This study examined the interaction between emotional face processing and memory as related to social anxiety in individuals with fragile X syndrome compared to typically-developing individuals. At the behavioral level, individuals with FXS demonstrated poorer ability to distinguish previously viewed faces compared to typically-developing individuals (i.e., poorer memory for faces), although this group difference was largely an effect of lower cognitive functioning. Further, gaze-fixation results provide evidence that although individuals with FXS showed significantly lower eye- and face-fixation compared to the control group, successful encoding of faces was not related to the amount of time spent looking at the eyes or face in either group. We speculate that if the encoding task had involved emotion (rather than gender) discrimination, these gaze-fixation results might have been different. In fact, data exist to suggest abnormal fusiform gyrus activation related to gaze-fixation patterns during an emotion discrimination task in individuals with FXS (Dalton et al., in press
), which indicates the possibility of distinct, task-dependent relationships between gaze-fixation and brain activation associated with face processing in FXS.
Our neuroimaging results revealed unique patterns of neural activation during face encoding in individuals with FXS, who showed highly contrasting relationships between brain activation and both gaze-fixation and social anxiety levels compared to typically-developing individuals. The control group demonstrated a stronger Dm effect than the FXS group in frontal regions associated with social cognition (SFG and MFG). Additionally, in the FXS group, eye-fixation was negatively associated with activation to subsequently remembered faces in regions involved in both attention (posterior cingulate gyrus) and orienting to emotional cues (insula), and positively related to activation in multisensory association regions (angular gyrus), patterns opposite of those seen in the control group. Finally, regression analyses demonstrated that individuals with FXS who have higher levels of social anxiety showed less activation in response to faces that they later remembered in frontal social cognition regions and in hippocampal memory areas, while reverse relationships were seen in the control group. We believe that our neuroimaging findings, which show dysfunction in several specialized neural networks, support the theory that neural functioning abnormalities in FXS derive from the interaction between genetic and neural processes throughout the brain that compound over time, leading to network-wide dysfunction (Belmonte and Bourgeron, 2006
As expected, both FXS and control groups demonstrated a robust Dm effect in the PHG and IFG, regions well-established as part of the successful encoding network (Paller and Wagner, 2002
). This across-group finding suggests that individuals with FXS were similar to typically-developing individuals in their ability to recruit networks involved in successful encoding. However, direct group contrast of Dm effect activation indicated that individuals in the control group exhibited a stronger Dm effect than the FXS group in the SFG and MFG, regions that fall within the boundaries of the ventrolateral prefrontal cortex (VLPFC). The VLPFC plays unique roles in both memory processes (updating and maintaining contents of working memory; for a review, see Fletcher and Henson, 2001
) and social cognition (controlled processes associated with awareness, intention, and effort; Wegner and Bargh, 1998
). In particular, the VLPFC is involved in tasks probing autobiographical and episodic memory (Gilboa, 2004
), judgment of another person's actions (Mason et al., 2004
), inhibiting the self-experience while considering another's perspective (Baron-Cohen et al., 1999
; Vogeley et al., 2001
), and recognition of self vs. others (Platek et al., 2006
; Uddin et al., 2005
). In addition, previous neuroimaging reports cite activation in prefrontal areas within or just medial to the current SFG and MFG regions during various types of face encoding tasks, including basic face encoding (Haxby et al., 1996
) and those that require subjects to form impressions of the individuals presented (Mitchell et al., 2004
) and judge the pleasantness of the face (Bernstein et al., 2002
). Moreover, medial prefrontal cortex (MPFC) activation has been shown to predict successful encoding of pictures with social content, as compared to non-social images, suggesting that MPFC is involved in self-referential processes which aid in the formation of socially-relevant memories (Harvey et al., 2007
). As such, this pattern of activation in the control group suggests that successful encoding of faces in typically-developing individuals involves engagement of social cognition networks.
