This study is the first to examine the neural response to general emotional stimuli in a pediatric OCD sample. In this study, less amygdala/hippocampus activation to facial expressions relative to fixation was found in a pediatric sample with OCD compared to healthy comparison subjects, replicating previous work in adult OCD [19
]. Due to the spatial resolution of fMRI, it is difficult to pinpoint the exact location of the group difference found at the border of the amygdala and hippocampus; however, based on the previous literature in adult OCD as well as studies of emotional face processing, this group difference likely emanates from the amygdala.
As in the previous study in adult OCD, the pediatric OCD group exhibited less amygdala activation to multiple facial expressions compared to the HC group. The amygdala activation is less in response to positive (i.e., happy), negative (i.e., fearful) and neutral facial expressions. In addition, this study provides evidence that the less amygdala activation in OCD patients extends to other negative emotions, i.e., disgust. In the literature, the amygdala has been shown to respond to all of these different types of emotion [40
] and given the lack of specificity in a previous study [19
], identifying less amygdala activation to multiple emotions is not surprising. While OCD may be similar to other anxiety disorders with respect to greater amygdala activation during symptom provocation [7
], the finding of less amygdala activation to facial expressions, general emotional stimuli, may distinguish OCD from other anxiety disorders.
Although speculative, the hyperactivity of the frontal cortical regions found in OCD may dampen the amygdala activation to disorder-irrelevant stimuli, such as facial expressions. The increased cortical activity may, in turn, suppress the subcortical and autonomic systems [10
]. Although no differences in frontal cortical activation in response to emotional faces relative to fixation were noted in this study, resting state studies have consistently reported enhanced activity in orbitofrontal-striatal regions in OCD [46
]. The tonic hyperactivity of the orbitofrontal regions in OCD may have prevented the detection of phasic changes in the amygdala and/or frontal cortical regions to general emotional stimuli in this study. This finding is consistent with the demonstrated blunted peripheral autonomic response to general stressors not relevant to OCD symptoms. Compared to HC subjects and other anxiety disorder groups, patients with OCD had lower levels of physiological responding to non-disorder related stressors (i.e., decreased physiological flexibility) [48
]. On the other hand, disorder-specific stimuli or increased disorder-related anxiety may elicit amygdala activation and hyperarousal symptoms in adult OCD [7
], like other anxiety disorders. It is unclear whether the different pattern of amygdala activation in response to symptom provocation versus general emotional stimuli applies to both adult and pediatric OCD. Only one published study has examined symptom provocation in pediatric OCD [49
]. In that study, reduced activation in the cortico-striatal-thalamic circuit as well as the insula was detected in the pediatric OCD group relative to healthy controls; however, no group differences were noted in the amygdala. Future studies will need to determine the pattern of amygdala activation to disorder-specific and general emotional stimuli.
Less amygdala activation in pediatric OCD in response to facial expressions could potentially be explained by group differences in amygdala structure. Previous literature has shown both decreased [50
] and increased amygdala volumes in OCD [52
]. To address this potential issue regarding amygdala structure, two separate structural analyses, including intracranial volume as a covariate, were completed to investigate any structural differences in the amygdala. A voxel based-morphometry (VBM) analysis assessed grey matter density in a whole-brain analysis and an automated segmentation method assessed anatomically-defined amygdala and hippocampus volumes [53
]. No group differences in amygdala or hippocampus structure were noted using either method.
No between-group behavioral differences were observed that would help explain the group differences in regional brain activation. The on-line performance of gender discrimination was similar in OCD subjects and comparison subjects and regressors coding accurate trials were used in the analysis. However, the OCD group did rate the faces more negatively after the fMRI session. Lower amygdala activation in the face of increased ratings of negative emotion is contrary to what might be expected. Amygdala activation has been shown to be modulated by arousal [54
] and is greater with higher emotional intensity in anxious individuals [55
]. Therefore, one might have hypothesized greater amygdala activation with greater negative ratings rather than less activation.
