However, we sawincreased activation of the right anterior insula, ventral prefrontal cortex,and midbrain. The ventrolateral prefrontal cortex has sensory and limbic inputs40 and is activated during the experience of emotions,including sadness41 and anxiety.42 Similarly,the midbrain has been activated in neuroimaging studies of several emotions,including anxiety.43 Insula activation is relatedto the experience of visceral and emotional symptoms, including chest constriction,fear, and uneasiness.44,45 Activationof this constellation of regions suggests an increased emotional responseto direct gaze in the fraX group. However, activation in these regions isnot specific to anxiety. In addition, greater left posterior insula activationwas seen in the control group. More research will be needed to determine whethersocial anxiety is related to altered gaze processing in fraX. It is possiblethat the photographs did not provoke anxiety in the fraX individuals becausethe scan did not involve an actual social situation, but only stimuli associatedwith social interactions. The knowledge that no real social interaction wouldtake place during the fMRI task could have helped to lessen the social anxietytypically observed in these subjects.

This study is significant in distinguishing brain responses to socialstimuli in fraX from those previously reported in autism. A subset of thesocial deficits seen in fraX is observed in autism, and hence the 2 developmentaldisorders have long been compared and contrasted.4 Forexample, both fraX and autistic individuals experience difficulties with verbaland nonverbal social communication.46 However,unlike autistic children, children with fraX show a propensity to engage insocial behaviors with caregivers,4 and theycorrectly identify facial and auditory emotion.25,47 Cohenand colleagues36,37 showed that,although both fraX and autistic children avoided social interactions, malefraX subjects avoided a stranger more than a parent, and autistic childrenavoided stranger and parent equally. Furthermore, analysis of dyadic socialgaze patterns suggest that male fraX subjects are sensitive to eye gaze butavoid it because they find it aversive, whereas autistic subjects are insensitiveto gaze and do not engage in social gaze, probably because of lack of interestor attention.36,37,48 Ourstudy furthers the distinction between fraX and autistic subjects by showingdifferences in neurofunctional responses to social stimuli. Previously, Schultzand colleagues49 found reduced right FG activationto forward faces in autistic subjects. Similarly, Pierce and colleagues50 found low or absent FG activation in response toface stimuli in autistic subjects, but not controls. In contrast, our studyfound activation of the FG in response to forward and angled faces in subjectswith fraX, although with less differentiation of FG response to face orientation.

Finally, this study did not test whether activation differences in theFG and STS in fraX are specific to face and eye gaze stimuli or can be generalizedto other visual stimuli. Also, further studies are needed to determine whetherincreased anxiety is related to STS dysfunction in fraX. Monitoring heartrate and eye gaze during scanning may help us to answer these questions infuture investigations.

Corresponding author: Amy S. Garrett, PhD, Department of Psychiatryand Behavioral Sciences, Stanford University School of Medicine, 401 QuarryRd, Stanford, CA 94305 (e-mail: agarrett@stanford.edu).

Submitted for publication March 11, 2003; final revision received July24, 2003; accepted August 5, 2003.

This study was supported by grants MH19908, MH64708, MH01142, MH50047,and HD31715 (Dr Reiss) and HD40761 (Dr Menon) from the National Institutesof Health, Bethesda, Md, and a gift from the Lynda and Scott Canel Fund forFragile X Research.

We thank Noah Merin and Chris White for data collection, David Hessl,PhD, for subject recruitment and testing, and Gary Glover, PhD, for technicalexpertise.