Interestingly, individuals with FXS not only failed to recruit these regions, they demonstrated decreased activation in the SFG and MFG in response to successfully encoded faces. This pattern of response is difficult to interpret. However, individuals with full mutation FXS have previously been found to exhibit decreased activation compared to typically-developing individuals in the SFG during arithmetic processing (Rivera et al., 2002
). Reduced VLPFC activation in response to a go/nogo task was recently reported in a group of males with FXS, similar to our VLPFC results (but in the contralateral (right) hemisphere; Hoeft et al., 2007
). These results, combined with findings of significant relationships between VLPFC and FMRP level (Hoeft et al., 2007
; Menon et al., 2004
), suggest this region may be consistently affected in FXS. In addition, recent findings suggest that male premutation carriers exhibit decreased activation in social cognition regions (such as the orbitofrontal cortex and superior temporal sulcus) during fearful face processing (Hessl et al., 2007
We did not find differential group activation of the amygdala in response to the Dm effect. While the FXS group showed a Dm effect in the amygdala, direct group comparison failed to identify this region as significantly more responsive to the Dm effect in the FXS group compared to the control group. The amygdala is heavily involved in the consolidation of emotional information (Kensington and Schacter, 2006
; for a review, see LaBar and Cabeza, 2006
; Phelps, 2006
) and in the successful encoding of unfamiliar faces (Bernstein et al., 2002
; Dubois et al., 1999
; Sergerie et al., 2006
). Coupled activation of the amygdala and hippocampus in particular has been implicated in encoding and retrieval of emotional information (Dolcos et al., 2004
; Erk et al., 2005
; Richardson et al., 2004
; Smith et al., 2006
). However, evidence from a recent study implies that amygdala activation specifically predicts successful encoding of emotional (vs. neutral) pictures, but is not involved in encoding related to the social nature of pictures (Harvey et al., 2007
). The lack of amygdala activation in response to the Dm effect the control group (and in the between-group comparison) in the current study may be due to the fact that individuals in the control group did not find the faces to be sufficiently emotional in nature. Consideration of previous findings and of the fact that we did not include a neutral face category may partially explain our findings (or lack thereof) in the amygdala.
Beyond this main set of group differences in the Dm effect, neural activity associated with successful encoding of faces was found to be related to the amount of time spent fixating the eyes, although the direction of this association differed between groups. Specifically, typically-developing individuals with greater eye fixation exhibited greater activity in the left insula and left posterior cingulate gyrus, while the opposite relationship held for the FXS group. Activity in these regions likely reflects neural substrates of attention and orientation to emotional expression, which, for the control group, appears to relate to the amount of time one spends looking at the eyes. In the FXS group, lower levels of activation in these regions for individuals who show increased eye fixation may be associated with phenomenological differences in the underlying neural mechanisms of gaze-fixation, which have been documented in this population (Dalton et al., 2006; Garrett et al., 2004
). Individuals with FXS have previously been found to exhibit decreased activation compared to typically-developing individuals in the left insula during tasks involving processing of direct- vs. angled-gaze faces (Garrett et al., 2004
) and cognitive interference (Tamm et al., 2002
). In addition, these findings may add support to recent evidence suggesting that gaze avoidance in FXS is possibly more related to multisensory and task demand avoidance than to social anxiety per se (Murphy et al., 2007
). Finally, individuals with FXS show a positive relationship between eye fixation and brain activation in the angular gyrus during face encoding. This relationship may be related to deficits in attention and multisensory integration as well as underlying molecular mechanisms, given that activation during a behavioral inhibition task in the left angular gyrus has previously been reported to be positively associated with FMRP expression in individuals with FXS (Menon et al., 2004
; Rivera et al., 2002
Neural dysfunction associated with social-emotional processing in FXS has been previously documented (Dalton et al., 2006; Garrett et al., 2004
). However, one of the main goals of the present study was to take the investigation of neural mechanisms of phenotypic behaviors in FXS one step further by identifying neural substrates more closely associated social anxiety in FXS. Results of the regression of social anxiety level on brain activation in response to successfully encoded faces indicate contrasting relationships between neural function and social anxiety in individuals with FXS compared to typically-developing individuals. The FXS group demonstrated a negative association between social anxiety and activation in the SFG, MFG, and IFG, while the control group exhibited positive relationships between activity in these regions and level of social anxiety, differences that cannot be attributed to varying cognitive functioning between groups. These data suggest that individuals with FXS who have high social anxiety fail to recruit networks associated with successful encoding and social cognition, while those with lower levels of social anxiety engage these regions to a certain degree. The positive relationship seen in the control group indicates phenomenological differences between these groups in underlying mechanisms of social anxiety. It is possible that in control subjects, heightened activation in social cognition and encoding networks is suggestive of heightened arousal related to social information processing, perhaps in attempts to override anxiety.
Individuals with FXS also showed a negative relationship between activation in the hippocampus and social anxiety, such that individuals with the highest levels of social anxiety were least able to recruit this important memory-associated region during face encoding. The hippocampus in FXS is abnormal both at the gross anatomical level (enlarged; Kates et al., 1997
; Reiss et al., 1994
) and at the functional level (decreased activation compared to controls; Menon et al., 2004
; Greicius et al., 2004
). Importantly, the hippocampus is one of the regions of the brain with the greatest expression of FMRP (Abitbol et al., 1993
; Hinds et al., 1993
). In FXS, FMRP is positively related to activation in the hippocampus during behavioral inhibition (Menon et al., 2004
). In light of these extant data, current findings suggest that hippocampal dysfunction in FXS extends to the interaction between behavioral symptoms of social anxiety and encoding of social information.
