Comparison of diffuse correlation spectroscopy analytical models for measuring cerebral blood flow in adults.

Significance: Although multilayer analytical models have been proposed to enhance brain sensitivity of diffuse correlation spectroscopy (DCS) measurements of cerebral blood flow, the traditional homogeneous model remains dominant in clinical applications. Rigorous in vivo comparison of these analytical models is lacking. Aim: We compare the performance of different analytical models to estimate a cerebral blood flow index (CBFi) with DCS in adults. Approach: Resting-state data were obtained on a cohort of 20 adult patients with subarachnoid hemorrhage. Data at 1 and 2.5 cm source-detector separations were analyzed with the homogenous, two-layer, and three-layer models to estimate scalp blood flow index and CBFi. The performance of each model was quantified via fitting convergence, fit stability, brain-to-scalp flow ratio (BSR), and correlation with transcranial Doppler ultrasound (TCD) measurements of cerebral blood flow velocity in the middle cerebral artery (MCA). Results: The homogeneous model has the highest pass rate (100%), lowest coefficient of variation (CV) at rest (median [IQR] at 1 Hz of 0.18 [0.13, 0.22]), and most significant correlation with MCA blood flow velocities (Rs=0.59, p=0.010) compared with both the two- and three-layer models. The multilayer model pass rate was significantly correlated with extracerebral layer thicknesses. Discarding datasets with non-physiological BSRs increased the correlation between DCS measured CBFi and TCD measured MCA velocities for all models. Conclusions: We found that the homogeneous model has the highest pass rate, lowest CV at rest, and most significant correlation with MCA blood flow velocities. Results from the multilayer models should be taken with caution because they suffer from lower pass rates and higher coefficients of variation at rest and can converge to non-physiological values for CBFi. Future work is needed to validate these models in vivo, and novel approaches are merited to improve the performance of the multimodel models.

Impaired cerebrovascular reactivity in pediatric sickle cell disease using diffuse correlation spectroscopy.

Cerebrovascular reactivity (CVR), defined as the ability of cerebral vasculature to dilate in response to a vasodilatory stimulus, is an integral mechanism in brain homeostasis that is thought to be impaired in sickle cell disease (SCD). This study used diffuse correlation spectroscopy and a simple breath-hold stimulus to quantify CVR non-invasively in a cohort of 12 children with SCD and 14 controls. Median [interquartile range] CVR was significantly decreased in SCD compared to controls (2.03 [1.31, 2.44] versus 3.49 [3.00, 4.11] %/mmHg, p = 0.028). These results suggest DCS may provide a feasible means to routinely monitor CVR impairments in pediatric SCD.

Normative cerebral microvascular blood flow waveform morphology assessed with diffuse correlation spectroscopy.

Microvascular cerebral blood flow exhibits pulsatility at the cardiac frequency that carries valuable information about cerebrovascular health. This study used diffuse correlation spectroscopy to quantify normative features of these waveforms in a cohort of thirty healthy adults. We demonstrate they are sensitive to changes in vascular tone, as indicated by pronounced morphological changes with hypercapnia. Further, we observe significant sex-based differences in waveform morphology, with females exhibiting higher flow, greater area-under-the-curve, and lower pulsatility. Finally, we quantify normative values for cerebral critical closing pressure, i.e., the minimum pressure required to maintain flow in a given vascular region.

Agreement in cerebrovascular reactivity assessed with diffuse correlation spectroscopy across experimental paradigms improves with short separation regression.