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Hessl  DR GBDyer-Friedman  JBlasey  CHastie  TGunnar  MReiss  AL Cortisol and behavior in fragile X syndrome. Psychoneuroendocrinology. 2002;27855- 872
PubMed
Puce  AAllison  TGore  JCMcCarthy  G Face-sensitive regions in human extrastriate cortex studied by functionalMRI. J Neurophysiol. 1995;741192- 1199
PubMed
Kanwisher  NMcDermott  JChun  MM The fusiform face area. J Neurosci. 1997;174302- 4311
PubMed
Clark  VPKeil  KMaisog  JMCourtney  SUngerleider  LGHaxby  JV Functional magnetic resonance imaging of human visual cortex duringface matching: a comparison with positron emission tomography. Neuroimage. 1996;41- 15
PubMed
Damasio  ARDamasio  HHoesen  GW Van Prosopagnosia: anatomic basis and behavioral mechanisms. Neurology. 1982;32331- 341
PubMed
Allison  TGinter  HMcCarthy  GNobre  ACPuce  ALuby  MSpencer  DD Face recognition in human extrastriate cortex. J Neurophysiol. 1994;71821- 825
PubMed
McCarthy  GPuce  ABelger  AAllison  T Electrophysiological studies of human face perception, II. Cereb Cortex. 1999;9431- 444
PubMed
Gauthier  ITarr  MJMoylan  JSkudlarski  PGore  JCAnderson  AW The fusiform "face area" is part of a network that processes facesat the individual level. J Cogn Neurosci. 2000;12495- 504
PubMed
Gauthier  ITarr  MJAnderson  AWSkudlarski  PGore  JC Activation of the middle fusiform "face area" increases with expertisein recognizing novel objects. Nat Neurosci. 1999;2568- 573
PubMed
Rossion  BDricot  LDevolder  ABodart  JMCrommelinck  MDe  Gelder BZoontjes  R Hemispheric asymmetries for whole-based and part-based face processingin the human fusiform gyrus. J Cogn Neurosci. 2000;12793- 802
PubMed
Wojciulik  EKanwisher  NDriver  J Covert visual attention modulates face-specific activity in the humanfusiform gyrus. J Neurophysiol. 1998;791574- 1578
PubMed
Grady  CL Age-related changes in cortical blood flow activation during perceptionand memory. Ann N Y Acad Sci. 1996;77714- 21
PubMed
Hoffman  EAHaxby  JV Distinct representations of eye gaze and identity in the distributedhuman neural system for face perception. Nat Neurosci. 2000;380- 84
PubMed
Campbell  RHeywood  CACowey  ARegard  MLandis  T Sensitivity to eye gaze in prosopagnosic patients and monkeys withsuperior temporal sulcus ablation. Neuropsychologia. 1990;281123- 1142
PubMed
Wicker  BMichel  FHenaff  MADecety  J Brain regions involved in the perception of gaze: a PET study. Neuroimage. 1998;8221- 227
PubMed
George  NDriver  JDolan  RJ Seen gaze-direction modulates fusiform activity and its coupling withother brain areas during face processing. Neuroimage. 2001;131102- 1112
PubMed
Calder  AJLawrence  ADKeane  JScott  SKOwen  AMChristoffels  IYoung  AW Reading the mind from eye gaze. Neuropsychologia. 2002;401129- 1138
PubMed
Turk  JCornish  K Face recognition and emotion perception in boys with fragile-X syndrome. J Intellect Disabil Res. 1998;42490- 499
PubMed
Friston  KJZarahn  EJosephs  OHenson  RNDale  AM Stochastic designs in event-related fMRI. Neuroimage. 1999;10607- 619
PubMed
Cohen  JDMacWhinney  BFlatt  MProvost  J PsyScope. Behav Res Methods Instrum Comput. 1993;25257- 271
Ranganath  CD'Esposito  M Medial temporal lobe activity associated with active maintenance ofnovel information. Neuron. 2001;31865- 873
PubMed
