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The National Aeronautics and Space Administration (NASA)’s Operation IceBridge (OIB) was a 13-year (2009–2021) airborne mission to survey land and sea ice across the Arctic, Antarctic, and Alaska. Here, we review OIB’s goals, instruments, campaigns, key scientific results, and implications for future investigations of the cryosphere. OIB’s primary goal was to use airborne laser altimetry to bridge the gap in fine-resolution elevation measurements of ice from space between the conclusion of NASA’s Ice, Cloud, and land Elevation Satellite (ICESat; 2003–2009) and its follow-on, ICESat-2 (launched 2018). Additional scientific requirements were intended to contextualize observed elevation changes using a multisensor suite of radar sounders, gravimeters, magnetometers, and cameras. Using 15 different aircraft, OIB conducted 968 science flights, of which 42% were repeat surveys of land ice, 42% were surveys of previously unmapped terrain across the Greenland and Antarctic ice sheets, Arctic ice caps, and Alaskan glaciers, and 16% were surveys of sea ice. The combination of an expansive instrument suite and breadth of surveys enabled numerous fundamental advances in our understanding of the Earth’s cryosphere. For land ice, OIB dramatically improved knowledge of interannual outlet-glacier variability, ice-sheet, and outlet-glacier thicknesses, snowfall rates on ice sheets, fjord and sub-ice-shelf bathymetry, and ice-sheet hydrology. Unanticipated discoveries included a reliable method for constraining the thickness within difficult-to-sound incised troughs beneath ice sheets, the extent of the firn aquifer within the Greenland Ice Sheet, the vulnerability of many Greenland and Antarctic outlet glaciers to ocean-driven melting at their grounding zones, and the dominance of surface-melt-driven mass loss of Alaskan glaciers. For sea ice, OIB significantly advanced our understanding of spatiotemporal variability in sea ice freeboard and its snow cover, especially through combined analysis of fine-resolution altimetry, visible imagery, and snow radar measurements of the overlying snow thickness. Such analyses led to the unanticipated discovery of an interdecadal decrease in snow thickness on Arctic sea ice and numerous opportunities to validate sea ice freeboards from satellite radar altimetry. While many of its data sets have yet to be fully explored, OIB’s scientific legacy has already demonstrated the value of sustained investment in reliable airborne platforms, airborne instrument development, interagency and international collaboration, and open and rapid data access to advance our understanding of Earth’s remote polar regions and their role in the Earth system.

Advances in medical and surgical care of the high-risk neonate have led to increased survival. A significant number of these neonates suffer from neurodevelopmental delays and failure in school. The focus of clinical research has shifted to understanding events contributing to neurological morbidity in these patients. Assessing changes in cerebral oxygenation and regulation of cerebral blood flow (CBF) is important in evaluating the status of the central nervous system. Traditional CBF imaging methods fail for both ethical and logistical reasons. Optical near infrared spectroscopy (NIRS) is increasingly being used for bedside monitoring of cerebral oxygenation and blood volume in both very low birth weight infants and neonates with congenital heart disease. Although trends in CBF may be inferred from changes in cerebral oxygenation and/or blood volume, NIRS does not allow a direct measure of CBF in these populations. Two relatively new modalities, arterial spin-labeled perfusion magnetic resonance imaging and optical diffuse correlation spectroscopy, provide direct, noninvasive measures of cerebral perfusion suitable for the high-risk neonates. Herein we discuss the instrumentation, applications, and limitations of these noninvasive imaging techniques for measuring and/or monitoring CBF. © Elsevier Inc. All rights reserved. [ABSTRACT FROM AUTHOR]

Abstract Background Very little is known about the physical health needs of lesbian and bisexual women in the UK; most research has looked at mental or sexual health only. This article reports the results of four surveys carried out in the West Midlands between 1995 and 2005. Methods The first two surveys were conducted in 1995–6 by a volunteer group, with participants from a lesbian health conference (n = 69) and in a convenience sample from a wide range of relevant groups and venues (n = 354). The second two surveys were commissioned by the West Midlands South Strategic Health Authority in partnership with the Gay Men's Health Network and were conducted in 2002 (n = 449) and 2005 (n = 166) and again used convenience sampling methods including the internet. Results The mean age of respondents varied between 29–33 years and 5–7% were from a non-white ethnic background. The smoking rates varied from 42% o 55%, being twice the West Midlands regional average of 21% for women aged 16 or more. Similarly, problems with alcohol were reported in 25–37% of respondents, higher than the West Midlands regional average of 7% for women aged 16+. The prevalence of any mental health problem varied between 31–35% and any suicide attempt between 20–31%. Only 29–45% had revealed their sexual orientation to their GP and of these, approximately 50% had experienced a positive reaction. Conclusion The results suggest health needs that current UK health services may not be meeting. There is a need to identify and target specific health measures for lesbians and bisexual women in order to ensure improved physical and mental health in the longer term.

We present a stand-alone blood flow index (BFI) pulse segmentation method for diffuse correlation spectroscopy that uses a wavelet-based representation of the BFI signal at the cardiac frequency in place of an exogenous physiological reference. We use this wavelet-based segmentation method to quantify BFI waveform morphology in a cohort of 30 healthy adults. We demonstrate that the waveform morphology features obtained with the wavelet approach strongly agree with those obtained using an exogenous blood pressure reference signal. These results suggest the promise of stand-alone wavelet-based BFI segmentation for quantifying BFI waveform morphological features., Competing Interests: The authors declare that there is no conflict of interests in this article., (© 2024 Optica Publishing Group.)

Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH that contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain is an off-label intervention that has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize the population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 13 females) treated with IT nicardipine every 6 h (q6h, n = 8) or every 8 h (q8h, n = 8) for an average of 72 ± 21 doses. High-performance liquid chromatography was used to quantify CSF concentration from each sample. Our popPK analysis showed that the CSF pharmacokinetics of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time. Model parameter estimates were reliable (relative standard error <50%). Intracranial pressure influenced both the total clearance and the central volume of nicardipine (i.e., negative correlation, P <-.001). Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine., (© 2024 The Author(s). The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Repetitive mild traumatic brain injuries (rmTBI) sustained within a window of vulnerability can result in long term cognitive deficits, depression, and eventual neurodegeneration associated with tau pathology, amyloid beta (Aβ) plaques, gliosis, and neuronal and functional loss. However, a comprehensive study relating acute changes in immune signaling and glial reactivity to neuronal changes and pathological markers after single and repetitive mTBIs is currently lacking. In the current study, we addressed the question of how repeated injuries affect the brain neuroimmune response in the acute phase of injury (< 24 h) by exposing the 3xTg-AD mouse model of tau and Aβ pathology to successive (1x-5x) once-daily weight drop closed-head injuries and quantifying immune markers, pathological markers, and transcriptional profiles at 30 min, 4 h, and 24 h after each injury. We used young adult 2-4 month old 3xTg-AD mice to model the effects of rmTBI in the absence of significant tau and Aβ pathology. We identified pronounced sexual dimorphism in this model, with females eliciting more diverse changes after injury compared to males. Specifically, females showed: (1) a single injury caused a decrease in neuron-enriched genes inversely correlated with inflammatory protein expression and an increase in AD-related genes within 24 h, (2) each injury significantly increased a group of cortical cytokines (IL-1α, IL-1β, IL-2, IL-9, IL-13, IL-17, KC) and MAPK phospho-proteins (phospho-Atf2, phospho-Mek1), several of which co-labeled with neurons and correlated with phospho-tau, and (3) repetitive injury caused increased expression of genes associated with astrocyte reactivity and macrophage-associated immune function. Collectively our data suggest that neurons respond to a single injury within 24 h, while other cell types, including astrocytes, transition to inflammatory phenotypes within days of repetitive injury., (© 2024. The Author(s).)

Abstract: Voxelotor is an inhibitor of sickle hemoglobin polymerization that is used to treat sickle cell disease. Although voxelotor has been shown to improve anemia, the clinical benefit on the brain remains to be determined. This study quantified the cerebral hemodynamic effects of voxelotor in children with sickle cell anemia (SCA) using noninvasive diffuse optical spectroscopies. Specifically, frequency-domain near-infrared spectroscopy combined with diffuse correlation spectroscopy were used to noninvasively assess regional oxygen extraction fraction (OEF), cerebral blood volume, and an index of cerebral blood flow (CBFi). Estimates of CBFi were first validated against arterial spin-labeled magnetic resonance imaging (ASL-MRI) in 8 children with SCA aged 8 to 18 years. CBFi was significantly positively correlated with ASL-MRI-measured blood flow (R2 = 0.651; P = .015). Next, a single-center, open-label pilot study was completed in 8 children with SCA aged 4 to 17 years on voxelotor, monitored before treatment initiation and at 4, 8, and 12 weeks (NCT05018728). By 4 weeks, both OEF and CBFi significantly decreased, and these decreases persisted to 12 weeks (both P < .05). Decreases in CBFi were significantly correlated with increases in blood hemoglobin (Hb) concentration (P = .025), whereas the correlation between decreases in OEF and increases in Hb trended toward significance (P = .12). Given that previous work has shown that oxygen extraction and blood flow are elevated in pediatric SCA compared with controls, these results suggest that voxelotor may reduce cerebral hemodynamic impairments. This trial was registered at www.ClinicalTrials.gov as #NCT05018728., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Significance: Diffuse correlation spectroscopy (DCS) permits non-invasive assessment of skeletal muscle blood flow but may misestimate changes in muscle perfusion., Aim: We aimed to highlight recent evidence that DCS blood flow index (BFI) misestimates changes in muscle blood flow during physiological perturbation and to introduce a novel approach that adjusts BFI for estimated changes in vasodilation., Approach: We measured changes in muscle BFI during quadriceps and forearm exercises using DCS, the latter of which were adjusted for estimated changes in microvascular flow area and then compared to Doppler ultrasound in the brachial artery. Then, we compared adjusted BFI- and arterial spin labeling (ASL) MRI measures of gastrocnemius blood flow during reactive hyperemia and plantar flexion exercise., Results: We observed little-to-no change in quadriceps BFI during maximal-effort exercise. Similarly, forearm BFI was modestly increased during handgrip exercise, but the magnitude was significantly lower than measured by Doppler ultrasound in the brachial artery. However, this difference was ameliorated after adjusting BFI for estimated changes in microvascular flow area. Similar observations were also observed in the gastrocnemius when directly comparing the adjusted BFI values to ASL-MRI., Conclusions: Adjusting BFI for estimated changes in microvascular flow area may improve DCS estimates of muscle blood flow, but further study is needed to validate these methods moving forward., (© 2024 The Authors.)

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 ( R s = 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., (© 2023 The Authors.)

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., Competing Interests: The authors of this manuscript report no relevant financial interests or other potential conflicts of interest., (© 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

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., Competing Interests: The authors declare that there are no conflicts of interest in this article., (© 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

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 (EtCO 2 ) and cerebral blood flow (CBF, assessed with diffuse correlation spectroscopy) were monitored continuously. CVR (%/mmHg) was quantified via linear regression of CBF versus EtCO 2 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., (© 2023 The Authors.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sathialingam, Cowdrick, Liew, Fang, Lee, McCracken, Akbik, Samuels, Kandiah, Sadan and Buckley.)