Significance: Cerebrovascular reactivity (CVR), i.e., the ability of cerebral vasculature to dilate or constrict in response to vasoactive stimuli, is a biomarker of vascular health. Exogenous administration of inhaled carbon dioxide, i.e., hypercapnia (HC), remains the "gold-standard" intervention to assess CVR. More tolerable paradigms that enable CVR quantification when HC is difficult/contraindicated have been proposed. However, because these paradigms feature mechanistic differences in action, an assessment of agreement of these more tolerable paradigms to HC is needed. Aim: We aim to determine the agreement of CVR assessed during HC, breath-hold (BH), and resting state (RS) paradigms. Approach: Healthy adults were subject to HC, BH, and RS paradigms. End tidal carbon dioxide (EtCO2) and cerebral blood flow (CBF, assessed with diffuse correlation spectroscopy) were monitored continuously. CVR (%/mmHg) was quantified via linear regression of CBF versus EtCO2 or via a general linear model (GLM) that was used to minimize the influence of systemic and extracerebral signal contributions. Results: Strong agreement ( CCC ≥ 0.69 ; R ≥ 0.76 ) among CVR paradigms was demonstrated when utilizing a GLM to regress out systemic/extracerebral signal contributions. Linear regression alone showed poor agreement across paradigms ( CCC ≤ 0.35 ; R ≤ 0.45 ). Conclusions: More tolerable experimental paradigms coupled with regression of systemic/extracerebral signal contributions may offer a viable alternative to HC for assessing CVR.

Microvascular cerebral blood flow response to intrathecal nicardipine is associated with delayed cerebral ischemia.

One of the common complications of non-traumatic subarachnoid hemorrhage (SAH) is delayed cerebral ischemia (DCI). Intrathecal (IT) administration of nicardipine, a calcium channel blocker (CCB), upon detection of large-artery cerebral vasospasm holds promise as a treatment that reduces the incidence of DCI. In this observational study, we prospectively employed a non-invasive optical modality called diffuse correlation spectroscopy (DCS) to quantify the acute microvascular cerebral blood flow (CBF) response to IT nicardipine (up to 90 min) in 20 patients with medium-high grade non-traumatic SAH. On average, CBF increased significantly with time post-administration. However, the CBF response was heterogeneous across subjects. A latent class mixture model was able to classify 19 out of 20 patients into two distinct classes of CBF response: patients in Class 1 (n = 6) showed no significant change in CBF, while patients in Class 2 (n = 13) showed a pronounced increase in CBF in response to nicardipine. The incidence of DCI was 5 out of 6 in Class 1 and 1 out of 13 in Class 2 (p < 0.001). These results suggest that the acute (<90 min) DCS-measured CBF response to IT nicardipine is associated with intermediate-term (up to 3 weeks) development of DCI.

Repetitive Low-level Blast Exposure and Neurocognitive Effects in Army Ranger Mortarmen.

INTRODUCTION: Occupational exposure to repetitive, low-level blasts in military training and combat has been tied to subconcussive injury and poor health outcomes for service members. Most low-level blast studies to date have focused on explosive breaching and firing heavy weapon systems; however, there is limited research on the repetitive blast exposure and physiological effects that mortarmen experience when firing mortar weapon systems. Motivated by anecdotal symptoms of mortarmen, the purpose of this paper is to characterize this exposure and its resulting neurocognitive effects in order to provide preliminary findings and actionable recommendations to safeguard the health of mortarmen. MATERIALS AND METHODS: In collaboration with the U.S. Army Rangers at Fort Benning, blast exposure, symptoms, and pupillary light reflex were measured during 3 days of firing 81 mm and 120 mm mortars in training. Blast exposure analysis included the examination of the blast overpressure (BOP) and cumulative exposure by mortarman position, as well as comparison to the 4 psi safety threshold. Pupillary light reflex responses were analyzed with linear mixed effects modeling. All neurocognitive results were compared between mortarmen (n = 11) and controls (n = 4) and cross-compared with blast exposure and blast history. RESULTS: Nearly 500 rounds were fired during the study, resulting in a high cumulative blast exposure for all mortarmen. While two mortarmen had average BOPs exceeding the 4 psi safety limit (Fig. 2), there was a high prevalence of mTBI-like symptoms among all mortarmen, with over 70% experiencing headaches, ringing in the ears, forgetfulness/poor memory, and taking longer to think during the training week (n ≥ 8/11). Mortarmen also had smaller and slower pupillary light reflex responses relative to controls, with significantly slower dilation velocity (P < 0.05) and constriction velocity (P < 0.10). CONCLUSION: Mortarmen experienced high cumulative blast exposure coinciding with altered neurocognition that is suggestive of blast-related subconcussive injury. These neurocognitive effects occurred even in mortarmen with average BOP below the 4 psi safety threshold. While this study was limited by a small sample size, its results demonstrate a concerning health risk for mortarmen that requires additional study and immediate action. Behavioral changes like ducking and standing farther from the mortar when firing can generally help reduce mortarmen BOP exposure, but we recommend the establishment of daily cumulative safety thresholds and daily firing limits in training to reduce cumulative blast exposure, and ultimately, improve mortarmen's quality of life and longevity in service.