Hayes  CMathias  C Improved brain coil for fMRI and high resolution imaging [abstract]. Proceedings of the Fourth Annual Meeting ofthe International Society for Magnetic Resonance in Medicine. Berkeley,Calif ISMRM1996;1414
Glover  GHLai  S Self-navigated spiral fMRI. Magn Reson Med. 1998;39361- 368
PubMed
Talairach  JTournoux  P Co-planar Stereotaxic Atlas of the Human Brain.  New York, NY Thieme-Stratton Inc1988;
Holmes  APFriston  KJ Generalizability, random effects, and population inference [abstract]. Neuroimage. 1998;7S754
Poline  JBWorsley  KJEvans  ACFriston  KJ Combining spatial extent and peak intensity to test for activationsin functional imaging. Neuroimage. 1997;583- 96
PubMed
Brett  M The MNI brain and the Talairach atlas. Available at:http://www.mrc-cbu.cam.ac.uk/Imaging/mnispace.html Accessed July 2001.
Reiss  AL BrainImage. 5.1.5 Stanford, Calif AL Reiss2002;
Cohen  ILVietze  PMSudhalter  VJenkins  ECBrown  WT Parent-child dyadic gaze patterns in fragile X males and in non–fragileX males with autistic disorder. J Child Psychol Psychiatry. 1989;30845- 856
PubMed
Cohen  ILVietze  PMSudhalter  VJenkins  ECBrown  WT Effects of age and communication level on eye contact in fragile Xmales and non–fragile X autistic males. Am J Med Genet. 1991;38498- 502
PubMed
Garrett  ASFlowers  DLAbsher  JRFahey  FHGage  HDKeyes  JWPorrino  LJWood  FB Cortical activity related to accuracy of letter recognition. Neuroimage. 2000;11111- 123
PubMed
Reiss  ALLee  JFreund  L Neuroanatomy of fragile X syndrome: the temporal lobe. Neurology. 1994;441317- 1324
PubMed
Price  JL Prefrontal cortical networks related to visceral function and mood. Ann N Y Acad Sci. 1999;877383- 396
PubMed
Levesque  JEugene  FJoanette  YPaquette  VMensour  BBeaudoin  GLeroux  JMBourgouin  PBeauregard  M Neural circuitry underlying voluntary suppression of sadness. Biol Psychiatry. 2003;53502- 510
PubMed
Fredrikson  MWik  GAnnas  PEricson  KStone-Elander  S Functional neuroanatomy of visually elicited simple phobic fear: additionaldata and theoretical analysis. Psychophysiology. 1995;3243- 48
PubMed
Chua  PKrams  MToni  IPassingham  RDolan  R A functional anatomy of anticipatory anxiety. Neuroimage. 1999;9563- 571
PubMed
Bouilleret  VDupont  SSpelle  LBaulac  MSamson  YSemah  F Insular cortex involvement in mesiotemporal lobe epilepsy. Ann Neurol. 2002;51202- 208
PubMed
Augustine  JR Circuitry and functional aspects of the insular lobe in primates includinghumans. Brain Res Brain Res Rev. 1996;22229- 244
PubMed
Mazzocco  MMKates  WRBaumgardner  TLFreund  LSReiss  AL Autistic behaviors among girls with fragile X syndrome. J Autism Dev Disord. 1997;27415- 435
PubMed
Simon  EWFinucane  BM Facial emotion identification in males with fragile X syndrome. Am J Med Genet. 1996;6777- 80
PubMed
Bregman  JDLeckman  JFOrt  SI Fragile X syndrome: genetic predisposition to psychopathology. J Autism Dev Disord. 1988;18343- 354
PubMed
Schultz  RTGauthier  IKlin  AFulbright  RKAnderson  AWVolkmar  FSkudlarski  PLacadie  CCohen  DJGore  JC Abnormal ventral temporal cortical activity during face discriminationamong individuals with autism and Asperger syndrome. Arch Gen Psychiatry. 2000;57331- 340
PubMed
Pierce  KMuller  RAAmbrose  JAllen  GCourchesne  E Face processing occurs outside the fusiform "face area" in autism:evidence from functional MRI. Brain. 2001;1242059- 20573
PubMed