Significance: Diffuse correlation spectroscopy (DCS) is an emerging optical modality for non-invasive assessment of an index of regional cerebral blood flow. By the nature of this noninvasive measurement, light must pass through extracerebral layers (i.e., skull, scalp, and cerebral spinal fluid) before detection at the tissue surface. To minimize the contribution of these extracerebral layers to the measured signal, an analytical model has been developed that treats the head as a series of three parallel and infinitely extending slabs (mimicking scalp, skull, and brain). The three-layer model has been shown to provide a significant improvement in cerebral blood flow estimation over the typically used model that treats the head as a bulk homogenous medium. However, the three-layer model is still a gross oversimplification of the head geometry that ignores head curvature, the presence of cerebrospinal fluid (CSF), and heterogeneity in layer thickness., Aim: Determine the influence of oversimplifying the head geometry on cerebral blood flow estimated with the three-layer model., Approach: Data were simulated with Monte Carlo in a four-layer slab medium and a three-layer sphere medium to isolate the influence of CSF and curvature, respectively. Additionally, simulations were performed on magnetic resonance imaging (MRI) head templates spanning a wide-range of ages. Simulated data were fit to both the homogenous and three-layer model for CBF. Finally, to mitigate the errors in potential CBF estimation due to the difficulty in defining layer thickness, we investigated an approach to identify an equivalent, "optimized" thickness via a pressure modulation., Results: Both head curvature and failing to account for CSF lead to significant errors in the estimation of CBF. However, the effect of curvature and CSF on relative changes in CBF is minimal. Further, we found that CBF was underestimated in all MRI-templates, although the magnitude of these underestimations was highly influenced by small variations in the source and detector optode positioning. The optimized thickness obtained from pressure modulation did not improve estimation accuracy of CBF, although it did significantly improve the estimation accuracy of relative changes in CBF., Conclusions: In sum, these findings suggest that the three-layer model holds promise for improving estimation of relative changes in cerebral blood flow; however, estimations of absolute cerebral blood flow with the approach should be viewed with caution given that it is difficult to account for appreciable sources of error, such as curvature and CSF., (© 2023 The Authors.)

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., (© 2022 The Authors.)

Significance: Diffuse correlation spectroscopy (DCS) is an emerging noninvasive optical technology for bedside monitoring of cerebral blood flow. However, extracerebral hemodynamics can significantly influence DCS estimations of cerebral perfusion. Advanced analytical models can be used to remove the contribution of extracerebral hemodynamics; however, these models are highly sensitive to measurement noise. There is a need for an empirical determination of the optimal source-detector separation(s) (SDS) that improves the accuracy and reduces sensitivity to noise in the estimation of cerebral blood flow with these models. Aim: To determine the influence of SDS on solution uniqueness, measurement accuracy, and sensitivity to inaccuracies in model parameters when using the three-layer model to estimate cerebral blood flow with DCS. Approach: We performed a series of in silico simulations on samples spanning a wide range of physiologically-relevant layer optical properties, thicknesses, and flow. Data were simulated at SDS ranging from 0.5 to 3.0 cm using the three-layer solution to the correlation diffusion equation (with and without noise added) and using three-layer slab Monte Carlo simulations. We quantified the influence of SDS on uniqueness, accuracy, and sensitivity to inaccuracies in model parameters using the three-layer inverse model. Results: Two SDS are required to ensure a unique solution of cerebral blood flow index (CBFi). Combinations of 0.5/1.0/1.5 and 2.5 cm provide the optimal choice for balancing the depth penetration with signal-to-noise ratio to minimize the error in CBFi across a wide range of samples with varying optical properties, thicknesses, and dynamics. Conclusions: These results suggest that the choice of SDS is critical for minimizing the estimated error of cerebral blood flow when using the three-layer model to analyze DCS data., (© 2022 The Authors.)

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 (CBF i ), and an index of cerebral oxygen metabolism (CMRO 2i ) 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). CMRO 2i did not statistically change from pre-transfusion levels ( p > 0.05). Multivariable analysis revealed varying degrees of associations between outcomes (i.e., OEF, CBF i , CBV, and CMRO 2i ), Hb, and demographics. OEF, CBF i , and CBV were all negatively associated with Hb, while CMRO 2i 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lee, Brothers, Turrentine, Quadri, Sathialingam, Cowdrick, Gillespie, Bai, Goldman-Yassen, Joiner, Brown and Buckley.)

Mild traumatic brain injuries (mTBIs) are a significant public health problem. Repeated exposure to mTBI can lead to cumulative, long-lasting functional deficits. Numerous studies by our group and others have shown that mTBI stimulates cytokine expression and activates microglia, decreases cerebral blood flow and metabolism, and impairs cerebrovascular reactivity. Moreover, several works have reported an association between derangements in these neuroinflammatory and hemodynamic markers and cognitive impairments. Herein we detail methods to characterize the neuroinflammatory and hemodynamic tissue response to mTBI in mice. Specifically, we describe how to perform a weight-drop model of mTBI, how to longitudinally measure cerebral blood flow using a non-invasive optical technique called diffuse correlation spectroscopy, and how to perform a Luminex multiplexed immunoassay on brain tissue samples to quantify cytokines and immunomodulatory phospho-proteins (e.g., within the MAPK and NFκB pathways) that respond to and regulate activity of microglia and other neural immune cells. Finally, we detail how to integrate these data using a multivariate systems analysis approach to understand the relationships between all of these variables. Understanding the relationships between these physiologic and molecular variables will ultimately enable us to identify mechanisms responsible for mTBI.

Neurophotonics was launched in 2014 coinciding with the launch of the BRAIN Initiative focused on development of technologies for advancement of neuroscience. For the last seven years, Neurophotonics ' agenda has been well aligned with this focus on neurotechnologies featuring new optical methods and tools applicable to brain studies. While the BRAIN Initiative 2.0 is pivoting towards applications of these novel tools in the quest to understand the brain, this status report reviews an extensive and diverse toolkit of novel methods to explore brain function that have emerged from the BRAIN Initiative and related large-scale efforts for measurement and manipulation of brain structure and function. Here, we focus on neurophotonic tools mostly applicable to animal studies. A companion report, scheduled to appear later this year, will cover diffuse optical imaging methods applicable to noninvasive human studies. For each domain, we outline the current state-of-the-art of the respective technologies, identify the areas where innovation is needed, and provide an outlook for the future directions., (© 2022 The Authors.)

