The present study is the first to use a facial-emotion matching task at high-field strengths to examine differences in functional brain activity between depressed adolescents without a comorbid psychiatric disorder and a group of well-matched healthy controls. This study yielded three main results. First, the ROI analysis showed that the facial-emotion matching paradigm activated the bilateral amygdala in the MDD and healthy adolescents. Second, the ROI analysis revealed that the left amygdala was significantly more active for the depressed adolescents without a concomitant psychiatric disorder compared to the matched controls. Third, the whole-brain analysis demonstrated that the ACC was significantly more active for the adolescents with MDD compared to controls.
The first result confirmed our original hypothesis and is consistent with published fMRI studies using the same facial-emotion matching paradigm and fMRI scanning parameters in adult7
and healthy adolescent16
The second result also confirmed our original a priori hypothesis that amygdala activation would be greater in the adolescents with MDD compared to controls. This finding is consistent with adult positron emission tomographic5
and fMRI studies.6,7,39,40
This result is also consistent with the majority of fMRI pediatric depression studies.10–14
However, in contrast to the finding of amygdala hyperactivity in several pediatric MDD studies including the present one, the first published study by Thomas et al.15
reported a reduction in the fMRI BOLD signal in the left amygdala.
There are several possible reasons for this difference in amygdala activation findings (i.e., hyperactivation versus hypoactivation). First, the studies varied in total sample size and gender composition. The first published fMRI study of pediatric MDD by Thomas et al.15
examined five girls and no boys, whereas all of the subsequent studies examined larger samples and included both genders.10–14
Second, Thomas et al.15
suggested that their findings might “reflect primarily increased baseline activation.”15
In their study, Thomas et al.15
compared fearful faces to fixation. None of the other studies,10–14
including the present one, used fixation as the baseline comparison condition. Furthermore, as shown by Canli et al.,41,42
the control condition (neutral baseline) can itself produce changes in activation as a function of the serotonin (5-HT) transporter (5-HTT) genotype. Using a fixation baseline condition, Canli et al.41,42
demonstrated that variation in the 5-HTT gene in adults is associated with differential activation to neutral, negative, and positive stimuli in the amygdala. Consistent with these adult findings, Lau et al.12
similarly reported differential amygdala activation to fearful faces depending on the adolescents’ 5-HTT genotype. Because the study by Lau et al.12
is the only pediatric MDD fMRI study to report on the subjects’ 5-HTT genotypes, it is unknown to what extent variations in the youths’ 5-HTT genotypes might have contributed to the differential findings of amygdala activation. Third, the studies varied in whether attention was constrained or unconstrained (passive viewing) during task performance. In the study by Thomas et al.,15
the subjects passively viewed the stimuli. In the present study, the participants were required to perform a facial-emotion matching task. The study by Beesdo et al.10
may provide significant insight because they examined amygdala activation under constrained and unconstrained conditions. They reported that the MDD and anxious adolescents demonstrated similar signs of amygdala hyperactivation to fearful faces when subjectively experienced fear was rated. However, of particular importance, the investigators also found that under the passive viewing condition, the adolescents with MDD (with or without a comorbid anxiety disorder) showed hypoactivation in the left amygdala compared to the healthy controls. Taken together, these results and the findings of the present study are consistent with the idea that differences in amygdala activation might be due to the differences in attentional condition under which the task is performed.
Overall, the adolescent MDD fMRI studies performed to date are generally consistent in their findings of a hyperactive amygdala. Taken together, the present study’s results and the previously published adolescent fMRI findings10,12–14
suggest that this observation of a hyperactive amygdala is consistent across several domains. First, we found that the amygdala is hyperactive in the MDD compared to healthy adolescents for both stimulus classes (positive and negative). Consistent with our finding, Lau et al.12
reported that genotypic differences in amygdala response in depressed and anxious adolescents were seen in fearful and (to a weaker extent) happy faces. Second, a hyperactive amygdala is observed in adolescents with MDD,10,12,13
and adolescents at high risk for MDD (offspring of parents with MDD).14
Third, we found a hyperactive amygdala using a pseudorandom block design that involved a single-attention condition. Other studies have reported similar results using an event-related fMRI design involving several different attention conditions including a passive viewing condition.10,12–14
It should again be emphasized, however, that as shown by Beesdo et al.,10
the finding of a hyperactive or hypoactive amygdala seems to be dependent on the attentional condition during which the task is performed.
