Learning-induced neuroplastic changes, further modulated by content and setting, are mirrored in brain functional connectivity (FC). In animal models, selective serotonin reuptake inhibitors (SSRIs) have been shown to facilitate neuroplasticity. This is especially prominent during emotional relearning, such as fear extinction, which may translate to clinical improvements in patients. To investigate a comparable modulation of neuroplasticity in humans, 99 healthy subjects underwent three weeks of emotional (matching faces) or non-emotional learning (matching Chinese characters to unrelated German nouns). Shuffled pairings of the original content were subsequently relearned for the same time. During relearning, subjects received either a daily dose of the SSRI escitalopram or placebo. Resting-state functional magnetic resonance imaging was performed before and after the (re-)learning phases. FC changes in a network comprising Broca's area, the medial prefrontal cortex, the right inferior temporal and left lingual gyrus were modulated by escitalopram intake. More specifically, it increased the bidirectional connectivity between medial prefrontal cortex and lingual gyrus for non-emotional and the connectivity from medial prefrontal cortex to Broca's area for emotional relearning. The context dependence of these effects together with behavioral correlations supports the assumption that SSRIs in clinical practice improve neuroplasticity rather than psychiatric symptoms per se. Beyond expanding the complexities of learning, these findings emphasize the influence of external factors on human neuroplasticity.