Diffuse correlation spectroscopy (DCS) is a non-invasive optical technology for the assessment of an index of cerebral blood flow (CBFi). Analytical methods that model the head as a three-layered medium (i.e., scalp, skull, brain) are becoming more commonly used to minimize the contribution of extracerebral layers to the measured DCS signal in adult cerebral blood flow studies. However, these models rely on a priori knowledge of layer optical properties and thicknesses. Errors in these values can lead to errors in the estimation of CBFi, although the magnitude of this influence has not been rigorously characterized. Herein, we investigate the accuracy of measuring cerebral blood flow with a three-layer model when errors in layer optical properties or thicknesses are present. Through a series of in silico experiments, we demonstrate that CBFi is highly sensitive to errors in brain optical properties and skull and scalp thicknesses. Relative changes in CBFi are less sensitive to optical properties but are influenced by errors in layer thickness. Thus, when using the three-layer model, accurate estimation of scalp and skull thickness are required for reliable results., Competing Interests: The authors declare no conflicts of interest., (© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

We lack reliable methods to continuously assess localized, resting-state muscle activity that are comparable across individuals. Near-infrared spectroscopy (NIRS) provides a low-cost, non-invasive means to assess localized, resting-state muscle oxygen metabolism during venous or arterial occlusions (VO 2VO and VO 2AO , respectively). However, this technique is not suitable for continuous monitoring, and its utility is limited to those who can tolerate occlusions. Combining NIRS with diffuse correlated spectroscopy (DCS) enables continuous measurement of an index of muscle oxygen metabolism (VO 2i ). Despite the lack of previous validation, VO 2i is employed as a measure of oxygen metabolism in the muscle. Here we characterized measurement repeatability and compared VO 2i with VO 2VO and VO 2AO in the medial gastrocnemius (MG) in 9 healthy adults. Intra-participant repeatability of VO 2i , VO 2VO , and VO 2AO were excellent. VO 2i was not significantly correlated with VO 2AO ( p = 0.15) nor VO 2VO ( p = 0.55). This lack of correlation suggests that the variability in the calibration coefficient between VO 2i and VO 2AO /VO 2VO in the MG is substantial across participants. Thus, it is preferable to calibrate VO 2i prior to every monitoring session. Important future work is needed to compare VO 2i against gold standard modalities such as positron emission tomography or magnetic resonance imaging.

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., (© 2021 The Authors.)

Background: Extra-corporeal membrane oxygenation (ECMO) is a life-saving intervention for severe respiratory and cardiac diseases. However, 50% of survivors have abnormal neurologic exams. Current ECMO management is guided by systemic metrics, which may poorly predict cerebral perfusion. Continuous optical monitoring of cerebral hemodynamics during ECMO holds potential to detect risk factors of brain injury such as impaired cerebrovascular autoregulation (CA)., Methods: We conducted daily measurements of microvascular cerebral blood flow (CBF), oxygen saturation, and total hemoglobin concentration using diffuse correlation spectroscopy (DCS) and frequency-domain diffuse optical spectroscopy in nine neonates. We characterize CA utilizing the correlation coefficient (DCSx) between CBF and mean arterial blood pressure (MAP) during ECMO pump flow changes., Results: Average MAP and pump flow levels were weakly correlated with CBF and were not correlated with cerebral oxygen saturation. CA integrity varied between individuals and with time. Systemic measurements of MAP, pulse pressure, and left cardiac dysfunction were not predictive of impaired CA., Conclusions: Our pilot results suggest that systemic measures alone cannot distinguish impaired CA from intact CA during ECMO. Furthermore, optical neuromonitoring could help determine patient-specific ECMO pump flows for optimal CA integrity, thereby reducing risk of secondary brain injury., Impact: Cerebral blood flow and oxygenation are not well predicted by systemic proxies such as ECMO pump flow or blood pressure. Continuous, quantitative, bedside monitoring of cerebral blood flow and oxygenation with optical tools enables new insight into the adequacy of cerebral perfusion during ECMO. A demonstration of hybrid diffuse optical and correlation spectroscopies to continuously measure cerebral blood oxygen saturation and flow in patients on ECMO, enabling assessment of cerebral autoregulation. An observation of poor correlation of cerebral blood flow and oxygenation with systemic mean arterial pressure and ECMO pump flow, suggesting that clinical decision making guided by target values for these surrogates may not be neuroprotective. ~50% of ECMO survivors have long-term neurological deficiencies; continuous monitoring of brain health throughout therapy may reduce these tragically common sequelae through brain-focused adjustment of ECMO parameters.

Data were collected using multimodal monitoring technologies pairing sound recorders with time-lapse camera systems. In the spring of 2015, 2016, and 2017, sound recordings and imagery were collected at a wet meadow and forested slough in the Central Platte River Valley of Nebraska. Boreal chorus frog ( Pseudacris maculata ) calling activity was obtained from analysing sound recordings. Habitat metrics including vegetation phenology and wet meadow hydropattern were derived from image analysis. This dataset can be used to assess phenology, anuran vocalization activity, and environmental change, as well as to further understanding of wetland ecology. Data are co-submitted with manuscript Brinley Buckley, E. M., Gottesman, B. L., Caven, A. J., Harner, M. J., and Pijanowski, B. C., Assessing ecological and environmental influences on Boreal Chorus Frog ( Pseudacris maculata ) spring calling phenology using multimodal passive monitoring technologies. Ecological Indicators (In Press)., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article., (© 2020 The Authors.)

