Functional Time Domain Diffuse Correlation Spectroscopy.

Time-domain diffuse correlation spectroscopy (TD-DCS) offers a novel approach to high-spatial resolution functional brain imaging based on the direct quantification of cerebral blood flow (CBF) changes in response to neural activity. However, the signal-to-noise ratio (SNR) offered by previous TD-DCS instruments remains a challenge to achieving the high temporal resolution needed to resolve perfusion changes during functional measurements. Here we present a next-generation optimized functional TD-DCS system that combines a custom 1,064 nm pulse-shaped, quasi transform-limited, amplified laser source with a high-resolution time-tagging system and superconducting nanowire single-photon detectors (SNSPDs). System characterization and optimization was conducted on homogenous and two-layer intralipid phantoms before performing functional CBF measurements in six human subjects. By acquiring CBF signals at over 5 Hz for a late gate start time of the temporal point spread function (TPSF) at 15 mm source-detector separation, we demonstrate for the first time the measurement of blood flow responses to breath-holding and functional tasks using TD-DCS.

Diffuse Correlation Spectroscopy Beyond the Water Peak Enabled by Cross-Correlation of the Signals From InGaAs/InP Single Photon Detectors.

OBJECTIVE: Diffuse correlation spectroscopy (DCS) is an optical technique that allows for the non-invasive measurement of blood flow. Recent work has shown that utilizing longer wavelengths beyond the traditional NIR range provides a significant improvement to signal-to-noise ratio (SNR). However, current detectors both sensitive to longer wavelengths and suitable for clinical applications (InGaAs/InP SPADs) suffer from suboptimal afterpulsing and dark noise characteristics. To overcome these barriers, we introduce a cross correlation method to more accurately recover blood flow information using InGaAs/InP SPADs. METHODS: Two InGaAs/InP SPAD detectors were used for during in vitro and in vivo DCS measurements. Cross correlation of the photon streams from each detector was performed to calculate the correlation function. Detector operating parameters were varied to determine parameters which maximized measurement SNR.State-space modeling was performed to determine the detector characteristics at each operating point. RESULTS: Evaluation of detector characteristics was performed across the range of operating conditions. Modeling the effects of the detector noise on the correlation function provided a method to correct the distortion of the correlation curve, yielding accurate recovery of flow information as confirmed by a reference detector. CONCLUSION: Through a combination of cross-correlation of the signals from two detectors, model-based characterization of detector response, and optimization of detector operating parameters, the method allows for the accurate estimation of the true blood flow index. SIGNIFICANCE: This work presents a method by which DCS can be performed at longer NIR wavelengths with existing detector technology, taking advantage of the increased SNR.

Superconducting nanowire single-photon sensing of cerebral blood flow.

Significance: The ability of diffuse correlation spectroscopy (DCS) to measure cerebral blood flow (CBF) in humans is hindered by the low signal-to-noise ratio (SNR) of the method. This limits the high acquisition rates needed to resolve dynamic flow changes and to optimally filter out large pulsatile oscillations and prevents the use of large source-detector separations ( ≥ 3 cm ), which are needed to achieve adequate brain sensitivity in most adult subjects. Aim: To substantially improve SNR, we have built a DCS device that operates at 1064 nm and uses superconducting nanowire single-photon detectors (SNSPD). Approach: We compared the performances of the SNSPD-DCS in humans with respect to a typical DCS system operating at 850 nm and using silicon single-photon avalanche diode detectors. Results: At a 25-mm separation, we detected 13 ± 6 times more photons and achieved an SNR gain of 16 ± 8 on the forehead of 11 subjects using the SNSPD-DCS as compared to typical DCS. At this separation, the SNSPD-DCS is able to detect a clean pulsatile flow signal at 20 Hz in all subjects. With the SNSPD-DCS, we also performed measurements at 35 mm, showing a lower scalp sensitivity of 31 ± 6 % with respect to the 48 ± 8 % scalp sensitivity at 25 mm for both the 850 and 1064 nm systems. Furthermore, we demonstrated blood flow responses to breath holding and hyperventilation tasks. Conclusions: While current commercial SNSPDs are expensive, bulky, and loud, they may allow for more robust measures of non-invasive cerebral perfusion in an intensive care setting.

Diffuse correlation spectroscopy measurements of blood flow using 1064 nm light.

SIGNIFICANCE: Diffuse correlation spectroscopy (DCS) is an established optical modality that enables noninvasive measurements of blood flow in deep tissue by quantifying the temporal light intensity fluctuations generated by dynamic scattering of moving red blood cells. Compared with near-infrared spectroscopy, DCS is hampered by a limited signal-to-noise ratio (SNR) due to the need to use small detection apertures to preserve speckle contrast. However, DCS is a dynamic light scattering technique and does not rely on hemoglobin contrast; thus, there are significant SNR advantages to using longer wavelengths (>1000 nm) for the DCS measurement due to a variety of biophysical and regulatory factors. AIM: We offer a quantitative assessment of the benefits and challenges of operating DCS at 1064 nm versus the typical 765 to 850 nm wavelength through simulations and experimental demonstrations. APPROACH: We evaluate the photon budget, depth sensitivity, and SNR for detecting blood flow changes using numerical simulations. We discuss continuous wave (CW) and time-domain (TD) DCS hardware considerations for 1064 nm operation. We report proof-of-concept measurements in tissue-like phantoms and healthy adult volunteers. RESULTS: DCS at 1064 nm offers higher intrinsic sensitivity to deep tissue compared with DCS measurements at the typically used wavelength range (765 to 850 nm) due to increased photon counts and a slower autocorrelation decay. These advantages are explored using simulations and are demonstrated using phantom and in vivo measurements. We show the first high-speed (cardiac pulsation-resolved), high-SNR measurements at large source-detector separation (3 cm) for CW-DCS and late temporal gates (1 ns) for TD-DCS. CONCLUSIONS: DCS at 1064 nm offers a leap forward in the ability to monitor deep tissue blood flow and could be especially useful in increasing the reliability of cerebral blood flow monitoring in adults.

