Diffuse correlation spectroscopy (DCS) is an emerging optical technique for non-invasive cerebral blood flow monitoring. Extraction of the DCS blood flow index typically involves calculating the temporal autocorrelation of the measured light intensity and then fitting its decay to a solution of the correlation diffusion equation. It is well-known that the experimental autocorrelation is a biased estimator of the true autocorrelation. This work explores this phenomenon as it relates to DCS, in particular implementations with single photon avalanche diode arrays (SPAD arrays). After deriving a first-order expression for the bias in DCS, we then quantify its impact as a function of sampling time in both simulation and experiment using SPAD array detection. We then present and explore two bias correction strategies to correct for its impact at fast sampling times (20-200 Hz) and in low-photon regimes.

Diffuse correlation spectroscopy (DCS) is a promising technique for noninvasive measurement of blood flow, especially for cerebral blood flow where other noninvasive techniques have shortcomings. Conventional DCS often requires multiple simultaneous measurements to enhance the signal-to-noise ratio (SNR) especially when probing deep into the brain with large source-detector separations where photons are scarce. However, this limits scalability when using discrete optical detectors. This study demonstrates the application of the 500 x 500 single-photon avalanche diode (SPAD) array, SwissSPAD3, coupled with a custom field-programmable gate array (FPGA) design, which enables significant increases in SNR compared to conventional DCS systems. We validate the fiber-coupled SPAD camera system against a lab-standard CW-DCS system in two-layer liquid phantoms and in human measurements, and demonstrate robust blood-flow tracking at source-detector separations up to 3.25 cm. These results support SPAD-based parallel detection as a scalable route to improved deep-tissue DCS performance in humans.

Diffuse Correlation Spectroscopy (DCS) allows the label-free investigation of microvascular dynamics deep within living tissue. However, common implementations of DCS are currently limited to measurement depths of $\sim 1-1.5cm$, which can limit the accuracy of cerebral hemodynamics measurement. Here we present massively parallelized DCS (pDCS) using novel single photon avalanche detector (SPAD) arrays with up to 500x500 individual channels. The new SPAD array technology can boost the signal-to-noise ratio by a factor of up to 500 compared to single-pixel DCS, or by more than 15-fold compared to the most recent state-of-the-art pDCS demonstrations. Our results demonstrate the first in vivo use of this massively parallelized DCS system to measure cerebral blood flow changes at $\sim 2cm$ depth in human adults. We compared different modes of operation and applied a dual detection strategy, where a secondary SPAD array is used to simultaneously assess the superficial blood flow as a built-in reference measurement. While the blood flow in the superficial scalp tissue showed no significant change during cognitive activation, the deep pDCS measurement showed a statistically significant increase in the derived blood flow index of 8-12% when compared to the control rest state.

Temporal photon correlations have been a crucial resource for quantum and quantum-enabled optical science for over half a century. However, attaining non-classical information through these correlations has typically been limited to a single point (or, at best, a few points) at a time. Here, we perform a massively multiplexed wide-field photon correlation measurement using a large 500 x 500 single-photon avalanche diode array, the SwissSPAD3. We demonstrate the performance of this apparatus by acquiring wide-field photon correlation measurements of single-photon emitters and illustrate two applications of the attained quantum information: wide-field emitter counting and quantum-enabled super-resolution imaging (by a factor of root 2). The considerations and limitations of applying this technique in a practical context are discussed. Ultimately, the realization of massively multiplexed wide-field photon correlation measurements can accelerate quantum sensing protocols and quantum-enabled imaging techniques by orders of magnitude. (c) 2025 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement

Continuous, noninvasive monitoring of cerebral blood flow (CBF) is vital for neurocritical care. Diffuse correlation spectroscopy (DCS) enables assessment of microvascular blood flow by analyzing speckle intensity fluctuations of near-infrared light. In this review, we summarize recent advances in TD-DCS using superconducting nanowire single-photon detectors (SNSPDs) at 1064 nm, as well as complementary developments in high-density CW-DCS systems using single-photon avalanche diode (SPAD) cameras. Time-gated photon detection improves depth sensitivity in TD-DCS, and the use of longer wavelengths provides advantages in tissue penetration, photon throughput, and safety margin under ANSI exposure limits. Clinically feasible SPAD-based implementations, while lacking time-of-flight resolution, enable large signal-to-noise ratio gains via massive pixel averaging and offer a room-temperature, scalable path to high-density optical tissue monitoring. Together, these developments highlight a growing set of technologies for clinical applications, including bedside brain monitoring in neurocritical care. We conclude with practical guidance on detector technologies, gating strategies, system packaging, and briefly discuss interferometric DCS and speckle contrast optical spectroscopy (SCOS) as synergistic extensions for high-resolution and high-coverage imaging.

The SwissSPAD2/3 camera family is based on quarter megapixel single-photon avalanche diode (SPAD) time gated imagers. The 16.38-µm low-noise pixels feature a single-bit memory and built-in all-solid-state nanosecond time gating without the need for external image intensifiers. Microlenses have also been made available to increase the overall system sensitivity, including for high NA applications. SwissSPAD2/3 are coupled to FPGA platforms enabling a virtually noiseless streaming at up to 100 kpfs. A 1-bit accumulation of frames to reconfigurable number of bits was programmed on the FPGA for applications such as fluorescence lifetime imaging microscopy (FLIM). In other applications, a burst-mode read-out of 130,000 binary frames to a DDD3 memory of one sensor half was programmed on one FPGA for applications requiring full bitplanes. These initial configurations were extended to dual-FPGA systems capable of streaming data at near 100 kfps in continuous mode for long acquisition times. In such configuration one FPGA streams data from one sensor half to the other FPGA, which then sends the combined data stream to a host PC over PCIe at up to 3 GB/s. The eight PCIe lanes require careful design with differential routing and controlled impedance and the whole development presented significant hardware and firmware challenges. We also achieved full synchronization of two SwissSPAD2 camera systems over PCIe and characterized the pixel-to-pixel exposure timing alignment error to better than 150 ps with a time gate of 10 ns. The resulting platforms are unique enablers for quantum imaging applications, such as plenoptic maging, quantum LIDAR or quanta burst photography.

Quantum ghost imaging approaches have been proposed to enhance biological microscopy, for example, using 2D visible detectors to provide IR images or providing additional dimensions of spatial or spectral information. Toward the goal of making such imaging schemes practical, we compare image quality and depth-of-field between traditional images and ghost images at the same excitation levels. We measure how image quality and depth-of-field depend on the parameters of the entangled light produced using type-I spontaneous parametric down-conversion (SPDC). We use a pair of time-synchronized, photon-timing single-photon avalanche diode (SPAD) array detectors to capture two distinct microscope imaging paths simultaneously on a photon-pair-by-photon-pair basis: one in a traditional imaging pathway and the other a quantum ghost imaging pathway. We calculate the depth-of-field, resolution, contrast, and signal-to-noise ratio (SNR) through the parameter space of a β-Barium Borate (BBO) type-I bulk non-linear crystal length and angle. Our results provide a basis for choosing parameters for quantum ghost imaging with type-I SPDC sources.

Diffuse Correlation Spectroscopy (DCS) allows the optical and label-free investigation of microvascular dynamics. Commonly, DCS is implemented with highly sensitive and ultra fast single-photon avalanche diodes (SPAD) for blood flow measurements from around 1-1.5cm deep inside tissue (source detector separation of 2.5-3 cm). In parallelized DCS (pDCS), we use arrays of multiple SPADs to boost the signal-to-noise ratio by averaging many independent DCS measurements. In this study, we explored the capabilities of an innovative, massively parallelized SPAD array with 500x500 single pixels for DCS for up to 250,000 parallel DCS measurements. We can show that this massively parallelized array enables viable blood flow measurements at 2cm depth (4cm source detector separation) in human subjects. Furthermore, we applied a dual detection strategy, where a secondary SPAD array probes the superficial blood flow simultaneously as a build-in reference measurement. In addition to our main results, we test and discuss methods to correct the deep flow measurement, by including simultaneously measured flow dynamics deep and superficial tissue layers via our novel dual-SPAD array measurement setup.

