This review is aimed at presenting the state-of-the-art of time domain (TD) functional near-infrared spectroscopy (fNIRS). We first introduce the physical principles, the basics of modeling and data analysis. Basic instrumentation components (light sources, detection techniques, and delivery and collection systems) of a TD fNIRS system are described. A survey of past, existing and next generation TD fNIRS systems used for research and clinical studies is presented. Performance assessment of TD fNIRS systems and standardization issues are also discussed. Main strengths and weakness of TD fNIRS are highlighted, also in comparison with continuous wave (CW) fNIRS. Issues like quantification of the hemodynamic response, penetration depth, depth selectivity, spatial resolution and contrast-to-noise ratio are critically examined, with the help of experimental results performed on phantoms or in vivo. Finally we give an account on the technological developments that would pave the way for a broader use of TD fNIRS in the neuroimaging community.

The study of photon propagation in highly scattering media (diffuse optics) is a powerful tool to noninvasively investigate biological tissues in depth.^1,2 For most biological media in the 600- to 1100-nm range, the scattering coefficient is much higher than the absorption coefficient, thus hindering information from the human body that in absence of scattering would appear transparent as a feebly colored glass. The attractiveness of probing the human tissues and their functions with light has fostered great efforts to cope with the challenges of “diffuse optics,” leading to a whole range of new physical concepts, theoretical models, instruments, measurement approaches, and applications. The terms near-infrared spectroscopy (NIRS) and diffuse optical imaging (DOI) are used in the scientific community to refer to the techniques used for noninvasive monitoring and imaging with diffuse light. Typically, light is injected into the medium and the signal re-emitted at some distance(s) on the surface is analyzed to retrieve information carried by photons along their paths. In the simplest case, continuous wave (CW) illumination and detection are employed.³ 4. ^{– 5} Conversely, the adoption either of a frequency-domain (FD)⁶ or of a time-domain (TD)⁷ 8. 9. ^{– 10} scheme permits to add a further dimension in the measurement, e.g., disentangling absorption from scattering contributions.

We present a CMOS imager consisting of 32×32 smart pixels, each one able to detect single photons in the 300-900 nm wavelength range and to perform both photon-counting and photon-timing operations on very fast optical events with faint intensities. In photon-counting mode, the imager provides photon-number (i.e, intensity) resolved movies of the scene under observation, up to 100 000 frames/s. In photon-timing, the imager provides photon arrival times with 312 ps resolution. The result are videos with either time-resolved (e.g., fluorescence) maps of a sample, or 3-D depth-resolved maps of a target scene. The imager is fabricated in a cost-effective 0.35-μm CMOS technology, automotive certified. Each pixel consists of a single-photon avalanche diode with 30 μm photoactive diameter, coupled to an in-pixel 10-bit time-to-digital converter with 320-ns full-scale range, an INL of 10% LSB and a DNL of 2% LSB. The chip operates in global shutter mode, with full frame times down to 10 μs and just 1-ns conversion time. The reconfigurable imager design enables a broad set of applications, like time-resolved spectroscopy, fluorescence lifetime imaging, diffusive optical tomography, molecular imaging, time-of-flight 3-D ranging and atmospheric layer sensing through LIDAR.

We demonstrate the feasibility of time-resolved diffuse reflectance measurements at small source-detector separations using a single-photon avalanche diode operated in time-gated mode. Photon time distributions at an interfiber distance of 2 mm were obtained on a homogeneous tissue phantom with a dynamic range of ${10}^6$ and collecting photons at arrival times up to 4 ns. Moreover, we were able to detect a local inhomogeneity deeply buried within a diffusive medium with better spatial resolution, higher signal intensity, and same contrast of a larger (20 mm) interfiber distance. Finally, the proposed approach proved valuable to detect in vivo a task-related brain activation.

In recent years, instruments and methodologies to noninvasively probe human tissues by diffuse light in the near-infrared spectral range have undergone translation from laboratory bench to bedside. For example, clinical trials have been performed targeting the female breast. Optical mammography has been developed and applied to detect and characterize breast lesions,^1,2 as well as to monitor the outcome of neoadjuvant chemotherapy of the breast.^3,4 Diffuse optical spectroscopy is a promising technique for cancer risk assessment.^5,6 In parallel, many clinical studies have been conducted targeting the brain. Optical imaging has been used to observe the hemodynamic response to cognitive, sensory, and motor stimuli,⁷ and to assess changes associated with traumatic brain injury,⁸ stroke,⁹ and epilepsy,¹⁰ with the aim of providing a less expensive and portable alternative to the existing neuroimaging techniques such as magnetic resonance imaging or x-ray computed tomography. Meanwhile, optical techniques have also been applied to other tissues such as muscle, joints, bone, and skin as a means of providing diagnostic information.

In biomedical optics, the characterization of instrumentation with the help of appropriate tissue-simulating phantoms¹ plays an important role, ranging from proof-of-principle tests at early stages of the development to quality assurance during routine clinical application.² Numerous performance studies have been carried out by individual research groups; however, there are only a few multilaboratory efforts to characterize and to compare multiple instruments. Such approaches are essential to provide a sound basis for achieving quantitatively comparable results in clinical studies. They require the development of standardized guidelines to perform the same measurements on phantoms with the same properties in different laboratories. In the field of photon migration instruments, the first systematic study of different instruments was performed on the basis of the MEDPHOT protocol.³ Recently, the development and testing of phantoms has been reported for quality assurance in a multicenter clinical trial to measure the response of breast tumors to neoadjuvant chemotherapy by means of diffuse optical spectroscopic imaging.⁴ In the context of fluorescence imaging of tissues, phantoms were developed to characterize and compare imaging systems and to train surgeons.⁵