Portable System for Time-Domain Diffuse Correlation Spectroscopy.

We introduce a portable system for clinical studies based on time-domain diffuse correlation spectroscopy (DCS). After evaluating different lasers and detectors, the final system is based on a pulsed laser with about 550 ps pulsewidth, a coherence length of 38 mm, and two types of single-photon avalanche diodes (SPAD). The higher efficiency of the red-enhanced SPAD maximizes detection of the collected light, increasing the signal-to-noise ratio, while the better timing response of the CMOS SPAD optimizes the selection of late photons and increases spatial resolution. We discuss component selection and performance, and we present a full characterization of the system, measurement stability, a phantom-based validation study, and preliminary in vivo results collected from the forearms and the foreheads of four healthy subjects. With this system, we are able to resolve blood flow changes 1 cm below the skin surface with improved depth sensitivity and spatial resolution with respect to continuous wave DCS.

Time domain diffuse correlation spectroscopy: modeling the effects of laser coherence length and instrument response function.

Diffuse correlation spectroscopy (DCS) is an optical technique that non-invasively quantifies an index of blood flow (BFi) by measuring the temporal autocorrelation function of the intensity fluctuations of light diffusely remitted from the tissue. Traditional DCS measurements use continuous wave (CW) lasers with coherence lengths longer than the photon path lengths in the sample to ensure that the diffusely remitted light is coherent and generates a speckle pattern. Recently, we proposed time domain DCS (TD-DCS) to allow measurements of the speckle fluctuations for specific path lengths of light through the tissue, which has the distinct advantage of permitting an analysis of selected long path lengths of light to improve the depth sensitivity of the measurement. However, compared to CW-DCS, factors including the instrument response function (IRF), the detection gate width, and the finite coherence length need to be considered in the model analysis of the experimental data. Here we present a TD-DCS model describing how the intensity autocorrelation functions measured for different path lengths of light depend on the coherence length, pulse width of the laser, detection gate width, IRF, BFi, and optical properties of the scattering sample. Predictions of the model are compared with experimental results using a homogeneous liquid phantom sample that mimics human tissue optical properties. The BFis obtained from the TD-DCS model for different path lengths of light agree with the BFi obtained from CW-DCS measurements, while the standard simplified model underestimates the BFi by a factor of ∼2. This Letter establishes the theoretical foundation of the TD-DCS technique and provides guidance for future BFi measurements in tissue.

Target-specific contrast agents for magnetic resonance microscopy.

High-resolution ex vivo magnetic resonance (MR) imaging can be used to delineate prominent architectonic features in the human brain, but increased contrast is required to visualize more subtle distinctions. To aid MR sensitivity to cell density and myelination, we have begun the development of target-specific paramagnetic contrast agents. This work details the first application of luxol fast blue (LFB), an optical stain for myelin, as a white matter-selective MR contrast agent for human ex vivo brain tissue. Formalin-fixed human visual cortex was imaged with an isotropic resolution between 80 and 150 microm at 4.7 and 14 T before and after en bloc staining with LFB. Longitudinal (R1) and transverse (R2) relaxation rates in LFB-stained tissue increased proportionally with myelination at both field strengths. Changes in R1 resulted in larger contrast-to-noise ratios (CNR), per unit time, on T1-weighted images between more myelinated cortical layers (IV-VI) and adjacent, superficial layers (I-III) at both field strengths. Specifically, CNR for LFB-treated samples increased by 229 +/- 13% at 4.7 T and 269 +/- 25% at 14 T when compared to controls. Also, additional cortical layers (IVca, IVd, and Va) were resolvable in 14 T-MR images of LFB-treated samples but not in control samples. After imaging, samples were sliced in 40-micron sections, mounted, and photographed. Both the macroscopic and microscopic distributions of LFB were found to mimic those of traditional histological preparations. Our results suggest target-specific contrast agents will enable more detailed MR images with applications in imaging pathological ex vivo samples and constructing better MR atlases from ex vivo brains.

Detection of entorhinal layer II using 7Tesla [corrected] magnetic resonance imaging.

The entorhinal cortex lies in the mediotemporal lobe and has major functional, structural, and clinical significance. The entorhinal cortex has a unique cytoarchitecture with large stellate neurons in layer II that form clusters. The entorhinal cortex receives vast sensory association input, and its major output arises from the layer II and III neurons that form the perforant pathway. Clinically, the neurons in layer II are affected with neurofibrillary tangles, one of the two pathological hallmarks of Alzheimer's disease. We describe detection of the entorhinal layer II islands using magnetic resonance imaging. We scanned human autopsied temporal lobe blocks in a 7T human scanner using a solenoid coil. In 70 and 100 microm isotropic data, the entorhinal islands were clearly visible throughout the anterior-posterior extent of entorhinal cortex. Layer II islands were prominent in both the magnetic resonance imaging and corresponding histological sections, showing similar size and shape in two types of data. Area borders and island location based on cytoarchitectural features in the mediotemporal lobe were robustly detected using the magnetic resonance images. Our ex vivo results could break ground for high-resolution in vivo scanning that could ultimately benefit early diagnosis and treatment of neurodegenerative disease.