Figures

Place holder to copy figure label and caption
Figure 1

Examples of photographs used asstimuli. Labels describe stimulus type. FD indicates forward face with directgaze; FA, forward face with averted gaze; AD, angled face with direct gaze;and AA, angled face with averted gaze.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Location of activation that is significantly differentbetween groups for the whole brain analysis of direct gaze compared with avertedgaze, after covarying for group differences in IQ. The Talairach atlas y-coordinateis given in the lower left corner of each image. The right side of image indicatesthe right side of brain. All clusters are significant at P<.05.A, Greater activation in the control compared with the fragile X syndrome(fraX) group, including left superior temporal sulcus, middle temporal sulcus,and hippocampus. Additional significant clusters are listed in Table 2. B, Greater activation in the fraX compared with the controlgroup in the right insula, posterior thalamus, and brainstem. Additional clustersare listed in Table 2.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3

Fusiform gyrus (FG) region ofinterest. A, Significant interaction between group and face orientation (F1,20 = 9.20 [P= .007]). Control subjects show significantlygreater FG activation for forward faces than for angled faces, and subjectswith fragile X syndrome (fraX) show no difference between forward and angledfaces. Activation of FG to angled faces is not significantly different betweengroups. B, Significant interaction between group and hemisphere (F1,20 = 5.75 [P= .03]). Control subjects have greater rightthan left hemisphere FG activation to all stimuli, whereas fraX subjects haveno significant difference in activation of the FG between hemispheres. Datapoints indicate means; error bars, SEM.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4

Superior temporal sulcus (STS)region of interest. A, The control group has significantly greater STS activationoverall compared with the fragile X syndrome (fraX) group (F1,19 =6.11 [P= .02]). B, All subjects had greater right than left hemisphereSTS activation (F1,20 = 14.61 [P= .001]).Post hoc comparisons show that this effect is carried by control subjects,who had greater right than left hemisphere STS activation (F1,20 =13.93 [P= .001]). AA indicates angled face with averted gaze;AD, angled face with direct gaze; FA, forward face with averted gaze; FD,forward face with direct gaze; data points, means; and error bars, SEM.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Gaze Orientation Task Performance*
Table Graphic Jump LocationTable 2. Brain Regions Showing Significantly Greater Activation toDirect Gaze Compared With Averted Gaze After Covarying for IQ*

