Diffuse correlation spectroscopy (DCS), an optical technique that relies on sampling the intensity fluctuations of a speckle pattern set-up by diffusely scattered coherent light to quantify deep tissue blood flow, is seeing increased adoption as a non-invasive research tool for cerebral perfusion monitoring in clinical settings including critical care and sleep apnea, and for functional brain imaging.^{1 – 6} However, as usually implemented, DCS relies on the use of single or few-mode fibers to sample the speckle pattern in conjunction with photon counting detectors to construct the intensity temporal auto-correlation function, $g_2(\tau )$.⁷ This dramatically limits the photon throughput [e.g., in comparison with near-infrared spectroscopy (NIRS) where large area detectors and multi-mode fiber bundles can be used] and poses practical challenges to the use of DCS in translational studies. Consequently, substantial effort in the field is now dedicated to improving the signal-to-noise ratio (SNR) of diffuse optical blood flow measurements.⁸

Diffuse optics (DO) encompasses a range of photonics tools based on the study of random photon migration in highly scattering media—biological tissues in particular. Due to its unique features, DO is emerging as a powerful means for clinical or homecare diagnostics.¹ The basic physics of DO is related to the detection of temporal or spatial alteration in photon distribution re-emitted on the tissue surface.² Due to the low power (typically few mW) of injected near-infrared light (600- to 1100-nm range), DO is inherently noninvasive. The photon temporal (or spatial) distribution carries information on the absorption—ultimately related to tissue chemical composition, such as water, lipid, collagen content, oxy- and deoxy-hemoglobin concentration, cytochrome c-oxidase³—and scattering properties—linked to tissue microstructure. Further, DO is one of the few noninvasive modalities capable of providing functional information, e.g., brain or muscle activation.⁴ It can be operated noncontact through remote light illumination and collection.⁵ It explores the tissue well below the skin at depths of up to 2 to 4 cm. It can provide quantitative operator-independent assessment of the tissue status, such as hemoglobin oxygenation level in the brain. Finally, it is highly scalable, sharing the same technology from large clinical tomographic systems down to wearable devices or homecare appliances.⁶ For all these aspects, DO is attracting more and more interest in many fields, such as monitoring vital signs like brain oxygenation in critical care or during interventions,⁷ tumor diagnostics as for breast cancer,⁸ investigating the impact of lifestyle and nutrition on our body,⁹ or other fields such as neuroscience and psychology,¹⁰ sports, and leisure.¹¹ Even further, the operator independence, the depth sensitivity, and the scalability in addition to noninvasiveness make this option attractive for telemedicine and homecare of patients remotely.

In this paper we present a novel single-photon detector specifically designed for Non-Line-Of-Sight (NLOS) imaging applications within the framework of the DARPA REVEAL program. The instrument is based on a linear 16 × 1 Complementary Metal-Oxide-Semiconductor (CMOS) Single-Photon Avalanche Diode (SPAD) array operated in fast-gated mode by a novel fast-gating Active Quenching Circuit (AQC) array, which enables the detectors with sub-ns transitions thanks to a SPAD-dummy approach. The detector exhibits a timing resolution better than 50 ps (Full Width at Half Maximum - FWHM) at a measurement repetition rate up to 40 MHz, and provides 16 independent outputs compatible with commercial Time-Correlated Single-Photon Counting (TCSPC) instrumentation. The instrument has been experimentally characterized and operated in preliminary NLOS imaging acquisitions where a 40 × 60 cm hidden object is successfully reconstructed by scanning over a grid of 150 × 150 positions.

