Prefrontal-limbic circuit modulation in anxiety disorders: Differential neural effects of psychotherapy versus pharmacotherapy revealed by ALE meta-analysis

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BACKGROUND: Anxiety disorders (ADs) involve dysregulation of prefrontal-limbic circuits, but the neural effects of psychotherapy and pharmacotherapy remain unclear. METHODS: We conducted an activation likelihood estimation (ALE) meta-analysis of task-based fMRI studies reporting pre- and post-treatment whole-brain coordinates in ADs. Separate analyses were performed for psychotherapy and pharmacotherapy. A random-effects synthesis assessed changes in primary anxiety symptoms where extractable data were available. RESULTS: 27 studies involving 561 patients were included. Psychotherapy was associated mainly with decreased activation in prefrontal and striatal regions, including the medial, middle, and inferior frontal gyri and caudate nucleus, whereas pharmacotherapy showed more focal decreases in the right uncus. Subgroup analyses suggested heterogeneity across therapies, diagnoses, and tasks. 9 independent active-treatment cohorts (179 participants) showed a large pooled symptom reduction (Hedges' g = 1.44, 95% CI 0.99-1.90; I² = 75.1%). CONCLUSIONS: Psychotherapy and pharmacotherapy may engage partly distinct neural pathways in ADs, with broader prefrontal-striatal modulation after psychotherapy and more focal limbic effects after pharmacotherapy. Findings remain exploratory given the limited and heterogeneous evidence base.

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