References

Irwin  SAPatel  BIdupulapati  MHarris  JBCrisostomo  RALarsen  BPKooy  FWillems  PJCras  PKozlowski  PBSwain  RAWeiler  IJGreenough  WT Abnormal dendritic spine characteristics in the temporal and visualcortices of patients with fragile-X syndrome. Am J Med Genet. 2001;98161- 167
PubMed
Cornish  KMMunir  FCross  G Differential impact of the FMR-1 full mutation on memory and attentionfunctioning. J Cogn Neurosci. 2001;13144- 150
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Wolff  PHGardner  JPaccla  JLappen  J The greeting behavior of fragile X males. Am J Ment Retard. 1989;93406- 411
PubMed
Reiss  ALFreund  L Behavioral phenotype of fragile X syndrome: DSM-III-R autistic behavior in male children. Am J Med Genet. 1992;4335- 46
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Lachiewicz  AM Abnormal behaviors of young girls with fragile X syndrome. Am J Med Genet. 1992;4372- 77
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Freund  LSReiss  ALAbrams  MT Psychiatric disorders associated with fragile X in the young female. Pediatrics. 1993;91321- 329
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Belser  RCSudhalter  V Conversational characteristics of children with fragile X syndrome:repetitive speech. Am J Ment Retard. 2001;10628- 38
PubMed
Hessl  DR GBDyer-Friedman  JBlasey  CHastie  TGunnar  MReiss  AL Cortisol and behavior in fragile X syndrome. Psychoneuroendocrinology. 2002;27855- 872
PubMed
Puce  AAllison  TGore  JCMcCarthy  G Face-sensitive regions in human extrastriate cortex studied by functionalMRI. J Neurophysiol. 1995;741192- 1199
PubMed
Kanwisher  NMcDermott  JChun  MM The fusiform face area. J Neurosci. 1997;174302- 4311
PubMed
Clark  VPKeil  KMaisog  JMCourtney  SUngerleider  LGHaxby  JV Functional magnetic resonance imaging of human visual cortex duringface matching: a comparison with positron emission tomography. Neuroimage. 1996;41- 15
PubMed
Damasio  ARDamasio  HHoesen  GW Van Prosopagnosia: anatomic basis and behavioral mechanisms. Neurology. 1982;32331- 341
PubMed
Allison  TGinter  HMcCarthy  GNobre  ACPuce  ALuby  MSpencer  DD Face recognition in human extrastriate cortex. J Neurophysiol. 1994;71821- 825
PubMed
McCarthy  GPuce  ABelger  AAllison  T Electrophysiological studies of human face perception, II. Cereb Cortex. 1999;9431- 444
PubMed
Gauthier  ITarr  MJMoylan  JSkudlarski  PGore  JCAnderson  AW The fusiform "face area" is part of a network that processes facesat the individual level. J Cogn Neurosci. 2000;12495- 504
PubMed
Gauthier  ITarr  MJAnderson  AWSkudlarski  PGore  JC Activation of the middle fusiform "face area" increases with expertisein recognizing novel objects. Nat Neurosci. 1999;2568- 573
PubMed
Rossion  BDricot  LDevolder  ABodart  JMCrommelinck  MDe  Gelder BZoontjes  R Hemispheric asymmetries for whole-based and part-based face processingin the human fusiform gyrus. J Cogn Neurosci. 2000;12793- 802
PubMed
Wojciulik  EKanwisher  NDriver  J Covert visual attention modulates face-specific activity in the humanfusiform gyrus. J Neurophysiol. 1998;791574- 1578
PubMed
Grady  CL Age-related changes in cortical blood flow activation during perceptionand memory. Ann N Y Acad Sci. 1996;77714- 21
PubMed
Hoffman  EAHaxby  JV Distinct representations of eye gaze and identity in the distributedhuman neural system for face perception. Nat Neurosci. 2000;380- 84
PubMed
Campbell  RHeywood  CACowey  ARegard  MLandis  T Sensitivity to eye gaze in prosopagnosic patients and monkeys withsuperior temporal sulcus ablation. Neuropsychologia. 1990;281123- 1142
PubMed
Wicker  BMichel  FHenaff  MADecety  J Brain regions involved in the perception of gaze: a PET study. Neuroimage. 1998;8221- 227
PubMed
George  NDriver  JDolan  RJ Seen gaze-direction modulates fusiform activity and its coupling withother brain areas during face processing. Neuroimage. 2001;131102- 1112
PubMed
Calder  AJLawrence  ADKeane  JScott  SKOwen  AMChristoffels  IYoung  AW Reading the mind from eye gaze. Neuropsychologia. 2002;401129- 1138