Diffuse correlation spectroscopy (DCS) is an optical modality used to measure an index of blood flow in biological tissue. This blood flow index depends on both the red blood cell flow rate and density (i.e., hematocrit), although the functional form of hematocrit dependence is not well delineated. Herein, we develop and validate a novel tissue-simulating phantom containing hundreds of microchannels to investigate the influence of hematocrit on blood flow index. For a fixed flow rate, we demonstrate a significant inverse relationship between hematocrit and blood flow index that must be accounted for to accurately estimate blood flow under anemic conditions., Competing Interests: The authors declare no conflicts of interest., (© 2020 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Repetitive mild traumatic brain injury during adolescence can induce neurological dysfunction through undefined mechanisms. Interleukin-1 (IL-1) contributes to experimental adult diffuse and contusion TBI models, and IL-1 antagonists have entered clinical trials for severe TBI in adults; however, no such data exist for adolescent TBI. We developed an adolescent mouse repetitive closed head injury (rCHI) model to test the role of IL-1 family members in post-injury neurological outcome. Compared to one CHI, three daily injuries (3HD) produced acute and chronic learning deficits and emergence of hyperactivity, without detectable gliosis, neurodegeneration, brain atrophy, and white matter loss at one year. Mature IL-1β and IL-18 were induced in brain endothelium in 3HD but not 1HD, three hit weekly, or sham animals. IL-1β processing was induced cell-autonomously in three-dimensional human endothelial cell cultures subjected to in vitro concussive trauma. Mice deficient in IL-1 receptor-1 or caspase-1 had improved post-injury Morris water maze performance. Repetitive mild CHI in adolescent mice may induce behavioral deficits in the absence of significant histopathology. The endothelium is a potential source of IL-1β and IL-18 in rCHI, and IL-1 family members may be therapeutic targets to reduce or prevent neurological dysfunction after repetitive mild TBI in adolescents.

Every heartbeat originates from a tiny tissue in the heart called the sinoatrial node (SAN). The SAN harbors only ≈10 000 cardiac pacemaker cells, initiating an electrical impulse that captures the entire heart, consisting of billions of cardiomyocytes for each cardiac contraction. How these rare cardiac pacemaker cells (the electrical source) can overcome the electrically hyperpolarizing and quiescent myocardium (the electrical sink) is incompletely understood. Due to the scarcity of native pacemaker cells, this concept of source-sink mismatch cannot be tested directly with live cardiac tissue constructs. By exploiting TBX18 induced pacemaker cells by somatic gene transfer, 3D cardiac pacemaker spheroids can be tissue-engineered. The TBX18 induced pacemakers (sphTBX18) pace autonomously and drive the contraction of neighboring myocardium in vitro. TBX18 spheroids demonstrate the need for reduced electrical coupling and physical separation from the neighboring ventricular myocytes, successfully recapitulating a key design principle of the native SAN. β-Adrenergic stimulation as well as electrical uncoupling significantly increase sphTBX18s' ability to pace-and-drive the neighboring myocardium. This model represents the first platform to test design principles of the SAN for mechanistic understanding and to better engineer biological pacemakers for therapeutic translation., Competing Interests: The authors declare no conflict of interest., (© 2019 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.)

Millimeter-depth sensitivity with frequency domain near-infrared spectroscopy has been challenging due to the breakdown of the diffusion equation for source-detection separations < 1cm. To overcome this challenge, we employ a Monte-Carlo lookup table-based inverse algorithm to fit small separation (3-6 mm) frequency-domain near-infrared spectroscopy (FDNIRS) data for absorption and reduced scattering coefficients. We verify this small separation FDNIRS method through a series of in vitro and in vivo studies . In vitro , we observed a root mean squared percent error (RMSE) in estimation of the reduced scattering coefficient and absorption coefficient of 2.8% and 7.6%, respectively, in liquid phantoms consisting of Intralipid and Indian ink, and a RMSE in estimation of oxygen saturation and total hemoglobin concentrations of 7.8 and 11.2%, respectively, in blood-mixed liquid phantoms. Next, we demonstrate one particularly valuable in vivo application of this technique wherein we non-invasively measure the optical properties of the mouse brain (n = 4). We find that the measured resting state cerebral oxygen saturation and hemoglobin concentration are consistent with literature reported values, and we observe expected trends during a hyper-/hypoxia challenge that qualitatively mimic changes in partial pressure of oxygen (pO 2 ) measured simultaneously with an invasive pO 2 sensor. Further, through simulations of the mouse head geometry, we demonstrate that the skull and scalp exert minimal influence on the estimate oxygen saturation, while leading to small but systematic underestimation of total hemoglobin concentration. In total, these results demonstrate the robustness of small separation FDNIRS to assess tissue optical properties at millimeter depth resolution., Competing Interests: The authors declare no conflicts of interest., (© 2019 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

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.