Optical imaging and spectroscopy for the study of the human brain: status report.

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.

Quantifying the Cerebral Hemometabolic Response to Blood Transfusion in Pediatric Sickle Cell Disease With Diffuse Optical Spectroscopies.

Red blood cell transfusions are common in patients with sickle cell disease who are at increased risk of stroke. Unfortunately, transfusion thresholds needed to sufficiently dilute sickle red blood cells and adequately restore oxygen delivery to the brain are not well defined. Previous work has shown that transfusion is associated with a reduction in oxygen extraction fraction and cerebral blood flow, both of which are abnormally increased in sickle patients. These reductions are thought to alleviate hemometabolic stress by improving the brain's ability to respond to increased metabolic demand, thereby reducing susceptibility to ischemic injury. Monitoring the cerebral hemometabolic response to transfusion may enable individualized management of transfusion thresholds. Diffuse optical spectroscopies may present a low-cost, non-invasive means to monitor this response. In this study, children with SCD undergoing chronic transfusion therapy were recruited. Diffuse optical spectroscopies (namely, diffuse correlation spectroscopy combined with frequency domain near-infrared spectroscopy) were used to quantify oxygen extraction fraction (OEF), cerebral blood volume (CBV), an index of cerebral blood flow (CBFi), and an index of cerebral oxygen metabolism (CMRO2i) in the frontal cortex immediately before and after transfusion. A subset of patients receiving regular monthly transfusions were measured during a subsequent transfusion. Data was captured from 35 transfusions in 23 patients. Transfusion increased median blood hemoglobin levels (Hb) from 9.1 to 11.7 g/dL (p < 0.001) and decreased median sickle hemoglobin (HbS) from 30.9 to 21.7% (p < 0.001). Transfusion decreased OEF by median 5.9% (p < 0.001), CBFi by median 21.2% (p = 0.020), and CBV by median 18.2% (p < 0.001). CMRO2i did not statistically change from pre-transfusion levels (p > 0.05). Multivariable analysis revealed varying degrees of associations between outcomes (i.e., OEF, CBFi, CBV, and CMRO2i), Hb, and demographics. OEF, CBFi, and CBV were all negatively associated with Hb, while CMRO2i was only associated with age. These results demonstrate that diffuse optical spectroscopies are sensitive to the expected decreases of oxygen extraction, blood flow, and blood volume after transfusion. Diffuse optical spectroscopies may be a promising bedside tool for real-time monitoring and goal-directed therapy to reduce stroke risk for sickle cell disease.

Cerebrovascular reactivity measured in awake mice using diffuse correlation spectroscopy.

Significance: Cerebrovascular reactivity (CVR), defined as the ability of the cerebral vasculature to dilate or constrict in response to a vasoactive stimulus, is an important indicator of the brain's vascular health. However, mechanisms of cerebrovascular dysregulation are poorly understood, and no effective treatment strategies for impaired CVR exist. Preclinical murine models provide an excellent platform for interrogating mechanisms underlying CVR dysregulation and determining novel therapeutics that restore impaired CVR. However, quantification of CVR in mice is challenging. Aim: We present means of assessing CVR in awake mice using intraperitoneal injection of acetazolamide (ACZ) combined with continuous monitoring of cerebral blood flow. Approach: Measurements of cerebral blood flow were made with a minimally invasive diffuse correlation spectroscopy sensor that was secured to an optical window glued to the intact skull. Two source-detector separations (3 and 4.5 mm) per hemisphere were used to probe different depths. CVR was quantified as the relative increase in blood flow due to ACZ. CVR was assessed once daily for 5 days in 5 mice. Results: We found that CVR and the response half-time were remarkably similar across hemispheres and across 3- versus 4.5-mm separations, suggesting a homogenous, whole brain response to ACZ. Mean(std) intra- and intermouse coefficients of variations were 15(9)% and 19(10)%, respectively, for global CVR and 24(15)% and 27(11)%, respectively, for global response half-time. Conclusion: In sum, we report a repeatable method of measuring CVR in free-behaving mice which can be used to screen for impairments with disease and to track changes in CVR with therapeutic interventions.

