Toward Constraintless Time-Correlated Single-Photon Counting Measurements: A New Method to Remove Pile-up Distortion

Time-Correlated Single-Photon Counting (TCSPC) is a well-renowned technique allowing to reconstruct light signals with high sensitivity and resolution. Nevertheless, to this day, its use in applications requiring a fast analysis of the sample is limited due to its long acquisition time. The reason is twofold: on one hand, it is based on a statistical method thus requiring the collection of a large number of events to properly reconstruct the signal waveform; on the other hand, the average number of photons impinging on the sensor has to be kept particularly low to avoid artifacts. Indeed, the existence of dead time of both single-photon detectors and electronics can lead to distortion in the reconstructed waveform, which can be mitigated only if the count rate is kept below few percent of the excitation frequency. Recently, it has been demonstrated that an appropriate tuning of detector dead time allows to remove such power restriction, but, unfortunately, this constraint also sets a limit to the maximum count rate of the detector. In this paper, we present a novel method for TCSPC measurements, which ensures negligible distortion at unprecedented rates without requiring any constraint on either illumination power or detector dead time. We will show that this is possible thanks to the acquisition of additional information on the status of TCSPC system. The theoretical analysis reported in this paper is supported by analytical computation and numerical simulation, taking into account also potential non idealities of a real implementation

Readout Architectures for High Efficiency in Time-Correlated Single Photon Counting Experiments—Analysis and Review

In recent years, time-correlated single photon counting (TCSPC) has become the technique of choice in many life science analyses, where fast and faint luminous signals are recorded with picosecond accuracy. Nevertheless, the maximum operating frequency of a single TCSPC acquisition channel limits the measurement speed, especially when scanning point systems are exploited. In order to increase the speed of TCSPC experiments, many multichannel systems based on single photon avalanche diode arrays have been proposed in the literature, which integrate thousands of pixels on the same chip. Unfortunately, the huge number of data generated by this kind of system can easily bring to the saturation of the transfer bandwidth to the external processing unit. For this reason, several different readout architectures have been proposed in the literature, attempting to exploit at best the limited bandwidth under TCSPC operating conditions. In this paper, some typical readout approaches, namely clock-driven and event-driven readouts, are discussed and compared, along with a recently-introduced router-based algorithm that is specifically designed to obtain maximum bandwidth exploitation under any condition. Quantitative comparisons are performed starting from imager response of the systems, which is the rate of recorded events in the case of uniform illumination of the detector array

A Multimodal Perception Framework for Users Emotional State Assessment in Social Robotics

In this work, we present an unobtrusive and non-invasive perception framework based on the synergy between two main acquisition systems: the Touch-Me Pad, consisting of two electronic patches for physiological signal extraction and processing; and the Scene Analyzer, a visual-auditory perception system specifically designed for the detection of social and emotional cues. It will be explained how the information extracted by this specific kind of framework is particularly suitable for social robotics applications and how the system has been conceived in order to be used in human-robot interaction scenarios

Fast fully-integrated front-end circuit to overcome pile-up limits in time-correlated single photon counting with single photon avalanche diodes

Time-Correlated Single Photon Counting (TCSPC) is an essential tool in many scientific applications, where the recording of optical pulses with picosecond precision is required. Unfortunately, a key issue has to be faced: distortion phenomena can affect TCSPC experiments at high count rates. In order to avoid this problem, TCSPC experiments have been commonly carried out by limiting the maximum operating frequency of a measurement channel below 5% of the excitation frequency, leading to a long acquisition time. Recently, it has been demonstrated that matching the detector dead time to the excitation period allows to keep distortion around zero regardless of the rate of impinging photons. This solution paves the way to unprecedented measurement speed in TCSPC experiments. In this scenario, the front-end circuits that drive the detector play a crucial role in determining the performance of the system, both in terms of measurement speed and timing performance. Here we present two fully integrated front-end circuits for Single Photon Avalanche Diodes (SPADs): a fast Active Quenching Circuit (AQC) and a fully-differential current pick-up circuit. The AQC can apply very fast voltage variations, as short as 1.6ns, to reset external custom-technology SPAD detectors. A fast reset, indeed, is a key parameter to maximize the measurement speed. The current pick-up circuit is based on a fully differential structure which allows unprecedented rejection of disturbances that typically affect SPAD-based systems at the end of the dead time. The circuit permits to sense the current edge resulting from a photon detection with picosecond accuracy and precision even a few picoseconds after the end of the dead time imposed by the AQC. This is a crucial requirement when the system is operated at high rates. Both circuits have been deeply characterized, especially in terms of achievable measurement speed and timing performance

High-efficiency integrated readout circuit for single photon avalanche diode arrays in fluorescence lifetime imaging

