Ultrasound-mediated focal serotonin delivery causally modulates motivation in primates

Serotonin's role in motivated behaviour remains unresolved due to a lack of causal, spatially precise, and translatable methods. Here, we introduce ultrasound-mediated neuromodulator delivery to achieve focal, non-invasive access to the primate brain by transiently opening the blood-brain barrier, enabling systemically administered serotonin to reach a targeted cortical region. We delivered serotonin to the perigenual anterior cingulate cortex (pgACC) of awake, behaving macaques and combined this with computational modelling and multimodal imaging, including resting-state fMRI and single-voxel MRS. Elevating pgACC serotonin reduced occupancy of high-motivation states by weakening the energizing influence of rich reward environments, while leaving sensitivity to immediate offer value intact. This was accompanied by altered frontal functional connectivity, reduced local glutamatergic metabolite signal, and changes in pupil-linked physiology. Repeated delivery was well tolerated, and histology confirmed increased serotonergic signal at the target. These findings establish a translatable approach for focal neuropharmacological manipulation and identify pgACC serotonin as a regulator of context-dependent motivation.