We present a first in vivo application of phase dual‐slopes (DSϕ), measured with frequency‐domain near‐infrared spectroscopy on four healthy human subjects, to demonstrate their enhanced sensitivity to cerebral hemodynamics. During arterial blood pressure oscillations elicited at a frequency of 0.1 Hz, we compare three different ways to analyze either intensity (I) or phase (ϕ) data collected on the subject's forehead at multiple source‐detector distances: Single‐distance, single‐slope and DS. Theoretical calculations based on diffusion theory show that the method with the deepest maximal sensitivity (at about 11 mm) is DSϕ. The in vivo results indicate a qualitative difference of phase data (especially DSϕ) and intensity data (especially single‐distance intensity [SDI]), which we assign to stronger contributions from scalp hemodynamics to SDI and from cortical hemodynamics to DSϕ. Our findings suggest that scalp hemodynamic oscillations may be dominated by blood volume dynamics, whereas cortical hemodynamics may be dominated by blood flow velocity dynamics.

Using diffusion theory, we show that a dual-slope method is more effective than single-slope methods or single-distance methods at enhancing sensitivity to deeper tissue. The dual-slope method requires a minimum of two sources and two detectors arranged in specially configured arrays. In particular, we present diffusion theory results for a symmetrical linear array of two sources (separated by 55 mm) that sandwich two detectors (separated by 15 mm), for which dual slopes achieve maximal sensitivity at a depth of about 5 mm for direct current (DC) intensity (as measured in continuous-wave spectroscopy) and 11 mm for phase (as measured in frequencydomain spectroscopy) under typical values of the tissue optical properties (absorption coefficient: ~0.01 mm −1 , reduced scattering coefficient: ~1 mm −1). This result is a major advance over singledistance or single-slope data, which feature maximal sensitivity to shallow tissue (<2 mm for the intensity, <5 mm for the phase).

We recently proposed a dual-slope technique for diffuse optical spectroscopy and imaging of scattering media. This technique requires a special configuration of light sources and optical detectors to create dual-slope sets. Here, we present methods for designing, optimizing, and building an optical imaging array that features m dual-slope sets to image n voxels. After defining the m × n matrix (S) that describes the sensitivity of the m dual-slope measurements to absorption perturbations in each of the n voxels, we formulate the inverse imaging problem in terms of the Moore–Penrose pseudoinverse matrix of S (S+). This approach allows us to introduce several measures of imaging performance: reconstruction accuracy (correct spatial mapping), crosstalk (incorrect spatial mapping), resolution (point spread function), and localization (offset between actual and reconstructed point perturbations). Furthermore, by considering the singular value decomposition formulation, we show the significance of visualizing the first m right singular vectors of S, whose linear combination generates the reconstructed map. We also describe methods to build a physical array using a three-layer mesh structure (two polyethylene films and polypropylene hook-and-loop fabric) embedded in silicone (PDMS). Finally, we apply these methods to design two arrays and choose one to construct. The chosen array consists of 16 illumination fibers, 10 detection fibers, and 27 dual-slope sets for dual-slope imaging optimized for the size of field of view and localization of absorption perturbations. This particular array is aimed at functional near-infrared spectroscopy of the human brain, but the methods presented here are of general applicability to a variety of devices and imaging scenarios.

. This report is the second part of a comprehensive two-part series aimed at reviewing an extensive and diverse toolkit of novel methods to explore brain health and function. While the first report focused on neurophotonic tools mostly applicable to animal studies, here, we highlight optical spectroscopy and imaging methods relevant to noninvasive human brain studies. We outline current state-of-the-art technologies and software advances, explore the most recent impact of these technologies on neuroscience and clinical applications, identify the areas where innovation is needed, and provide an outlook for the future directions.

