Transcranial focused ultrasound stimulation of the anterior temporal lobe enhances semantic memory by modulating brain morphology, neurochemistry and neural dynamics

Understanding neural functioning and plasticity of the brain is a fundamental goal of neuroscience. The ventromedial anterior temporal lobe (ATL) has been suggested as the centre-point of a core transmodal hub for semantic memory, playing a crucial role in the representation of coherent conceptual knowledge. However, non-invasive direct modulation of the ventromedial ATL has remained challenging. Transcranial ultrasound stimulation (TUS) is an emerging neuromodulatory technique that delivers acoustic energy with high spatial precision, making it uniquely suited for targeting deep brain structures non-invasively. In this study, we investigated whether theta-burst TUS (tbTUS) to the ventromedial ATL could enhance semantic memory performance in the adult brain. Using a multimodal neuroimaging approach— magnetic resonance spectroscopy (MRS), functional MRI (fMRI), and voxel-based morphometry (VBM)—we assessed tbTUS-induced changes in neurochemical concentrations, functional network connectivity, structural plasticity, and semantic memory performance. Compared to control stimulation (ventricle), tbTUS at the ventromedial ATL significantly improved semantic task performance in healthy individuals. MRS analysis revealed that tbTUS decreased GABA and increased Glx levels, reflecting shifts in excitation-inhibition balance. Additionally, tbTUS increased neurometabolites in the ATL, including NAA, creatine and choline, suggesting enhanced neuronal function and metabolism. fMRI analysis demonstrated that tbTUS reduced task-induced regional activity in the ATL and functionally connected semantic regions, while also enhancing intrinsic and effective connectivity across the semantic network. Structural analysis revealed increased grey matter volume in the ATL following tbTUS compared to control stimulation. These findings provide the first convergent evidence that tbTUS can modulate neurochemistry, functional dynamics, and brain morphology to enhance semantic memory function. Our results highlight TUS as a powerful neuromodulatory tool with potential applications in cognitive enhancement and neurorehabilitation, offering a promising intervention for dementia and neurodegenerative disorders.