Spatial nonstationarity of image noise in widefield optical imaging and its effects on cluster-based inference for resting-state functional connectivity.

BACKGROUND: Resting-state functional connectivity (RSFC) analysis with widefield optical imaging (WOI) is a potentially powerful tool to develop imaging biomarkers in mouse models of disease before translating them to human neuroimaging with functional magnetic resonance imaging (fMRI). The delineation of such biomarkers depends on rigorous statistical analysis. However, statistical understanding of WOI data is limited. In particular, cluster-based analysis of neuroimaging data depends on assumptions of spatial stationarity (i.e., that the distribution of cluster sizes under the null is equal at all brain locations). Whether actual data deviate from this assumption has not previously been examined in WOI. NEW METHOD: In this manuscript, we characterize the effects of spatial nonstationarity in WOI RSFC data and adapt a "two-pass" technique from fMRI to correct cluster sizes and mitigate spatial bias, both parametrically and nonparametrically. These methods are tested on multi-institutional data. RESULTS AND COMPARISON WITH EXISTING METHODS: We find that spatial nonstationarity has a substantial effect on inference in WOI RSFC data with false positives much more likely at some brain regions than others. This pattern of bias varies between imaging systems, contrasts, and mouse ages, all of which could affect experimental reproducibility if not accounted for. CONCLUSIONS: Both parametric and nonparametric corrections for nonstationarity result in significant improvements in spatial bias. The proposed methods are simple to implement and will improve the robustness of inference in optical neuroimaging data.

Patent ductus arteriosus and coarctation of the aorta in association with PRDM6 variants.

Patent ductus arteriosus (PDA) and coarctation of the aorta (CoA) are relatively common congenital heart defects. Pathogenic variants in PRDM6, which encodes a smooth-muscle-cell-specific transcription factor, have now been etiologically associated with non-syndromic PDA. We present three patients with PDA and CoA found to harbor PRDM6 variants, including a novel, likely-pathogenic variant.

Cardiac magnetic resonance predictors for successful primary biventricular repair of unbalanced complete common atrioventricular canal.

BACKGROUND: Patients with unbalanced common atrioventricular canal can be difficult to manage. Surgical planning often depends on pre-operative echocardiographic measurements. We aimed to determine the added utility of cardiac MRI in predicting successful biventricular repair in common atrioventricular canal. METHODS: We conducted a retrospective cohort study of children with common atrioventricular canal who underwent MRI prior to repair. Associations between MRI and echocardiographic measures and surgical outcome were tested using logistic regression, and models were compared using area under the receiver operator characteristic curve. RESULTS: We included 28 patients (median age at MRI: 5.2 months). The optimal MRI model included the novel end-diastolic volume index (using the ratio of left ventricular end-diastolic volume to total end-diastolic volume) and the left ventricle-right ventricle angle in diastole (area under the curve 0.83, p = 0.041). End-diastolic volume index ≤ 0.18 and left ventricle-right ventricle angle in diastole ≤ 72° yield a sensitivity of 83% and specificity of 81% for successful biventricular repair. The optimal multimodality model included the end-diastolic volume index and the echocardiographic atrioventricular valve index with an area under the curve of 0.87 (p = 0.026). CONCLUSIONS: Cardiac MRI can successfully predict successful biventricular repair in patients with unbalanced common atrioventricular canal utilising the end-diastolic volume index alone or in combination with the MRI left ventricle-right ventricle angle in diastole or the echocardiographic atrioventricular valve index. A prospective cardiac MRI study is warranted to better define the multimodality characteristic predictive of successful biventricular surgery.

Cerebral microhemorrhages in children with congenital heart disease: Prevalence, risk factors, and impact on neurodevelopmental outcomes.

Background: Infants with complex congenital heart disease (CHD) require life-saving corrective/palliative heart surgery in the first weeks of life. These infants are at risk for brain injury and poor neurodevelopmental outcomes. Cerebral microhemorrhages (CMH) are frequently seen after neonatal bypass heart surgery, but it remains unknown if CMH are a benign finding or constitute injury. Herein, we investigate the risk factors for developing CMH and their clinical significance. Methods: 192 infants with CHD undergoing corrective cardiac surgery with cardiopulmonary bypass (CPB) at a single institution were prospectively evaluated with pre-(n = 183) and/or postoperative (n = 162) brain magnetic resonance imaging (MRI). CMH severity was scored based on total number of microhemorrhages. Antenatal, perioperative, and postoperative candidate risk factors for CMH and neurodevelopmental (ND) outcomes were analyzed. Eighteen-month neurodevelopmental outcomes were assessed using the Bayley-III Scales of Infants and Toddler Development in a subset of patients (n = 82). Linear regression was used to analyze associations between risk factors or ND outcomes and presence/number of CMH. Results: The most common CHD subtypes were hypoplastic left heart syndrome (HLHS) (37%) and transposition of the great arteries (TGA) (33%). Forty-two infants (23%) had CMH present on MRI before surgery and 137 infants (85%) post-surgery. No parameters evaluated were significant risk factors for preoperative CMH. In multivariate analysis, cardiopulmonary bypass (CPB) duration (p < 0.0001), use of extracorporeal membrane oxygenation (ECMO) support (p < 0.0005), postoperative seizure(s) (p < 0.03), and lower birth weight (p < 0.03) were associated with new or worsened CMH postoperatively. Higher CMH number was associated with lower scores on motor (p < 0.03) testing at 18 months. Conclusion: CMH is a common imaging finding in infants with CHD with increased prevalence and severity after CPB and adverse impact on neurodevelopmental outcomes starting at a young age. Longer duration of CPB and need for postoperative ECMO were the most significant risk factors for developing CMH. However, presence of CMH on preoperative scans indicates non-surgical risk factors that are yet to be identified. Neuroprotective strategies to mitigate risk factors for CMH may improve neurodevelopmental outcomes in this vulnerable population.