Previous work has shown that non-invasive optical measurement of low cerebral blood flow (CBF) is an acute biomarker of poor long-term cognitive outcome after repetitive mild traumatic brain injury (rmTBI). Herein, we explore the relationship between acute cerebral blood flow and underlying neuroinflammation. Specifically, because neuroinflammation is a driver of secondary injury after TBI, we hypothesized that both glial activation and inflammatory signaling are associated with acute CBF and, by extension, with long-term cognitive outcome after rmTBI. To test this hypothesis, cortical CBF was non-invasively measured in anesthetized mice 4 h after 3 repetitive closed head injuries spaced once-daily, at which time brains were collected. Right hemispheres were fixed for immunohistochemical staining for glial activation markers Iba1 and GFAP while left hemispheres were used to quantify Iba1 and GFAP expression via Western blot as well as 32 cytokines and 21 phospho-proteins in the MAPK, PI3K/Akt, and NF-κB pathways using a Luminex multiplexed immunoassay. N = 8/7 injured/sham C57/black-6 adult male mice were studied. Within the injured group, CBF inversely correlated with Iba1 expression (R = -0.86, p < .01). Further, partial least squares regression analysis revealed significant correlations between CBF and expression of multiple pro-inflammatory cytokines, including RANTES and IL-17. Finally, within the injured group, phosphorylation of specific signals in the MAPK and NF-κB intracellular signaling pathways (e.g., p38 MAPK and NF-κB) were significantly positively correlated with Iba1. In total, our data indicate that acute cerebral blood flow after rmTBI is a biomarker of underlying neuroinflammatory pathology., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Important differences in the biology of focal and diffuse traumatic brain injury (TBI) subtypes may result in unique pathophysiological responses to shared molecular mechanisms. Interleukin-1 (IL-1) signaling has been tested as a potential therapeutic target in preclinical models of cerebral contusion and diffuse TBI, and in a phase II clinical trial, but no published studies have examined IL-1 signaling in an impact/acceleration closed head injury (CHI) model. We hypothesized that genetic deletion of IL-1 receptor-1 (IL-1R1 KO) would be beneficial in focal (contusion) and CHI in mice. Wild type and IL-1R1 KO mice were subjected to controlled cortical impact (CCI), or to CHI. CCI produced brain leukocyte infiltration, HMGB1 translocation and release, edema, cell death, and cognitive deficits. CHI induced peak rotational acceleration of 9.7 × 10 5  ± 8.1 × 10 4 rad/s 2 , delayed time to righting reflex, and robust Morris water maze deficits without deficits in tests of anxiety, locomotion, sensorimotor function, or depression. CHI produced no discernable acute plasmalemma damage or cell death, blood-brain barrier permeability to IgG, or brain edema and only a modest increase in brain leukocyte infiltration at 72 h. In both models, mature (17 kDa) interleukin-1 beta (IL-1β) was induced by 24 h in CD31+ endothelial cells isolated from injured brain but was not induced in CD11b + cells in either model. High mobility group box protein-1 was released from injured brain cells in CCI but not CHI. Surprisingly, cognitive outcome in mice with global deletion of IL-1R1 was improved in CHI, but worse after CCI without affecting lesion size, edema, or infiltration of CD11b + /CD45 + leukocytes in CCI. IL-1R1 may induce unique biological responses, beneficial or detrimental to cognitive outcome, after TBI depending on the pathoanatomical subtype. Brain endothelium is a hitherto unrecognized source of mature IL-1β in both models.

Diffuse correlation spectroscopy (DCS) has shown promise as a means to non-invasively measure cerebral blood flow in small animal models. Here, we characterize the validity of DCS at small source-detector reflectance separations needed for small animal measurements. Through Monte Carlo simulations and liquid phantom experiments, we show that DCS error increases as separation decreases, although error remains below 12% for separations > 0.2 cm. In mice, DCS measures of cerebral blood flow have excellent intra-user repeatability and strongly correlate with MRI measures of blood flow (R = 0.74, p <0.01). These results are generalizable to other DCS applications wherein short-separation reflectance geometries are desired., Competing Interests: Authors discloses no conflict of interest.

The datasets in this article are associated with the research article ' Assessing biological and environmental effects of a total solar eclipse with passive multimodal technologies' (Brinley Buckley et al., 2018). We documented biotic and abiotic changes during a total solar eclipse on 21 August 2017, in south-central Nebraska, USA, with a multimodal suite of tools, including time-lapse camera systems, data loggers, and sound recording devices. Time-lapse images were used to approximate changes in light, data loggers were used to record temperature and humidity, and sound recordings were used to calculate acoustic indices characterizing variation in the soundscape, as well as to manually identify and estimate avian vocalization activity.

Though optical imaging of human brain function is gaining momentum, widespread adoption is restricted in part by a tradeoff among cap wearability, field of view, and resolution. To increase coverage while maintaining functional magnetic resonance imaging (fMRI)-comparable image quality, optical systems require more fibers. However, these modifications drastically reduce the wearability of the imaging cap. The primary obstacle to optimizing wearability is cap weight, which is largely determined by fiber diameter. Smaller fibers collect less light and lead to challenges in obtaining adequate signal-to-noise ratio. Here, we report on a design that leverages the exquisite sensitivity of scientific CMOS cameras to use fibers with ∼ 30 × smaller cross-sectional area than current high-density diffuse optical tomography (HD-DOT) systems. This superpixel sCMOS DOT (SP-DOT) system uses 200 - μ m -diameter fibers that facilitate a lightweight, wearable cap. We developed a superpixel algorithm with pixel binning and electronic noise subtraction to provide high dynamic range ( > 10 5 ), high frame rate ( > 6    Hz ), and a low effective detectivity threshold ( ∼ 200    fW / Hz 1 / 2 - mm 2 ), each comparable with previous HD-DOT systems. To assess system performance, we present retinotopic mapping of the visual cortex ( n = 5 subjects). SP-DOT offers a practical solution to providing a wearable, large field-of-view, and high-resolution optical neuroimaging system.