The present study examined a group of adolescents with MDD without a comorbid psychiatric disorder compared to a group of carefully matched controls. Our findings are consistent with the results of Beesdo et al.10
In their study, the investigators reported greater amygdala activation in the anxiety and MDD (with and without anxiety) adolescent groups compared to controls in the a priori-defined fearful-afraid versus fearful-passive contrast. Functional MRI studies have found a hyperactive amygdala in adolescents with an anxiety disorder.13,43,44
In an fMRI study of adolescents with generalized anxiety disorder, McClure et al.43
found greater amygdala activation to fearful faces while the subjects attended to their own subjective level of fear. Taken together, our results and the findings of these other fMRI studies suggest that adolescents with only an anxiety disorder or only MDD or both disorders appear to have a hyperactive amygdala compared to healthy controls. It is important to note, however, that the findings by Beesdo et al.10
show that amygdala activity in adolescents with anxiety or MDD appear to be both similar and different depending on the attentional condition under which the fMRI task is performed.
Our finding of significant differences in left amygdala activation between the MDD and healthy adolescents is consistent with the results of Thomas et al.,15
Roberson-Nay et al.,13
and Beesdo et al.10
However, Lau et al.12
found differences in the right amygdala, and Monk et al.14
and Forbes et al.11
found differences in the bilateral amygdala. Hence, although the published adolescent MDD studies suggest that differences in amygdala activation are often observed in the left side, they also demonstrate that the results are mixed with regard to laterality. Although the task of Hariri et al.45
tends to elicit greater right than left amygdala reactivity in adults, a large meta-analysis done on the adult fMRI studies to examine the question of laterality effect on emotional-faces processing found no support for the hypothesis of overall right lateralization of emotional processing.46
Therefore, because the number of published adolescent amygdala fMRI studies is far fewer than in adults and no similar meta-analysis of the adolescent findings has been performed, we suggest that it is premature to draw any conclusions regarding the laterality of our left amygdala result.
Although the focus of our study was the amygdala and not the ACC, we found greater ACC activity in the adolescents with MDD. To our knowledge, this study is the first one to report greater ACC activity in adolescents with MDD without a comorbid psychiatric disorder compared to a group of well-matched controls using a facial-emotion matching paradigm. Our results are consistent with the only other published adolescent depression fMRI study of the ACC.47
Of note, however, most models of adult depression have emphasized the importance of function in the subgenual cingulate (BA 25), which did not differ between groups in the present study. Future studies should use the same fMRI task and scanning parameters to determine how adolescents with MDD and adults with MDD are similar or different in their activation of the ACC.
The results from the present study have several important clinical implications. In a model describing the putative roles of the amygdala in organizing multiple aspects of emotional and stress responses, Drevets8
detailed how abnormally increased amygdala activity might explain several of the clinical symptoms seen in adults with MDD. In another model, Mayberg9
proposed that adult depression is a result of a “network dysfunction.” Among the key brain areas included in Mayberg’s network are the amygdala and ACC. The results of the present study showing greater amygdala and ACC activation in adolescents with MDD compared to controls suggest that perhaps Drevets’ and May-berg’s network dysfunction models of adult depression might be extended to apply to depressed adolescents. Because our results are consistent with the models of adult depression, they support the further exploration and possible therapeutic applications of neuropsychiatric interventions that have been developed based on the functional neuroimaging research in adults. However, because the potential consequences of how the interventions designed for adults might affect the maturing adolescent brain is unknown, future explorations and studies of these and other potential treatments in depressed adolescents must be pursued with great care and caution.
The present study’s results are tempered by several limitations. First, our study used an emotion-matching task that is not directly relevant to MDD theoretically and empirically. Unlike several prior adolescent MDD studies,10,12–14
we did not examine successful versus unsuccessful face encoding. We also did not find a behavioral group effect. We used a predictable, non-jittered, block design that reduced behavioral variance. This design may have resulted in our finding of no significant group behavioral effects. However, the absence of behavioral differences between the two groups is also advantageous because it removes any performance confound. In addition, this design was selected because of greater statistical power and an enduring history of this task being used in adults32,33
Second, another limitation of our task design was that adolescents were engaged for a significant amount of time in passive viewing of the stimuli after they had made their behavioral response. Because it is unknown what mental processes the adolescents were engaged in during passive viewing, our results must be moderated by this reality. Third, in contrast to our findings using an ROI approach, significant amygdala activity did not emerge from our whole-brain analyses. Although there is good scientific justification for using an ROI approach to examine the amygdala, our results suggest that there still exists room for future studies to develop improved fMRI tasks and pulse sequences to examine the adolescent amygdala.
In summary, our findings contribute to the field of adolescent depression by demonstrating that adolescents with MDD without a concomitant psychiatric disorder have greater left amygdala and bilateral ACC activity compared to a group of well-matched healthy controls. These results suggest that models of adult depression might be extended to include adolescents, and that therapeutic interventions developed based on the adult models of depression should be further examined as potential treatments for adolescents with depression.