Anticipatory activation in the amygdala and anterior cingulate in generalized anxiety disorder and prediction of treatment response

Abstract

Objective: The anticipation of adverse outcomes, or worry, is a cardinal symptom of generalized anxiety disorder. Prior work with healthy subjects has shown that anticipating aversive events recruits a network of brain regions, including the amygdala and anterior cingulate cortex. This study tested whether patients with generalized anxiety disorder have alterations in anticipatory amygdala function and whether anticipatory activity in the anterior cingulate cortex predicts treatment response.

Method: Functional magnetic resonance imaging (fMRI) was employed with 14 generalized anxiety disorder patients and 12 healthy comparison subjects matched for age, sex, and education. The event-related fMRI paradigm was composed of one warning cue that preceded aversive pictures and a second cue that preceded neutral pictures. Following the fMRI session, patients received 8 weeks of treatment with extended-release venlafaxine.

Results: Patients with generalized anxiety disorder showed greater anticipatory activity than healthy comparison subjects in the bilateral dorsal amygdala preceding both aversive and neutral pictures. Building on prior reports of pretreatment anterior cingulate cortex activity predicting treatment response, anticipatory activity in that area was associated with clinical outcome 8 weeks later following treatment with venlafaxine. Higher levels of pretreatment anterior cingulate cortex activity in anticipation of both aversive and neutral pictures were associated with greater reductions in anxiety and worry symptoms.

Conclusions: These findings of heightened and indiscriminate amygdala responses to anticipatory signals in generalized anxiety disorder and of anterior cingulate cortex associations with treatment response provide neurobiological support for the role of anticipatory processes in the pathophysiology of generalized anxiety disorder.

FIGURE 1. Anticipatory Amygdala Activity Differentiating Patients With Generalized Anxiety Disorder and Healthy Comparison Subjects a

^aPatients with generalized anxiety disorder showed greater bilateral amygdala activation than healthy comparison subjects during the anticipation of both aversive and neutral pictures, as indicated by a group main effect (red) for a voxelwise group by valence analysis of variance (ANOVA) for the anticipation period only (N=26, p<0.05, corrected, Table 2). Depicted in blue are bilateral amygdala areas showing a group by period interaction for a voxelwise group by valence by period ANOVA (N=26, p<0.05, corrected, Table 2). In a more medial area of the amygdala, all subjects showed greater bilateral amygdala activation on aversive than neutral trials across both anticipation and picture periods, as indicated by a valence main effect (green) for a voxelwise group by valence by period ANOVA (N=26, p<0.05, corrected; Table 2, data supplement Figure 3). Bar graphs of the circled clusters for the group main effect illustrate average percentage signal change for the anticipation period. The data depicted in the brain images and bar graphs are beta-weights indicating fit to an ideal hemodynamic response. These beta-weights were used for analyses on the anticipation period indicated by the shaded area for the time series, which were derived from deconvolved estimates for display purposes only. Time series plots of the circled clusters illustrate average percentage signal change across all time points of the aversive (red) and neutral (blue) trials for patients with generalized anxiety disorder (solid lines) and healthy comparison subjects (dotted lines) separately. The onset of the 1-second picture (P) occurred 3 seconds after cue (C) onset on half of the trials and 5 seconds after cue onset on the other half.

FIGURE 2. Pretreatment Anticipatory Anterior Cingulate Cortex Activity in Patients With Generalized Anxiety Disorder Predicting Treatment Response 8 Weeks Latera

^aFor patients with generalized anxiety disorder, greater pretreatment anterior cingulate cortex activation during the anticipation of both aversive and neutral trials predicted better treatment response on the HAM-A (A) and Penn State Worry Questionnaire (B), as indicated by voxelwise regression analysis for the anticipation period only (N=13, p<0.05, corrected,Table 2). Values on the×axis indicate posttreatment scores after statistical control was added for pretreatment scores and for depression as measured by the HAM-D, with lower values indicative of better treatment response. The magnitude of the correlations for the HAM-A (r=−0.82) and the Penn State Worry Questionnaire (r=−0.84) was not appreciably affected by excluding the individual with the highest pretreatment anterior cingulate cortex activity and best treatment response in each scatterplot (r=−0.76 and r=−0.74, respectively).