Non-human primates (NHPs) for biomedical research are commonly infected with Shigella spp. that can cause acute dysentery or chronic episodic diarrhea. These animals are often prophylactically and clinically treated with quinolone antibiotics to eradicate these possible infections. However, chromosomally- and plasmid-mediated antibiotic resistance has become an emerging concern for species in the family Enterobacteriaceae . In this study, five individual isolates of multi-drug resistant Shigella flexneri were isolated from the feces of three macaques. Antibiotic susceptibility testing confirmed resistance or decreased susceptibility to ampicillin, amoxicillin-clavulanic acid, cephalosporins, gentamicin, tetracycline, ciprofloxacin, enrofloxacin, levofloxacin, and nalidixic acid. S. flexneri isolates were susceptible to trimethoprim-sulfamethoxazole, and this drug was used to eradicate infection in two of the macaques. Plasmid DNA from all isolates was positive for the plasmid-encoded quinolone resistance gene qnrS , but not qnrA and qnrB . Conjugation and transformation of plasmid DNA from several S. flexneri isolates into antibiotic-susceptible Escherichia coli strains conferred the recipients with resistance or decreased susceptibility to quinolones and beta-lactams. Genome sequencing of two representative S. flexneri isolates identified the qnrS gene on a plasmid-like contig. These contigs showed >99% homology to plasmid sequences previously characterized from quinolone-resistant Shigella flexneri 2a and Salmonella enterica strains. Other antibiotic resistance genes and virulence factor genes were also identified in chromosome and plasmid sequences in these genomes. The findings from this study indicate macaques harbor pathogenic S. flexneri strains with chromosomally- and plasmid-encoded antibiotic resistance genes. To our knowledge, this is the first report of plasmid-mediated quinolone resistance in S. flexneri isolated from NHPs and warrants isolation and antibiotic testing of enteric pathogens before treating macaques with quinolones prophylactically or therapeutically.

Investigating the cerebral physiology of healthy term newborns' brains is important for better understanding perinatal brain injuries, of which the most common etiologies are hypoxia and ischemia. Hence, cerebral blood flow and cerebral oxygenation are important biomarkers of brain health. In this study, we employed a hybrid diffuse optical system consisting of diffuse correlation spectroscopy (DCS) and frequency-domain near infrared spectroscopy (FDNIRS) to measure hemoglobin concentration, oxygen saturation, and indices of cerebral blood flow and metabolism. We measured 30 term infants to assess the optical and physiological characteristics of the healthy neonatal brain in the frontal, temporal, and parietal lobes. We observed higher metabolism in the right hemisphere compared to the left and a positive correlation between gestational age and the level of cerebral hemoglobin concentration, blood volume, and oxygen saturation. Moreover, we observed higher cerebral blood flow and lower oxygen saturation in females compared to males. The delayed maturation in males and the sexual dimorphism in cerebral hemodynamics may explain why males are more vulnerable to perinatal brain injuries than females.

Repetitive concussions are associated with long-term cognitive dysfunction that can be attenuated by increasing the time intervals between concussions; however, biomarkers of the safest rest interval between injuries remain undefined. We hypothesize that deranged cerebral blood flow (CBF) is a candidate biomarker for vulnerability to repetitive concussions. Using a mouse model of human concussion, we examined the effect of single and repetitive concussions on cognition and on an index of CBF (CBFi) measured with diffuse correlation spectroscopy. After a single mild concussion, CBFi was reduced by 35±4% at 4 hours (P<0.01 versus baseline) and returned to preinjury levels by 24 hours. After five concussions spaced 1 day apart, CBFi was also reduced from preinjury levels 4 hours after each concussion but had returned to preinjury levels by 72 hours after the final concussion. Interestingly, in this repetitive concussion model, lower CBFi values measured both preinjury and 4 hours after the third concussion were associated with worse performance on the Morris water maze assessed 72 hours after the final concussion. We conclude that low CBFi measured either before or early on in the evolution of injury caused by repetitive concussions could be a useful predictor of cognitive outcome.

Congenital heart disease (CHD) patients are at risk for neurodevelopmental delay. The etiology of these delays is unclear, but abnormal prenatal cerebral maturation and postoperative hemodynamic instability likely play a role. A better understanding of these factors is needed to improve neurodevelopmental outcome. In this study, we used bedside frequency-domain near infrared spectroscopy (FDNIRS) and diffuse correlation spectroscopy (DCS) to assess cerebral hemodynamics and oxygen metabolism in neonates with single-ventricle (SV) CHD undergoing surgery and compared them to controls. Our goals were 1) to compare cerebral hemodynamics between unanesthetized SV and healthy neonates, and 2) to determine if FDNIRS-DCS could detect alterations in cerebral hemodynamics beyond cerebral hemoglobin oxygen saturation (SO 2). Eleven SV neonates were recruited and compared to 13 controls. Preoperatively, SV patients showed decreased cerebral blood flow (CBFi ), cerebral oxygen metabolism (CMRO 2i ) and SO 2; and increased oxygen extraction fraction (OEF) compared to controls. Compared to preoperative values, unstable postoperative SV patients had decreased CMRO 2i and CBFi , which returned to baseline when stable. However, SO 2 showed no difference between unstable and stable states. Preoperative SV neonates are flow-limited and show signs of impaired cerebral development compared to controls. FDNIRS-DCS shows potential to improve assessment of cerebral development and postoperative hemodynamics compared to SO 2 alone.

Background: Currently two magnetic resonance imaging (MRI) methods have been used to assess periventricular leukomalacia (PVL) severity in infants with congenital heart disease: manual volumetric lesion segmentation and an observational categorical scale. Volumetric classification is labor intensive and the categorical scale is quick but unreliable. We propose the quartered point system (QPS) as a novel, intuitive, time-efficient metric with high interrater agreement., Methods: QPS is an observational scale that asks the rater to score MRIs on the basis of lesion size, number, and distribution. Pre- and postoperative brain MRIs were obtained on term congenital heart disease infants. Three independent observers scored PVL severity using all three methods: volumetric segmentation, categorical scale, and QPS., Results: One-hundred and thirty-five MRIs were obtained from 72 infants; PVL was seen in 48 MRIs. Volumetric measurements among the three raters were highly concordant (ρc = 0.94-0.96). Categorical scale severity scores were in poor agreement between observers (κ = 0.17) and fair agreement with volumetrically determined severity (κ = 0.26). QPS scores were in very good agreement between observers (κ = 0.82) and with volumetric severity (κ = 0.81)., Conclusion: QPS minimizes training and sophisticated radiologic analysis and increases interrater reliability. QPS offers greater sensitivity to stratify PVL severity and has the potential to more accurately correlate with neurodevelopmental outcomes.