Noninvasive optical assessment of resting-state cerebral blood flow in children with sickle cell disease.

Sickle cell disease (SCD) is a genetic blood disorder that has profound effects on the brain. Chronic anemia combined with both macro- and microvascular perfusion abnormalities that arise from stenosis or occlusion of blood vessels increased blood viscosity, adherence of red blood cells to the vascular endothelium, and impaired autoregulatory mechanisms in SCD patients all culminate in susceptibility to cerebral infarction. Indeed, the risk of stroke is 250 times higher in children with SCD than in the general population. Unfortunately, while transcranial Doppler ultrasound (TCD) has been widely clinically adopted to longitudinally monitor macrovascular perfusion in these patients, routine clinical screening of microvascular perfusion abnormalities is challenging with current modalities (e.g., positron emission tomography and magnetic resonance imaging) given their high-cost, requirement for sedation in children < 6 year, and need for trained personnel. We assess the feasibility of a low-cost, noninvasive optical technique known as diffuse correlation spectroscopy (DCS) to quantify an index of resting-state cortical cerebral blood flow (BFI) in 11 children with SCD along with 11 sex- and age-matched healthy controls. As expected, BFI was significantly higher in SCD subjects compared to healthy controls ( p < 0.001 ). Within SCD subjects, BFI was inversely proportional to resting-state arterial hemoglobin levels ( p = 0.012 ), consistent with expected anemia-induced compensatory vasodilation that aims to maintain adequate oxygen delivery to the tissue. Further, in a subset of patients measured with TCD ( n = 7 ), DCS-measured blood flow was correlated with TCD-measured blood flow velocity in middle cerebral artery ( R s = 0.68 ), although the trend was not statistically significant ( p = 0.11 ). These results are consistent with those of several previous studies using traditional neuroimaging techniques, suggesting that DCS may be a promising low-cost tool for assessment of tissue-level CBF in pediatric SCD.

An Integrative Platform for Three-dimensional Quantitative Analysis of Spatially Heterogeneous Metastasis Landscapes.

Metastatic microenvironments are spatially and compositionally heterogeneous. This seemingly stochastic heterogeneity provides researchers great challenges in elucidating factors that determine metastatic outgrowth. Herein, we develop and implement an integrative platform that will enable researchers to obtain novel insights from intricate metastatic landscapes. Our two-segment platform begins with whole tissue clearing, staining, and imaging to globally delineate metastatic landscape heterogeneity with spatial and molecular resolution. The second segment of our platform applies our custom-developed SMART 3D (Spatial filtering-based background removal and Multi-chAnnel forest classifiers-based 3D ReconsTruction), a multi-faceted image analysis pipeline, permitting quantitative interrogation of functional implications of heterogeneous metastatic landscape constituents, from subcellular features to multicellular structures, within our large three-dimensional (3D) image datasets. Coupling whole tissue imaging of brain metastasis animal models with SMART 3D, we demonstrate the capability of our integrative pipeline to reveal and quantify volumetric and spatial aspects of brain metastasis landscapes, including diverse tumor morphology, heterogeneous proliferative indices, metastasis-associated astrogliosis, and vasculature spatial distribution. Collectively, our study demonstrates the utility of our novel integrative platform to reveal and quantify the global spatial and volumetric characteristics of the 3D metastatic landscape with unparalleled accuracy, opening new opportunities for unbiased investigation of novel biological phenomena in situ.