It is striking that most of these regression results trend in the direction of negative relationships between brain activity and behavioral measures in the FXS group, except for the finding of a positive relationship between angular gyrus activation and eye fixation. We hypothesize that this relationship represents the confluence of molecular and neural mechanisms in a region uniquely involved in eye fixation. The angular gyrus represents the only one among these regions (i.e., those demonstrating relationships between brain activity and behavioral measures) that is not consistently involved in social/emotional processing. The angular gyrus, in addition to playing a role in reading and language (Humphries et al., 2007
; Phinney et al., 2007
) and math processing (Grabner et al., 2007
), has also been shown to be involved in multisensory integration, specifically in non-voluntary (i.e., reflexive) visual field examination (Mort et al., 2003
). Given the social and emotional deficits involved in the FXS phenotype, it is therefore not surprising that this region might demonstrate a somewhat different pattern, one in which increased activation during visual exploration of faces is directly and positively related to the amount of eye fixation. This trend may represent compensatory involvement of a region strictly involved in sensory processing. In addition, unlike the posterior cingulate and left insula, studies consistently report a positive relationship between angular gyrus activation (during both arithmetic processing and behavioral inhibition tasks) and FMRP expression (Menon et al., 2004
; Rivera et al., 2002
). Thus, while the control group demonstrated a positive relationship between eye fixation and activation in the insula and posterior cingulate, two regions involved in emotional processing, the FXS group, hampered by an inability to correctly recruit these regions during the task, may have relied on the angular gyrus for visual field examination of faces. Taken together, this suggests possible compensatory participation of the angular gyrus related to eye gaze fixation in individuals with FXS, which might relate to FMRP expression (though this latter idea remains untested and speculative).
Although the current data advance the understanding of social anxiety in FXS, several limitations to this study should be acknowledged, especially with respect to generalizability of our findings. First, the sample size was small, limiting our power to detect meaningful results. Thus, these findings should be considered preliminary. Additionally, we included a mixed group of individuals with FXS, with almost equal numbers of males and females. While males and females in this study showed differences in IQ and social anxiety level, they did not differ significantly in their level of gaze fixation or face encoding, either behaviorally or in their neural response associated with the Dm effect. The literature on FXS has documented phenotypic differences between males and females with FXS, and our inclusion of both genders may limit our ability to generalize to the FXS population as a whole. However, this study represents only the second fMRI study to include a large group of males with FXS who have lower cognitive functioning, a portion of the FXS population that has yet to be extensively studied.
Another limitation of the study was the wide age range across groups and significant group difference in IQ. Although we controlled for these factors in our analyses, a more valid approach would have been to narrow the age range and to include a group of individuals with developmental disabilities matched on chronological and mental age, in addition to the typically-developing control group. In addition, we did not include a comparison group of individuals with autism, who demonstrate similar heightened social anxiety level and deficits in face memory as individuals with FXS. Inclusion of these groups would have allowed for more meaningful conclusions regarding the role of cognitive ability and etiology of autistic behaviors (respectively) in the delineation of neural mechanisms of social anxiety in FXS. Further, we did not collect SCQ data for the TD group. Although we did not suspect any of the individuals in this group of meeting criteria for an autism spectrum disorder, nor did we observe any autism behaviors in these individuals, we cannot definitively rule out the possibility of the presence of autism characteristics in this group. Additionally, one of our FXS participants was taking methylphenidate at the time of the study. While this medication is known to affect frontal cortex function, within and between group results did not change significantly when this subject was excluded from analysis (data not shown). Finally, facial expression of the target stimuli was not varied. Such a design would have allowed for investigation of whether current findings are specific to fearful expressions or might be different (especially in the amygdala) according to the type and degree of emotion shown.
In conclusion, individuals with FXS were found to exhibit less activation in social cognition regions during successful vs. unsuccessful face encoding, compared to typically-developing individuals. Additional diverging results between groups were revealed in the relationships between activation in social cognition areas and behavioral measures of social anxiety, suggesting that social anxiety in FXS is likely related to the inability to recruit higher-level regions associated with processing of social information during the initial phases of memory formation. Future studies should utilize larger samples of individuals with FXS, systematically examine possible gender differences in FXS, and include comparison groups of individuals with IA and those matched on IQ.