Background: Neonatal hypoxic-ischemic (HI) encephalopathy occurs in 1-4 per 1,000 live term births and can cause devastating neurodevelopmental disabilities. Currently, therapeutic hypothermia (TH) is the only treatment with proven efficacy. Since TH is associated with decreased cerebral metabolism and cerebral blood flow (CBF), it is important to assess CBF at the bedside. Diffuse correlation spectroscopy (DCS) has emerged as a promising optical modality to noninvasively assess an index of CBF (CBFi) in both humans and animals. In this initial descriptive study, we employ DCS to monitor the evolution of CBFi following HI with or without TH in immature rats. We investigate potential relationships between CBF and subsequent cerebral damage., Methods: HI was induced on postnatal day 10 or 11 rat pups by right common carotid artery ligation followed by 60-70 min hypoxia (8% oxygen). After HI, the pups recovered for 4 h under hypothermia (HI-TH group, n = 23) or normothermia (HI-N group, n = 23). Bilateral measurements of hemispheric CBFi were made with DCS in unanesthetized animals at baseline, before HI, and 0, 1, 2, 3, 4, 5, and 24 h after HI. The animals were sacrificed at either 1 or 4 weeks, and brain injury was scored on an ordinal scale of 0-5 (0 = no injury)., Results: Carotid ligation caused moderate bilateral decreases in CBFi. Following HI, an initial hyperemia was observed that was more prominent in the contralateral hemisphere. After initiation of TH, CBFi dropped significantly below baseline levels and remained reduced for the duration of TH. In contrast, CBFi in the HI-N group was not significantly decreased from baseline levels. Reductions in CBFi after 4 h of TH were not associated with reduced damage at 1 or 4 weeks. However, elevated ipsilateral CBFi and ipsilateral-to-contralateral CBFi ratios at 24 h were associated with worse outcome at 1 week after HI., Conclusions: Both HI and TH alter CBFi, with significant differences in CBFi between hypothermic and normothermic groups after HI. CBFi may be a useful biomarker of subsequent cerebral damage., (© 2015 S. Karger AG, Basel.)

Objective: Hypoxic-ischemic white mater brain injury commonly occurs in neonates with hypoplastic left heart syndrome (HLHS). Approximately one half of HLHS survivors will exhibit neurobehavioral symptoms believed to be associated with this injury, although the exact timing of the injury is unknown., Methods: Neonates with HLHS were recruited for pre- and postoperative monitoring of cerebral oxygen saturation, cerebral oxygen extraction fraction, and cerebral blood flow using 2 noninvasive optical-based techniques: diffuse optical spectroscopy and diffuse correlation spectroscopy. Anatomic magnetic resonance imaging was performed before and approximately 1 week after surgery to quantify the extent and timing of the acquired white matter injury. The risk factors for developing new or worsened white matter injury were assessed using uni- and multivariate logistic regression., Results: A total of 37 neonates with HLHS were studied. On univariate analysis, neonates who developed a large volume of new, or worsened, postoperative white matter injury had a significantly longer time to surgery (P=.0003). In a multivariate model, a longer time between birth and surgery, delayed sternal closure, and greater preoperative cerebral blood flow were predictors of postoperative white matter injury. Additionally, a longer time to surgery and greater preoperative cerebral blood flow on the morning of surgery correlated with lower cerebral oxygen saturation (P=.03 and P=.05, respectively) and greater oxygen extraction fraction (P=.05 for both)., Conclusions: A longer time to surgery was associated with new postoperative white matter injury in otherwise healthy neonates with HLHS. The results suggest that earlier Norwood palliation might decrease the likelihood of acquiring postoperative white matter injury., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Klebsiella oxytoca is an opportunistic pathogen implicated in various clinical diseases in animals and humans. Studies suggest that in humans K. oxytoca exerts its pathogenicity in part through a cytotoxin. However, cytotoxin production in animal isolates of K. oxytoca and its pathogenic properties have not been characterized. Furthermore, neither the identity of the toxin nor a complete repertoire of genes involved in K. oxytoca pathogenesis have been fully elucidated. Here, we showed that several animal isolates of K. oxytoca, including the clinical isolates, produced secreted products in bacterial culture supernatant that display cytotoxicity on HEp-2 and HeLa cells, indicating the ability to produce cytotoxin. Cytotoxin production appears to be regulated by the environment, and soy based product was found to have a strong toxin induction property. The toxin was identified, by liquid chromatography-mass spectrometry and NMR spectroscopy, as low molecular weight heat labile benzodiazepine, tilivalline, previously shown to cause cytotoxicity in several cell lines, including mouse L1210 leukemic cells. Genome sequencing and analyses of a cytotoxin positive K. oxytoca strain isolated from an abscess of a mouse, identified genes previously shown to promote pathogenesis in other enteric bacterial pathogens including ecotin, several genes encoding for type IV and type VI secretion systems, and proteins that show sequence similarity to known bacterial toxins including cholera toxin. To our knowledge, these results demonstrate for the first time, that animal isolates of K. oxytoca, produces a cytotoxin, and that cytotoxin production is under strict environmental regulation. We also confirmed tilivalline as the cytotoxin present in animal K. oxytoca strains. These findings, along with the discovery of a repertoire of genes with virulence potential, provide important insights into the pathogenesis of K. oxytoca. As a novel diagnostic tool, tilivalline may serve as a biomarker for K oxytoca-induced cytotoxicity in humans and animals through detection in various samples from food to diseased samples using LC-MS/MS. Induction of K. oxytoca cytotoxin by consumption of soy may be in part involved in the pathogenesis of gastrointestinal disease.