The Piccolo gated sensor features a 32x32 SPAD array of single-photon avalanche diodes (SPADs) operating in time-correlated single-photon counting (TCSPC). The chip enables event-driven readout and a maximum count rate of 220 Mcps. The sensor is based on the original Piccolo architecture, whereas the pixel was redesigned to accommodate a sub-nanosecond time gating circuitry. As a result, the pitch was increased by 3 μm to 31 μm with a slightly lower fill factor of 23.7%. The time-gating circuitry comprises active recharge to activate the gate and a fast switch to de-activate the SPAD. The sensor is equipped with 128 dynamically allocated, 50 ps time-to-digital converters (TDCs) at the bottom of the array. Four TDCs are shared among 32 SPADs in each column, where a mechanism of reallocation is used to optimize the use of TDCs and to minimize photon loss. Time gating can reduce both uncorrelated and correlated noise by reducing overall active time and by increasing relaxation time after detection, respectively. Upon acquisition of TCSPC data, the FPGA reorganizes it in histograms, which may be dynamically allocated and reduced in the number of bins to optimize memory use and data transfer from the FPGA to an external Mac/PC. The TDCs may also be calibrated to suppress differential and integral nonlinearities on-FPGA. Timestamps are stored in DDR3 and streamed out of the FPGA through PCIe with a data rate of 5.12 Gbps. Thanks to these techniques, the maximum count rate of the sensor was increased by about 3×. The time gating feature was implemented to extend dynamic range, and therefore depth, of near-infrared optical tomography (NIROT) and g(2) multi-depth time-domain diffuse correlation spectroscopy (TD-mDCS). Time gating is especially useful in NIROT and mDCS, as it helps suppress large numbers of early photons reflected back from the sample's surface, e.g. the skull or skin. Thus, the Piccolo-gated architecture could show its suitability in these imaging modality.

Correlation plenoptic imaging (CPI) is a novel technological imaging modality enabling to overcome drawbacks of standard plenoptic devices, while preserving their advantages. However, a major challenge in view of real-time application of CPI is related to the relevant amount of required frames and the consequent computational-intensive processing algorithm. In this work, we describe the design and implementation of an optimized processing algorithm that is portable to an efficient computational environment and exploits the highly parallel algorithm offered by GPUs. Improvements by a factor ranging from 20X, for correlation measurement, to 500X, for refocusing, are demonstrated. Exploration of the relation between the improvement in performance achieved and actual GPU capabilities also indicates the feasibility of near-real-time processing capability, opening up to the potential use of CPI for practical real-time application.

SPAD arrays have shown potential for improving SNR for diffuse correlation spectroscopy in low photon regimes. Here, we will explore different methods of integrating parallelized DCS signals in such regimes for deep blood flow extraction.

Scintillating fibre detectors combine sub-mm resolution particle tracking, precise measurements of the particle stopping power and sub-ns time resolution. Typically, fibres are read out with silicon photomultipliers (SiPM). Hence, if fibres with a few hundred $\mu$m diameter are used, either they are grouped together and coupled with a single SiPM, losing spatial resolution, or a very large number of electronic channels is required. In this article we propose and provide a first demonstration of a novel configuration which allows each individual scintillating fibre to be read out regardless of the size of its diameter, by imaging them with Single-Photon Avalanche Diode (SPAD) array sensors. Differently from SiPMs, SPAD array sensors provide single-photon detection with single-pixel spatial resolution. In addition, O(us) or faster coincidence of detected photons allows to obtain noise-free images. Such a concept can be particularly advantageous if adopted as a neutrino active target, where scintillating fibres alternated along orthogonal directions can provide isotropic, high-resolution tracking in a dense material and reconstruct the kinematics of low-momentum protons (down to 150 MeV/c), crucial for an accurate characterisation of the neutrino nucleus cross section. In this work the tracking capabilities of a bundle of scintillating fibres coupled to SwissSPAD2 is demonstrated. The impact of such detector configuration in GeV-neutrino experiments is studied with simulations and reported. Finally, future plans, including the development of a new SPAD array sensor optimised for neutrino detection, are discussed.

