High-speed timE Resolved fluorescence iMaging with no pilE-up diStortion

The overarching goal of HÈRMES is to establish a new methodology for time-resolved imaging by means of Time-Correlated Single Photon Counting(TCSPC). Since its debut in the literature, the potential of TCSPC as non-invasive, ultra-sensitive and extremely precise imaging tool was manifest. Numerous applications have benefited from it so far, but a key limitation still prevents its wide use in many other crucial applications: the speed of a TCSPC acquisition chain must be kept low(few Mcount/s in the best case) to avoid distortion due to pile-up of events. Up to now researchers in this field have tried to work around this limit mainly by posing multiple channels in parallel, but still facing severe limitations mainly due to efficiency, fill factor, precision, linearity and readout complexity.I propose an innovative methodology for removing all constraints on TCSPC, promising a change in the paradigm of how TCSPC systems are conceived and how time-resolved measurements are carried out. To achieve such an ambitious goal, a radical change is necessary. I expect to develop a comprehensive mathematical model showing that pile-up distortion can be avoided with any combination of single photon detector and laser excitation power if additional picosecond-precision information on the status of system in each time bin is acquired at run-time. I will develop ultrafast electronics for Single Photon Avalanche Diodes to move from theory to the real experimental world. Moreover, I will empower the new constraint-less TCSPC by developing an innovative computational imaging framework, opening the way to the real-time acquisition of 4D images. Next-generation TCSPC systems based on the HÈRMES methodology will allow the exploitation of this powerful tool in crucial applications such as, for example, intraoperative and neuron imaging, where an ultrafast but still linear acquisition is necessary to enable complex operations like image-assisted brain surgery and spike analysis of neurons.