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Diffuse correlation spectroscopy (DCS) is an optical technique that can be used to characterize blood flow in tissue. The measurement of cerebral hemodynamics has arisen as a promising use case for DCS, though traditional implementations of DCS exhibit suboptimal signal-to-noise ratio (SNR) and cerebral sensitivity to make robust measurements of cerebral blood flow in adults. In this work, we present long wavelength, interferometric DCS (LW-iDCS), which combines the use of a longer illumination wavelength (1064 nm), multi-speckle, and interferometric detection, to improve both cerebral sensitivity and SNR. Through direct comparison with long wavelength DCS based on superconducting nanowire single photon detectors, we demonstrate an approximate 5× improvement in SNR over a single channel of LW-DCS in the measured blood flow signals in human subjects. We show equivalence of extracted blood flow between LW-DCS and LW-iDCS, and demonstrate the feasibility of LW-iDCS measured at 100 Hz at a source-detector separation of 3.5 cm. This improvement in performance has the potential to enable robust measurement of cerebral hemodynamics and unlock novel use cases for diffuse correlation spectroscopy.

To assess the association between cerebral saturation (crSOsub2/sub) using Near-Infrared Spectroscopy (NIRS) and brain injury in extremely preterm infants.This retrospective study includes 62 infants (lt;28 weeks gestation) who underwent continuous NIRS monitoring in the first 5 days after birth. Median crSOsub2/subwere compared in 12 h increments between infants with and without germinal matrix/intraventricular hemorrhage (GM/IVH). crSOsub2/subwas also compared by IVH severity, onset, and by grade of injury on term equivalent MRI.After 48 h of life (HOL), infants with GM/IVH had significantly lower crSOsub2/subthan those without GM/IVH in analysis adjusted for potential confounding e.g., at 49-60 HOL (69.5 (66.2, 72.8) vs. 74.7 (71.8, 77.6), p = 0.023). There were no significant differences in crSOsub2/subby IVH subcategory or injury severity on MRI.Clinical use of NIRS has the potential to identify crSOsub2/subpatterns associated with development of GM/IVH.

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.

Background: Transcranial photobiomodulation (tPBM) has recently emerged as a potential cognitive enhancement technique and clinical treatment for various neuropsychiatric and neurodegenerative disorders by delivering invisible near-infrared light to the scalp and increasing energy metabolism in the brain. Objective: We assessed whether transcranial photobiomodulation with near-infrared light modulates cerebral electrical activity through electroencephalogram (EEG) and cerebral blood flow (CBF). Methods: We conducted a single-blind, sham-controlled pilot study to test the effect of continuous (c-tPBM), pulse (p-tPBM), and sham (s-tPBM) transcranial photobiomodulation on EEG oscillations and CBF using diffuse correlation spectroscopy (DCS) in a sample of ten healthy subjects [6F/4 M; mean age 28.6±12.9 years]. c-tPBM near-infrared radiation (NIR) (830 nm; 54.8 mW/cm2; 65.8 J/cm2; 2.3 kJ) and p-tPBM (830 nm; 10 Hz; 54.8 mW/cm2; 33%; 21.7 J/cm2; 0.8 kJ) were delivered concurrently to the frontal areas by four LED clusters. EEG and DCS recordings were performed weekly before, during, and after each tPBM session. Results: c-tPBM significantly boosted gamma (t = 3.02, df = 7, p

We characterize cerebral sensitivity across the entire adult human head for diffuse correlation spectroscopy, an optical technique increasingly used for bedside cerebral perfusion monitoring. Sixteen subject-specific magnetic resonance imaging-derived head models were used to identify high sensitivity regions by running Monte Carlo light propagation simulations at over eight hundred uniformly distributed locations on the head. Significant spatial variations in cerebral sensitivity, consistent across subjects, were found. We also identified correlates of such differences suitable for real-time assessment. These variations can be largely attributed to changes in extracerebral thickness and should be taken into account to optimize probe placement in experimental settings.

We present a light emitting diode (LED) based spectroscopic method for application in highly scattering materials. Using an LED as a light source, frequency domain measurement and the diffusion model of photon migration, we measured the absorption spectrum of a chromophore (methylene blue) suspended in a highly scattering medium (1.54% solids content Liposyn fat emulsion). The resulting spectrum agrees both qualitatively and quantitatively with standard spectropho-tometric measurements obtained without the scattering. Finally, we enumerate reasons why LED-based frequency-domain techniques are very appropriate for medical applications.