Near-infrared spectroscopy (NIRS) is an established non-invasive diffuse optical method used to quantify hemoglobin oxygen saturation (${\mathrm{SO}}_2$) and hemoglobin concentration (Hb) changes from light attenuation at different wavelengths.^1,2 Diffuse correlation spectroscopy (DCS) is a more recent optical technology that uses speckle fluctuations to measure an index for blood flow (${\mathrm{BF}}_{\mathrm{i}}$). Specifically, DCS measures the intensity temporal autocorrelation function ($g_2$), which characterizes the displacement dynamics of scattering particles in the sample under interrogation.^{3 – 5} Combining DCS with NIRS allows for calculating the cerebral metabolic rate of oxygen⁶ and furthering our understanding of the relationship between hemoglobin concentration and cerebral blood flow (CBF) changes in healthy^7,8 and pathological conditions.^9,10 More recently, our and other groups have proposed the use of DCS pulsatile CBF index signals (${\mathrm{pCBF}}_{\mathrm{i}}$) to quantify intracranial pressure (ICP), critical closing pressure (CrCP), pulsatility index (PI), and cerebrovascular resistance index (${\mathrm{CVR}}_{\mathrm{i}}$) continuously and non-invasively.^{11 – 16} Despite the encouraging results, the low signal-to-noise ratio (SNR) of current DCS devices limits ${\mathrm{pCBF}}_{\mathrm{i}}$ to source-detector separations (SDsep) of up to 2.5 cm, which reduces brain sensitivity in adults,¹⁷ and to achieve sufficient time-points within a pulsatile waveform, it requires cardiac-gated averaging of 50 arterial pulses,¹¹ which dampens the pulsatile peaks and provides CrCP and ${\mathrm{CVR}}_{\mathrm{i}}$ estimates at 0.02 to 0.07 Hz, rates that are too low to investigate the dynamic pressure-flow relationship of the cerebral vasculature.¹⁸ To overcome the DCS noise, increase SDsep, and recover ${\mathrm{pCBF}}_{\mathrm{i}}$ with much less averaging, we propose a new method based on the combination of NIRS and DCS pulsatile signals.

In this paper, we present an innovative instrument for near-infrared time-resolved spectroscopy. The system is based on eight custom-designed pulsed diode lasers emitting at different wavelengths in the near-infrared region (635-1050 nm), all exhibiting an average optical power higher than 1 mW at 40 MHz pulse repetition rate, two custom-made single-photon detectors based on wide-area silicon photomultipliers and two time-measurement units based on a custom time-to-digital converter with 10 ps timing resolution. The system instrument response function has a width narrower than 160 ps (fullwidth at half-maximum) and stability better than ±1% for several hours for all the wavelengths. All the components of the instrument were designed in order to be compact. The entire system will be hosted in a standard 19 inches, 5U rack case (size 48 × 38 × 20 cm ³ ). The system communicates with the external computer through a USB 2.0 link and is designed to be employed in a clinical environment. The proposed instrument, thanks to the reduction of its cost and dimensions, paves the way to a wider diffusion of multiwavelengths near-infrared time-resolved spectroscopy systems.

We present a novel instrument for fast-gated operation of a 50 μm CMOS SPAD (Complementary Metal-Oxide-Semiconductor Single-Photon Avalanche Diode), driven by an integrated fast-gated active quenching circuit with transition times faster than 300 ps (20-80%). The instrument is based on a custom system-in-package where the SPAD and its driving electronics are housed in a TO-8 package. The detector can be operated at repetition rates up to 160 MHz, with gate on-times as short as 500 ps, always guaranteeing a temporal response with 60 ps (FWHM) timing jitter and short exponential decay (53 ps time-constant). A dark-count rate as low as 1 cps is achieved operating the CMOS SPAD at 5 V above breakdown at a temperature of 263 K, still keeping the afterpulsing probability lower than 2%, with only 50 ns hold-off time, thanks to the fast-gating driving electronics. The instrument is housed in a compact 5 4 8 cm³ case and can be triggered by either an external or internal source. A USB link allows to adjust measurement parameters, SPAD bias voltage and operating temperature. The high re-configurability of the instrument and its state-of-the-art performance make it suitable for applications where high detection rates and low timing jitter are required