SwissSPAD3 is the latest of a family of widefield time-gated SPAD imagers developed for fluorescence lifetime imaging (FLI) applications. Its distinctive features are (i) the ability to define shorter gates than its predecessors (width W < 1 ns), (ii) support for laser repetition rates up to at least 80 MHz and (iii) a dual-gate architecture providing an effective duty cycle of 100%. We present widefield macroscopic FLI measurements of short lifetime NIR dyes, analyzed using the phasor approach. The results are compared with those previously obtained with SwissSPAD2 and to theoretical predictions.

Diffuse correlation spectroscopy (DCS) is a promising noninvasive technique for monitoring cerebral blood flow and measuring cortex functional activation tasks. Taking multiple parallel measurements has been shown to increase sensitivity, but is not easily scalable with discrete optical detectors. Here we show that with a large 500 × 500 SPAD array and an advanced FPGA design, we achieve an SNR gain of almost 500 over single-pixel mDCS performance. The system can also be reconfigured to sacrifice SNR to decrease correlation bin width, with 400 ns resolution being demonstrated over 8000 pixels.

While great progress has been achieved in developing optical methods for measuring fast changes in membrane potential (like action potentials) in excitable cells, less progress has been made in precise (and calibrated) measurements of steady state resting membrane potentials (RMPs) and small changes in RMPs (in excitable or non-excitable cells). In excitable cells, small changes in RMPs are associated with multiple physiological processes such as sub-threshold events in neuronal signaling and in synaptic plasticity. They also play an important role in cell differentiation and proliferation of cardiomyocytes. In non-excitable cells, such as bacterial colonies, RMP changes play important roles in intercellular communication, coordination, metabolism, and stress response. Accurate and precise recordings of minute RMP changes require noise-immune optical tools. We have been developing an RMP (calibrated) recording approach that is capable of measuring small changes RMPs. Our approach relies on 3 components: (i) a novel optical transducer (voltage sensing dye) that utilizes intrinsic photoinduced electron transfer (PeT) mechanism to sense RMP by fluorescence lifetime changes; (ii) a novel time-gated SPAD array imager that allows widefield fluorescence lifetime imaging (FLIM); (iii) a quantitative phasor analysis of the recoded FLIM data. This package provides high-throughput, quantification of pixel-wise lifetime information. Two aspects of our approach - the novel VSD and the data analysis - have been tested in excitable cardiac muscle cells (NVRM) and in non-excitable bacterial cells (B. subtilis). B. subtilis RMPs have been estimated for normal cultures and for cultures under perturbing chemical conditions. Drug induced changes of NVRM RMPs have been also estimated. Implementation of our 3-pronged approach towards studying electrical signaling/coupling networks in bacterial biofilms and in cardiomyocytes will be discussed.

We demonstrate the single-shot confidence estimation for individual quantum measurement outcomes using the continuous measurement theory of the quantum counting process applied to the quantum state identification problem. We experimentally obtain single-shot and average confidences for quantum measurements and show that they favorably compare to that of the idealized classical measurement. Finally, we demonstrate that single-shot confidence estimations correctly represent observed experimental outcomes for a large ensemble of measurements.

