Emerging techniques for precision neuromodulation: A comparative framework from bench to bedside

Precision neuromodulation has emerged as a transformative field in neuroscience, enabling both targeted treatment of neurological disorders and mechanistic dissection of brain function. While classical techniques like deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) are widely used in clinical practice, they lack the fine-scale specificity required for precise control of specific neuronal subtypes or neural circuits. In contrast, emerging strategies, including genetics-based (optogenetics, chemogenetics, sonogenetics, magnetogenetics), materials-based (photothermal, photoelectric, piezoelectric), and physics-based (infrared, ultrasound, temporal interference) neuromodulation techniques, hold the potential for enhancing spatiotemporal resolution, cell-type specificity, and novel delivery mechanisms. Here, we systematically compare classical and emerging neuromodulation techniques across six critical dimensions: spatial resolution, temporal resolution, cell-type specificity, biosafety, depth of stimulation, and clinical feasibility. We highlight the divergent precision requirements of basic research and clinical applications and categorize all methods by actuator type and stimulation modality to guide practical use. We further examine translational strategies for integrating advanced tools into human therapies. While no single method satisfies all criteria, complementary approaches can be tailored to meet distinct goals of precision in experimental neuroscience and clinical applications. This review provides a conceptual and practical roadmap for selecting and optimizing precision neuromodulation strategies, offering insights that bridge mechanistic research and clinical translation.