We report non-invasive, bilateral optical measurements on the forehead of five healthy human subjects, of 0.1 Hz oscillatory hemodynamics elicited either by cyclic inflation of pneumatic thigh cuffs, or by paced breathing. Optical intensity and the phase of photon-density waves were collected with frequency-domain near-infrared spectroscopy at seven source-detector distances (1140 mm). Coherent hemodynamic oscillations are represented by phasors of oxyhemoglobin (O) and deoxyhemoglobin (D) concentrations, and by the vector D/O that represents the amplitude ratio and phase difference of D and O. We found that, on an average, the amplitude ratio (|D/O|) and the phase difference (∠(D/O)) obtained with single-distance intensity at 11–40 mm increase from 0.1° and −330° to 0.2° and −200°, respectively. Single-distance phase and the intensity slope featured a weaker dependence on source-detector separation, and yielded |D/O| and ∠(D/O) values of about 0.5 and −200°, respectively, at distances greater than 20 mm. The key findings are: (1) Single-distance phase and intensity slope are sensitive to deeper tissue compared to single-distance intensity; (2) deeper tissue hemodynamic oscillations, which more closely represent the brain, feature D and O phasors that are consistent with a greater relative flow-to-volume contributions in brain tissue compared to extracerebral, superficial tissue.

We report a near-infrared spectroscopy (NIRS) study of coherent hemodynamic oscillations measured on the human forehead at multiple source-detector distances (1 to 4 cm). The physiological source of the coherent hemodynamics is arterial blood pressure oscillations at a frequency of 0.1 Hz, induced by cyclic inflation (to a pressure of 200 mmHg) and deflation of two thigh cuffs wrapped around the subject's thighs. To interpret our results, we use a recently developed hemodynamic model and a phasor representation of the oscillations of oxyhemoglobin, deoxyhemoglobin, and total hemoglobin concentrations in the tissue (phasors O, D, and T, respectively). The increase in the phase angle between D and O at larger source-detector separations is assigned to greater flow versus volume contributions and to a stronger blood flow autoregulation in deeper tissue (brain cortex) with respect to superficial tissue (scalp and skull). The relatively constant phase lag of T versus arterial blood pressure oscillations at all source-detector distances was assigned to competing effects from stronger autoregulation and smaller arterial-to-venous contributions in deeper tissue with respect to superficial tissue. We demonstrate the application of a hemodynamic model to interpret coherent hemodynamics measured with NIRS and to assess the different nature of shallow (extracerebral) versus deep (cerebral) tissue hemodynamics.

We propose a new near-infrared spectroscopy (NIRS) method for quantitative measurements of cerebral blood flow (CBF). Because this method uses concepts of coherent hemodynamics spectroscopy (CHS), we identify this new method with the acronym NIRS-CHS. We tested this method on the prefrontal cortex of six healthy human subjects during mean arterial pressure (MAP) transients induced by the rapid deflation of pneumatic thigh cuffs. A comparison of CBF dynamics measured with NIRS-CHS and with diffuse correlation spectroscopy (DCS) showed a good agreement for characteristic times of the CBF transient. We also report absolute measurements of baseline CBF with NIRS-CHS (69 ± 6 ml/100g/min over the six subjects). NIRS-CHS can provide more accurate measurements of CBF with respect to previously reported NIRS surrogates of CBF.

The concept of region of sensitivity is central to the field of diffuse optics and is closely related to the Jacobian matrix used to solve the inverse problem in imaging. It is well known that, in diffuse reflectance, the region of sensitivity associated with a given source–detector pair is shaped as a banana, and features maximal sensitivity to the portions of the sample that are closest to the source and the detector. We have recently introduced a dual-slope (DS) method based on a special arrangement of two sources and two detectors, which results in deeper and more localized regions of sensitivity, resembling the shapes of different kinds of nuts. Here, we report the regions of sensitivity associated with a variety of source–detector arrangements for DS measurements of intensity and phase with frequency-domain spectroscopy (modulation frequency: 140[Formula: see text]MHz) in a medium with absorption and reduced scattering coefficients of 0.1 and 12 cm[Formula: see text], respectively. The main result is that the depth of maximum sensitivity, considering only cases that use source-detector separations of 25 and 35 mm, progressively increases as we consider single-distance intensity (2.0[Formula: see text]mm), DS intensity (4.6[Formula: see text]mm), single-distance phase (7.5[Formula: see text]mm), and DS phase (10.9[Formula: see text]mm). These results indicate the importance of DS measurements, and even more so of phase measurements, when it is desirable to selectively probe deeper portions of a sample with diffuse optics. This is certainly the case in non-invasive optical studies of brain, muscle, and breast tissue, which are located underneath the superficial tissue at variable depths.