In recent years, lifetime measurements by means of the Time Correlated Single Photon Counting (TCSPC) technique have led to a significant breakthrough in medical and biological fields. Unfortunately, the many advantages of TCSPC-based approaches come along with the major drawback of a relatively long acquisition time. The exploitation of multiple channels in parallel could in principle mitigate this issue, and at the same time it opens the way to a multi-parameter analysis of the optical signals, e.g., as a function of wavelength or spatial coordinates. The TCSPC multichannel solutions proposed so far, though, suffer from a tradeoff between number of channels and performance, and the overall measurement speed has not been increased according to the number of channels, thus reducing the advantages of having a multichannel system. In this paper, we present a novel readout architecture for bi-dimensional, high-density Single Photon Avalanche Diode (SPAD) arrays, specifically designed to maximize the throughput of the whole system and able to guarantee an efficient use of resources. The core of the system is a routing logic that can provide a dynamic connection between a large number of SPAD detectors and a much lower number of high-performance acquisition channels. A key feature of our smart router is its ability to guarantee high efficiency under any operating condition

High-speed and low-distortion solution for time-correlated single photon counting measurements: A theoretical analysis

In this paper, we describe a novel solution to increase the speed of Time-Correlated Single Photon Counting (TCSPC) measurements by almost an order of magnitude while providing, in principle, zero distortion regardless of the experimental conditions. Typically, the relatively long dead time associated with the conversion electronics requires a proper tune of the excitation power in order to avoid distortions of the reconstructed waveform due to pileup and counting loss. As a result, the maximum operating rate of a TCSPC channel is now limited between 1% and 5% of the excitation frequency, thus leading to relatively long acquisition times. We show that negligible distortion (below 1%) is guaranteed if the dead time associated with the converter is kept below the dead time of the detector, and at the same time the detector dead time is matched to the duration of the excitation period. In this way, unprecedented high-speed operation is possible. In this paper, we provide a theoretical analysis of the technique, including the main non-idealities which are introduced by a generic physical implementation. The results are supported by both numerical simulations and analytical calculations

Phosphocaveolin-1 enforces tumor growth and chemoresistance in rhabdomyosarcoma

Caveolin-1 (Cav-1) can ambiguously behave as either tumor suppressor or oncogene depending on its phosphorylation state and the type of cancer. In this study we show that Cav-1 was phosphorylated on tyrosine 14 (pCav-1) by Src-kinase family members in various human cell lines and primary mouse cultures of rhabdomyosarcoma (RMS), the most frequent soft-tissue sarcoma affecting childhood. Cav-1 overexpression in the human embryonal RD or alveolar RH30 cells yielded increased pCav-1 levels and reinforced the phosphorylation state of either ERK or AKT kinase, respectively, in turn enhancing in vitro cell proliferation, migration, invasiveness and chemoresistance. In contrast, reducing the pCav-1 levels by administration of a Src-kinase inhibitor or through targeted Cav-1 silencing counteracted the malignant in vitro phenotype of RMS cells. Consistent with these results, xenotransplantation of Cav-1 overexpressing RD cells into nude mice resulted in substantial tumor growth in comparison to control cells. Taken together, these data point to pCav-1 as an important and therapeutically valuable target for overcoming the progression and multidrug resistance of RMS

Epidermal growth factor receptor expression identifies functionally and molecularly distinct tumor-initiating cells in human glioblastoma multiforme and is required for gliomagenesis

Epidermal growth factor receptor (EGFR) is a known diagnostic and, although controversial, prognostic marker of human glioblastoma multiforme (GBM). However, its functional role and biological significance in GBM remain elusive. Here, we show that multiple GBM cell subpopulations could be purified from the specimens of patients with GBM and from cancer stem cell (CSC) lines based on the expression of EGFR and of other putative CSC markers. All these subpopulations are molecularly and functionally distinct, are tumorigenic, and need to express EGFR to promote experimental tumorigenesis. Among them, EGFR-expressing tumor-initiating cells (TIC) display the most malignant functional and molecular phenotype. Accordingly, modulation of EGFR expression by gain-of-function and loss-of-function strategies in GBM CSC lines enhances and reduces their tumorigenic ability, respectively, suggesting that EGFR plays a fundamental role in gliomagenesis. These findings open up the possibility of new therapeutically relevant scenarios, as the presence of functionally heterogeneous EGFR(pos) and EGFR(neg) TIC subpopulations within the same tumor might affect clinical response to treatment

Fully integrated electronics for high-performance time-resolved imagers with single photon avalanche diode arrays

reserved4noTime-resolved imaging by means of Single Photon Avalanche Diodes (SPADs) has been subject to a widespread interest in recent years, especially since technological breakthroughs have opened the way to the development of multichannel Time Correlated Single Photon Counting (TCSPC) acquisition systems. Nevertheless, a main drawback of TCSPC has to be taken into account: it is an intrinsically slow technique because it requires the collection of a statistically-significant number of events to build a histogram that accurately reconstructs the time-domain waveform. As a result, the acquisition time needed for imaging can be relatively long. Two main solutions can be adopted to push the speed of a TCSPC measurement: the increment of the acquisition rate of the single channel and the exploitation of a high number of channels operating in parallel. The actual implementation of these solutions requires complex highperformance electronics designed on purpose. In this paper we report and discuss fully-integrated solutions for the development of a high-throughput and high-performance TCSPC acquisition system.mixedGiulia Acconcia, Alessandro Cominelli, Massimo Ghioni, Ivan RechAcconcia, Giulia; Cominelli, Alessandro; Ghioni, MASSIMO ANTONIO; Rech, Iva