Pretreatment fMRI responsivity during presentation of biologically relevant stimuli associated with threat (i.e., fearful faces) predicted treatment response to venlafaxine in subjects with GAD. Specifically, greater rACC and lesser amygdala responsivity to fearful faces predicted greater decreases in anxiety after 8 weeks of treatment. This effect was specific to fearful faces, as no such effect was observed to either happy or neutral faces when directly contrasted ().
Given the correlational nature of the present findings, the directional nature of rACC-amygdala interaction during pretreatment facial expression processing and its relationship with treatment outcomes cannot be known. One possibility is that activation of the rACC in response to fearful faces exerts a regulatory influence over the amygdala (6
) and lower amygdala activation to fearful faces predicts a more beneficial outcome in terms of reported anxiety with venlafaxine. This hypothesis is consistent with anatomical data in nonhuman primates showing that the multiple regions of the ACC that send direct projections to the amygdala include a more dorsal portion of the rACC (4
) similar to that identified here in humans, as well as a recent report suggesting that the outputs from the ACC to the amygdala greatly outnumber the amygdala's reciprocal inputs (35
). That said, based upon the present data, the opposite alternative explanation is equally plausible; namely, that subjects who respond with a higher amygdala response to fearful faces, in turn, show a lesser rACC response, which predicts a less beneficial outcome in terms of reported anxiety with venlafaxine. Available anatomical data in nonhuman primates support this interpretation as well: the amygdala is known to project to a more dorsal region of the rACC in nonhuman primates (5
) similar to that identified here in human subjects. Finally, despite the existence of direct reciprocal connections between these two regions, the present effects do not necessitate a functional interaction, as activity at each region could be independently related to change in anxiety.
The present study in subjects reporting high levels of anxiety complements previous studies in subjects with depression showing that neural responsivity in the rACC (36
) and amygdala (38
) can predict drug treatment outcomes (18
). Here we show that inverse rACC-amygdala activity can predict changes in reported anxiety as measured by the HAM-A in adult subjects with GAD who were specifically recruited because of their low levels of depressive symptoms and lack of comorbid diagnosis. Given the high comorbidity between GAD and depression (40
) and the fact that amygdala reactivity can be related to the severity of reported depression (41
), future studies could assess subjects with varying degrees of anxious and depressive symptoms to determine any overlapping and nonoverlapping neural substrates that predict changes in anxious versus depressive symptoms with treatment.
Interestingly, the present findings were observed in a group of subjects with GAD whose overall magnitude of amygdala reactivity did not differ from the control group. This finding adds to existing experimental data assessing amygdala responsivity to fearful face stimuli across different anxiety disorders. To date, exaggerated amygdala responsivity to emotional facial expressions has been documented in PTSD (13
) and social phobia (20
) but not in simple phobia (43
) or GAD (present study). More complex fMRI response patterns have been observed in other studies, perhaps owing to differences in the acuteness of the disorder (PTSD) (44
), stimulus presentation parameters (i.e., masked vs. unmasked, PTSD) (16
), and medication status (panic disorder) (45
). The relatively small number of subjects assessed in this initial study calls for caution in the interpretation of the present between-group null effect, since such an effect could be due to insufficient statistical power, though we note that the comparison studies referenced above (some showing positive between-group effects) comprised subject samples of similar size. Alternatively, the lack of group differences reported here could be an artifact of elevated baseline amygdala blood flow in GAD consistent with findings that baseline blood flow correlates negatively with the magnitude of evoked blood oxygenation level-dependent (BOLD) responses (46
). This possibility could be explicitly tested using positron-emission tomography (PET) imaging or perfusion imaging in future fMRI studies.
The present results are qualified by the following limitations. For this initial study, we employed an open-label design with no comparison group of subjects with GAD receiving a placebo treatment. Thus, we cannot know if the subjects who improved would have shown this effect irrespective of venlafaxine treatment. That said, we point out that while prior studies predict that 39% of subjects would be expected to improve on a placebo basis (25
), 73% of subjects within the present study showed a significant drop in anxiety symptoms with venlafaxine treatment (defined as >50% decrease according to the criteria of Pollack et al.
]). The present study design is further limited by our use of self-report as a measure of drug compliance. A more rigorous means of documenting compliance in future studies would entail blood/urine samples. Finally, our use of a passive viewing task does not allow us to verify that subjects were attentive to the presented stimuli.
Despite the lack of a between-group main effect in the present study, individual differences in rACC and amygdala activation predicted beneficial treatment outcomes for the subjects with GAD. These pretreatment individual differences in rACC-amygdala reactivity were observed even though all subjects with GAD showed a homogeneous level of pretreatment anxiety (HAM-A scores for all subjects ranged from 18 to 21). Thus, the observed individual differences in pretreatment rACC-amygdala reactivity to fearful faces do not identify the presence of GAD or its accompanying anxiety symptoms per se. Nor can these homogeneous pretreatment levels of anxiety explain the degree of improvement with treatment in some but not other subjects. Taken together, these data suggest that the presentation of fearful faces to assess ACC-amygdala responsivity can identify some subjects reporting high anxiety but low depression symptoms who will benefit from venlafaxine treatment. Perhaps the fMRI response pattern identified here in subjects showing a greater treatment effect (i.e., higher rACC-lower amygdala) indicates an integrity of rACC-amygdala responsivity and/or interaction that can benefit from venlafaxine treatment. Clearly, replication of the present effect, along with further research into the possible mechanisms for such an outcome, is needed. More generally, the present study suggests that there is promise for the use of fMRI as a tool to predict drug treatment outcomes for patients with clinically significant anxiety.