FiND: Few-shot three-dimensional image-free confocal focusing on point-like emitters

Confocal fluorescence microscopy is widely applied for the study of point-like emitters such as biomolecules, material defects, and quantum light sources. Confocal techniques offer increased optical resolution, dramatic fluorescence background rejection and sub-nanometer localization, useful in super-resolution imaging of fluorescent biomarkers, single-molecule tracking, or the characterization of quantum emitters. However, rapid, noise-robust automated 3D focusing on point-like emitters has been missing for confocal microscopes. Here, we introduce FiND (Focusing in Noisy Domain), an imaging-free, non-trained 3D focusing framework that requires no hardware add-ons or modifications. FiND achieves focusing for signal-to-noise ratios down to 1, with a few-shot operation for signal-to-noise ratios above 5. FiND enables unsupervised, large-scale focusing on a heterogeneous set of quantum emitters. Additionally, we demonstrate the potential of FiND for real-time 3D tracking by following the drift trajectory of a single NV center indefinitely with a positional precision of < 10 nm. Our results show that FiND is a useful focusing framework for the scalable analysis of point-like emitters in biology, material science, and quantum optics.