Abstract
Hyperactivity of limbic (e.g., amygdalar) responses to negative stimuli has been implicated in the pathophysiology of generalized anxiety disorder (GAD). Evidence has also suggested that even a simple cognitive task involving emotionally salient stimuli can modulate limbic and prefrontal neural activation. However, whether neural modulation of emotional stimulus processing in a cognitive task is defective in adolescents with GAD has not yet been investigated. In this study, 20 adolescents with GAD and 14 comparable healthy controls underwent event-related functional magnetic resonance imaging (fMRI) coupled with an emotional valence evaluation task. During the evaluation of negative versus neutral stimuli, we found significant activation of the right inferior frontal gyrus (IFG) in healthy controls, while the bilateral amygdala was activated in GAD patients. Between-group analyses showed dramatically reduced task-activation of the right IFG in GAD patients, and the magnitude of IFG activity negatively correlated with symptom severity. Psychophysiological interaction analysis further revealed significantly decreased functional interaction between right IFG and anterior cingulate cortex and ventromedial prefrontal cortex in GAD patients compared with healthy controls. Taken together, our findings show failure to suppress negative affect by recruiting a cognitive distraction in adolescents with GAD, providing new insights into the pathophysiology of GAD.
Highlights
Functional magnetic resonance imaging coupled with overt symptom provocation paradigm has been widely used to examine emotion-related circuitry and elucidate the pathophysiology of generalized anxiety disorder (GAD)
During the evaluation of negative versus neutral stimuli, we found the right inferior frontal gyrus (IFG), insula, middle temporal gyrus (MTG), middle occipital gyrus (MOG), and sensorimotor area to be significantly activated in healthy controls (HCs); in contrast, adolescents with GAD exhibited activation in the bilateral amygdala/hippocampus, ventromedial prefrontal cortex, posterior cingulate cortex (PCC), insula, thalamus, MTG, MOG, and sensorimotor area (Fig. 2 and Table 2)
Compared with HCs, we found that functional interaction between right IFG and anterior cingulate cortex (ACC) and ventromedial prefrontal cortex (vmPFC) was significantly decreased in adolescents with GAD (Fig. 6 and Table 3)
Summary
Functional magnetic resonance imaging (fMRI) coupled with overt symptom provocation paradigm has been widely used to examine emotion-related circuitry and elucidate the pathophysiology of GAD. To better characterize the uncontrollable and diffuse anxiety experienced by GAD patients, Strawn and colleagues utilized an attention-demanding task with different non-face probes as emotional and neutral distractors to reveal dysfunction in additional circuits[13] They identified increased activation in both the medial prefrontal cortex and ventrolateral prefrontal cortex in response to visual stimuli with emotional content[13], further expanding the candidate regions of heuristic emotion circuits that may constitute the pathological basis of www.nature.com/scientificreports/. There is emerging evidence that rating the subjective experience of an aversive visual stimulus can decrease limbic activation and increase activity in the medial frontal regions[15] These studies consistently suggest that even a simple cognitive task performed on emotionally salient stimuli can modulate neural activation in the limbic system and prefrontal cortex.
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