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.

BACKGROUND: Cortical spreading depolarizations (CSDs) are associated with worse outcomes in many forms of acute brain injury, including traumatic brain injury (TBI). Animal models could be helpful in developing new therapies or biomarkers to improve outcomes in survivors of TBI. Recently, investigators have observed CSDs in murine models of mild closed head injury (CHI). We designed the currently study to determine additional experimental conditions under which CSDs can be observed, from mild to relatively more severe TBI. METHODS: Adult male C57Bl/6J mice (8–14 weeks old) were anesthetized with isoflurane and subjected to CHI with an 81-g weight drop from 152 or 183 cm. CSDs were detected with minimally invasive visible light optical intrinsic signal imaging. Cerebral blood flow index (CBFi) was measured in the 152-cm drop height cohort using diffuse correlation spectroscopy at baseline before and 4 min after CHI. Cognitive outcomes were assessed at 152- and 183-cm drop heights for the Morris water maze hidden platform, probe, and visible platform tests. RESULTS: CSDs occurred in 43% (n = 12 of 28) of 152-cm and 58% (n = 15 of 26) of 183-cm drop height CHI mice (p = 0.28). A lower baseline preinjury CBFi was associated with development of CSDs in CHI mice (1.50 ± 0.07 × 10(−7) CHI without CSD [CSD−] vs. 1.17 ± 0.04 × 10(−7) CHI with CSD [CSD+], p = 0.0001). Furthermore, in CHI mice that developed CSDs, the ratio of post-CHI to pre-CHI CBFi was lower in the hemisphere ipsilateral to a CSD compared with non-CSD hemispheres (0.19 ± 0.07 less in the CSD hemisphere, p = 0.028). At a 152-cm drop height, there were no detectable differences between sham injured (n = 10), CHI CSD+ (n = 12), and CHI CSD− (n = 16) mice on Morris water maze testing at 4 weeks. At a 183-cm drop height, CHI CSD+ mice had worse performance on the hidden platform test at 1–2 weeks versus sham mice (n = 15 CHI CSD+, n = 9 sham, p = 0.045), but there was no appreciable differences compared with CHI CSD− mice (n = 11 CHI CSD−). CONCLUSIONS: The data suggest that a lower baseline cerebral blood flow prior to injury may contribute to the occurrence of a CSD. Furthermore, a CSD at the time of injury can be associated with worse cognitive outcome under the appropriate experimental conditions in a mouse CHI model of TBI.

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.

Background and Purpose— We aimed to determine if microemboli after endovascular thrombectomy correlate with unfavorable outcomes despite successful recanalization. Methods— This is a prospective multicenter study of consecutive patients with ischemic stroke and occlusion of anterior circulation vessels (terminal internal carotid or main trunk of the middle cerebral artery/first-order branch of the main trunk of the middle cerebral artery segments of middle cerebral artery) after successful thrombectomy (modified Treatment In Cerebral Ischemia grades 2b-3). Microembolic signals (MES) were assessed by 30 minutes of transcranial Doppler monitoring within 72 hours of the last-seen-well time. Major outcomes included modified Rankin Scale at 90 days and infarct volume on head computed tomography at 24 hours. We also assessed early outcomes based on National Institutes of Health Stroke Scale variation and recurrence of stroke, transient ischemic attack, or systemic embolism within 90 days. Results— Among 111 patients, MES were detected in 43 (39%), with a median rate of 4 counts/h (interquartile range 2–12). The occurrence of MES was not associated with a significant difference in modified Rankin Scale (ordinal shift analysis, adjusted odds ratio, 1.06 [95% CI, 0.48–2.34] P =0.85) nor in functional independence (modified Rankin Scale, 0–2: adjusted odds ratio, 0.52 [95% CI, 0.19–1.39] P =0.19). Patients with and without MES had similar infarct volumes (adjusted beta, 11.2 [95% CI, −46.6 to +22.9] P =0.51) on 24-hour computed tomography. MES did predict new embolic events (adjusted Cox hazard ratio, 6.78 [95% CI, 1.63–27.8] P =0.01). Conclusions— MES detected by transcranial Doppler following endovascular treatment of anterior circulation occlusions do not predict clinical or radiological outcome. However, such emboli are an independent marker of recurrent embolic events within 90 days.

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.