In this article, we report on SwissSPAD3 (SS3), a 500 $\times$ 500 pixel single-photon avalanche diode (SPAD) array, fabricated in 0.18- $\mu \text{m}$ CMOS technology. In this sensor, we introduce a novel dual-gate architecture with two contiguous temporal windows, or gates, guaranteed by the circuit architecture to be nonoverlapping and covering the totality of the sensor’s exposure period. The gates can be adjusted with a temporal resolution of 17.9 ps, and the minimum measured gate width is 0.99 ns; to our knowledge, the shortest reported to date among large-format SPAD imagers. In the dual-channel mode, the burst frame rate is 49.8 and 97.7 kframes/s in the single-channel mode. A 2690-MB/s PCI express (PCIe) interface has been added to the data acquisition framework, enabling continuous operation at approximately 44 and 88 kframes/s. Due to optimizations of the gate-signal tree, we achieved a significant reduction to gate skew and gate width variation, which is negligible with respect to the SPAD temporal jitter. These improvements, along with sub-10-cps dark count rate (DCR) per pixel and 50% maximum photon detection probability (PDP), result in a sensor particularly well suited for fast acquisition fluorescence lifetime imaging microscopy (FLIM) experiments, for which we demonstrate reduced dispersion versus a single-gated sensor.

We demonstrate a method that allows a high-efficiency single-photon-avalanche diode (SPAD) with a thick absorption region (> 10 μm) to count single photons at rates significantly higher than previously demonstrated. We apply large (> 30 V) AC bias gates to the SPAD at 1 GHz and detect minute avalanches with a discrimination threshold of 5(1) mV by means of radio-frequency (RF) interferometry. We measure a reduction by a factor of ≈ 500 in the average charge per avalanche when compared to operation in its traditional active-quenching module, and a relative increase of >19 % in detection efficiency at 850 nm. The reduction in charge strongly suppresses self-heating effects in the diode that can degrade performance at high avalanche rates. We show that the single-photon detection system maintains high efficiency at count rates exceeding 108s-1.

We review the advancement of the research toward the design and implementation of quantum plenoptic cameras, radically novel 3D imaging devices that exploit both momentum-position entanglement and photon-number correlations to provide the typical refocusing and ultra-fast, scanning-free, 3D imaging capability of plenoptic devices, along with dramatically enhanced performances, unattainable in standard plenoptic cameras: diffraction-limited resolution, large depth of focus, and ultra-low noise. To further increase the volumetric resolution beyond the Rayleigh diffraction limit, and achieve the quantum limit, we are also developing dedicated protocols based on quantum Fisher information. However, for the quantum advantages of the proposed devices to be effective and appealing to end-users, two main challenges need to be tackled. First, due to the large number of frames required for correlation measurements to provide an acceptable SNR, quantum plenoptic imaging would require, if implemented with commercially available high-resolution cameras, acquisition times ranging from tens of seconds to a few minutes. Second, the elaboration of this large amount of data, in order to retrieve 3D images or refocusing 2D images, requires high-performance and time-consuming computation. To address these challenges, we are developing high-resolution SPAD arrays and high-performance low-level programming of ultra-fast electronics, combined with compressive sensing and quantum tomography algorithms, with the aim to reduce both the acquisition and the elaboration time by two orders of magnitude. Routes toward exploitation of the QPI devices will also be discussed.

Schr\"odinger held that a local quantum system has some objectively real quantum state and no other (hidden) properties. He therefore took the Einstein-Podolsky-Rosen (EPR) phenomenon, which he generalized and called `steering', to require nonlocal wavefunction collapse. Because this would entail faster-than-light (FTL) information transmission, he doubted that it would be seen experimentally. Here we report a demonstration of EPR steering with entangled photon pairs that puts--in Schr\"odinger's interpretation--a non-zero lower bound on the amount of FTL information transmission. We develop a family of $n$-setting loss-tolerant EPR-steering inequalities allowing for a size-$d$ classical message sent from Alice's laboratory to Bob's. For the case $n=3$ and $d=2$ (one bit) we observe a statistically significant violation. Our experiment closes the efficiency and locality loopholes, and we address the freedom-of-choice loophole by using quantum random number generators to independently choose Alice's and Bob's measurement basis settings. To close the efficiency and locality loopholes simultaneously, we introduce methods for quickly switching between three mutually unbiased measurement bases and for accurately characterizing the efficiency of detectors. From the space-time arrangement of our experiment, we can conclude that if the mechanism for the observed bipartite correlations is that Alice's measurement induces wave-function collapse of Bob's particle, then more than one bit of information must travel from Alice to Bob at more than three times the speed of light.