PubMed
Turk  JCornish  K Face recognition and emotion perception in boys with fragile-X syndrome. J Intellect Disabil Res. 1998;42490- 499
PubMed
Friston  KJZarahn  EJosephs  OHenson  RNDale  AM Stochastic designs in event-related fMRI. Neuroimage. 1999;10607- 619
PubMed
Cohen  JDMacWhinney  BFlatt  MProvost  J PsyScope. Behav Res Methods Instrum Comput. 1993;25257- 271
Ranganath  CD'Esposito  M Medial temporal lobe activity associated with active maintenance ofnovel information. Neuron. 2001;31865- 873
PubMed
Hayes  CMathias  C Improved brain coil for fMRI and high resolution imaging [abstract]. Proceedings of the Fourth Annual Meeting ofthe International Society for Magnetic Resonance in Medicine. Berkeley,Calif ISMRM1996;1414
Glover  GHLai  S Self-navigated spiral fMRI. Magn Reson Med. 1998;39361- 368
PubMed
Talairach  JTournoux  P Co-planar Stereotaxic Atlas of the Human Brain.  New York, NY Thieme-Stratton Inc1988;
Holmes  APFriston  KJ Generalizability, random effects, and population inference [abstract]. Neuroimage. 1998;7S754
Poline  JBWorsley  KJEvans  ACFriston  KJ Combining spatial extent and peak intensity to test for activationsin functional imaging. Neuroimage. 1997;583- 96
PubMed
Brett  M The MNI brain and the Talairach atlas. Available at:http://www.mrc-cbu.cam.ac.uk/Imaging/mnispace.html Accessed July 2001.
Reiss  AL BrainImage. 5.1.5 Stanford, Calif AL Reiss2002;
Cohen  ILVietze  PMSudhalter  VJenkins  ECBrown  WT Parent-child dyadic gaze patterns in fragile X males and in non–fragileX males with autistic disorder. J Child Psychol Psychiatry. 1989;30845- 856
PubMed
Cohen  ILVietze  PMSudhalter  VJenkins  ECBrown  WT Effects of age and communication level on eye contact in fragile Xmales and non–fragile X autistic males. Am J Med Genet. 1991;38498- 502
PubMed
Garrett  ASFlowers  DLAbsher  JRFahey  FHGage  HDKeyes  JWPorrino  LJWood  FB Cortical activity related to accuracy of letter recognition. Neuroimage. 2000;11111- 123
PubMed
Reiss  ALLee  JFreund  L Neuroanatomy of fragile X syndrome: the temporal lobe. Neurology. 1994;441317- 1324
PubMed
Price  JL Prefrontal cortical networks related to visceral function and mood. Ann N Y Acad Sci. 1999;877383- 396
PubMed
Levesque  JEugene  FJoanette  YPaquette  VMensour  BBeaudoin  GLeroux  JMBourgouin  PBeauregard  M Neural circuitry underlying voluntary suppression of sadness. Biol Psychiatry. 2003;53502- 510
PubMed
Fredrikson  MWik  GAnnas  PEricson  KStone-Elander  S Functional neuroanatomy of visually elicited simple phobic fear: additionaldata and theoretical analysis. Psychophysiology. 1995;3243- 48
PubMed
Chua  PKrams  MToni  IPassingham  RDolan  R A functional anatomy of anticipatory anxiety. Neuroimage. 1999;9563- 571
PubMed
Bouilleret  VDupont  SSpelle  LBaulac  MSamson  YSemah  F Insular cortex involvement in mesiotemporal lobe epilepsy. Ann Neurol. 2002;51202- 208
PubMed
Augustine  JR Circuitry and functional aspects of the insular lobe in primates includinghumans. Brain Res Brain Res Rev. 1996;22229- 244
PubMed
Mazzocco  MMKates  WRBaumgardner  TLFreund  LSReiss  AL Autistic behaviors among girls with fragile X syndrome. J Autism Dev Disord. 1997;27415- 435
PubMed
Simon  EWFinucane  BM Facial emotion identification in males with fragile X syndrome. Am J Med Genet. 1996;6777- 80
PubMed
Bregman  JDLeckman  JFOrt  SI Fragile X syndrome: genetic predisposition to psychopathology. J Autism Dev Disord. 1988;18343- 354
PubMed
Schultz  RTGauthier  IKlin  AFulbright  RKAnderson  AWVolkmar  FSkudlarski  PLacadie  CCohen  DJGore  JC Abnormal ventral temporal cortical activity during face discriminationamong individuals with autism and Asperger syndrome. Arch Gen Psychiatry. 2000;57331- 340
PubMed
Pierce  KMuller  RAAmbrose  JAllen  GCourchesne  E Face processing occurs outside the fusiform "face area" in autism:evidence from functional MRI. Brain. 2001;1242059- 20573
PubMed

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