The current finding in a pediatric sample extends prior work in adult OCD, despite methodological differences. In the adult study, individuals passively viewed facial expressions in a block design [19
]. In the current study in youth, individuals completed a gender discrimination task in an event-related design. Previous studies have used block designs to illustrate exaggerated amygdala activation to facial expressions [9
]. The amygdala response to repeatedly presenting faces in a blocked fashion is subject to unfavorable habituation effects [57
]. Habituation effects are reduced by using an event-related design. With respect to the differences in task, it is well-known that amygdala activity is modulated by task demands. In healthy subjects, cognitive tasks (e.g., rating and reappraising) tend to increase mPFC activation and consequently reduce amygdala activation [44
], and threat appraisal tasks tend to be associated with increased amygdala activation [60
]. In most anxiety disorders, the exaggerated amygdala activation to facial expressions is task-independent. For example, exaggerated amygdala activation has been noted in anxiety disorders using passive viewing [9
], using emotion appraisal tasks such as emotional labeling [11
], and using incidental processing tasks such as gender discrimination [12
Several limitations of this study should be noted. First, the sample size of our pediatric OCD group is modest, though comparable to that of other pediatric functional neuroimaging studies. Despite the small sample size, significant group differences in amygdala activation were detected. Future studies examining emotional activation patterns in pediatric populations with increased numbers are needed. Second, our OCD sample had higher depression symptoms compared with the healthy controls. To address this in the current study, when CDI depression scores were included as a covariate of non-interest, the group differences in amygdala/hippocampus remained significant. Additional analyses were also conducted by excluding individuals with a comorbid diagnosis of MDD or Depression NOS and the study results were not altered. Finally, our pediatric OCD sample consisted mostly of medicated individuals. Treatment effects on amygdala activation have been previously reported in adults with depression. Following anti-depressant treatment in depressed adults, exaggerated amygdala activation to emotional faces was reduced [61
] and the coupling between frontal cortical regions and the amygdala during incidental face processing was increased [63
]. Rather than changes in amygdala activation [64
], anti-depressant treatment effects reported in adult OCD show reduced frontal hyperactivity [65
]. It is unclear what the effects of anti-depressant medication are in pediatric OCD. Although we cannot exclude the possibility that medication may contribute to our findings, the adult OCD subjects in a previous study that demonstrated a comparable amygdala activation pattern to emotional faces were medication-free [19
]. Future studies should examine medication effects on amygdala function in both adult and pediatric OCD.
Given that the neural pattern in response to emotional faces observed in adults with OCD appears to arise at an early age, the lower amygdala activation to emotional faces in pediatric OCD found in this study may precede symptom onset. Several findings suggest that amygdala activation to facial expressions may represent a risk factor for anxiety and depression; however, the results are not straightforward due to variations in the definition of risk and in task demands. In concordant twin pairs at risk for anxiety and depression determined by neuroticism, anxiety, and depression surveys, the high-risk adults showed reduced amygdala activation compared with the low-risk adults when identifying gender on emotional faces [67
]. Adolescents with behavioral inhibition, an early-appearing personality temperament and anxiety-disorder risk factor, have shown lower amygdala activation in response to facial expressions during passive viewing and greater amygdala activation during emotion appraisal compared to behaviorally-uninhibited adolescents [68
]. In contrast, adolescent offspring of parents with major depression show exaggerated amygdala activation while passively viewing facial expressions [69
]. Across all individuals, only amygdala activation to happy faces relative to fixation was positively correlated with age in the current study, which may indicate that this group difference may be the final one to develop. Longitudinal studies of individuals at-risk for developing OCD and cross-sectional studies in unaffected relatives should examine amygdala activation in response to facial expressions to determine if this reduced amygdala activation may predict onset and/or be an endophenotype of OCD.
In summary, the amygdala/hippocampus activation to facial expressions was lower in a pediatric OCD sample when compared to healthy age-matched individuals. This finding replicates previous work in adult OCD [19
]. Future studies are required to investigate whether this reduced amygdala activation to facial expressions predicts symptom onset and is present in unaffected relatives of OCD probands.