Diffuse Optical Monitoring of Cerebral Hemodynamics and Oxygen Metabolism during and after Cardiopulmonary Bypass: Hematocrit Correction and Neurological Vulnerability.

Cardiopulmonary bypass (CPB) provides cerebral oxygenation and blood flow (CBF) during neonatal congenital heart surgery, but the impacts of CPB on brain oxygen supply and metabolic demands are generally unknown. To elucidate this physiology, we used diffuse correlation spectroscopy and frequency-domain diffuse optical spectroscopy to continuously measure CBF, oxygen extraction fraction (OEF), and oxygen metabolism (CMRO2) in 27 neonatal swine before, during, and up to 24 h after CPB. Concurrently, we sampled cerebral microdialysis biomarkers of metabolic distress (lactate-pyruvate ratio) and injury (glycerol). We applied a novel theoretical approach to correct for hematocrit variation during optical quantification of CBF in vivo. Without correction, a mean (95% CI) +53% (42, 63) increase in hematocrit resulted in a physiologically improbable +58% (27, 90) increase in CMRO2 relative to baseline at CPB initiation; following correction, CMRO2 did not differ from baseline at this timepoint. After CPB initiation, OEF increased but CBF and CMRO2 decreased with CPB time; these temporal trends persisted for 0-8 h following CPB and coincided with a 48% (7, 90) elevation of glycerol. The temporal trends and glycerol elevation resolved by 8-24 h. The hematocrit correction improved quantification of cerebral physiologic trends that precede and coincide with neurological injury following CPB.

Non-invasive diffuse optical monitoring of cerebral physiology in an adult swine-model of impact traumatic brain injury.

In this study, we used diffuse optics to address the need for non-invasive, continuous monitoring of cerebral physiology following traumatic brain injury (TBI). We combined frequency-domain and broadband diffuse optical spectroscopy with diffuse correlation spectroscopy to monitor cerebral oxygen metabolism, cerebral blood volume, and cerebral water content in an established adult swine-model of impact TBI. Cerebral physiology was monitored before and after TBI (up to 14 days post injury). Overall, our results suggest that non-invasive optical monitoring can assess cerebral physiologic impairments post-TBI, including an initial reduction in oxygen metabolism, development of cerebral hemorrhage/hematoma, and brain swelling.

Controlling the familywise error rate in widefield optical neuroimaging of functional connectivity in mice.

Significance: Statistical inference in functional neuroimaging is complicated by the multiple testing problem and spatial autocorrelation. Common methods in functional magnetic resonance imaging to control the familywise error rate (FWER) include random field theory (RFT) and permutation testing. The ability of these methods to control the FWER in optical neuroimaging has not been evaluated. Aim: We attempt to control the FWER in optical intrinsic signal imaging resting-state functional connectivity using both RFT and permutation inference at a nominal value of 0.05. The FWER was derived using a mass empirical analysis of real data in which the null is known to be true. Approach: Data from normal mice were repeatedly divided into two groups, and differences between functional connectivity maps were calculated with pixel-wise t -tests. As the null hypothesis was always true, all positives were false positives. Results: Gaussian RFT resulted in a higher than expected FWER with either cluster-based (0.15) or pixel-based (0.62) methods. t -distribution RFT could achieve FWERs of 0.05 (cluster-based or pixel-based). Permutation inference always controlled the FWER. Conclusions: RFT can lead to highly inflated FWERs. Although t -distribution RFT can be accurate, it is sensitive to statistical assumptions. Permutation inference is robust to statistical errors and accurately controls the FWER.

Comparison of optical measurements of critical closing pressure acquired before and during induced ventricular arrhythmia in adults.

Significance: The critical closing pressure (CrCP) of cerebral circulation, as measured by diffuse correlation spectroscopy (DCS), is a promising biomarker of intracranial hypertension. However, CrCP techniques using DCS have not been assessed in gold standard experiments. Aim: CrCP is typically calculated by examining the variation of cerebral blood flow (CBF) during the cardiac cycle (with normal sinus rhythm). We compare this typical CrCP measurement with a gold standard obtained during the drops in arterial blood pressure (ABP) caused by rapid ventricular pacing (RVP) in patients undergoing invasive electrophysiologic procedures. Approach: Adults receiving electrophysiology procedures with planned ablation were enrolled for DCS CBF monitoring. CrCP was calculated from CBF and ABP data by three methods: (1) linear extrapolation of data during RVP ( CrCP RVP ; the gold standard); (2) linear extrapolation of data during regular heartbeats ( CrCP Linear ); and (3) fundamental harmonic Fourier filtering of data during regular heartbeats ( CrCP Fourier ). Results: CBF monitoring was performed prior to and during 55 episodes of RVP in five adults. CrCP RVP and CrCP Fourier demonstrated agreement ( R = 0.66 , slope = 1.05 (95%CI, 0.72 to 1.38). Agreement between CrCP RVP and CrCP Linear was worse; CrCP Linear was 8.2 ± 5.9 mmHg higher than CrCP RVP (mean ± SD; p < 0.001 ). Conclusions: Our results suggest that DCS-measured CrCP can be accurately acquired during normal sinus rhythm.

Correlation of Cerebral Microdialysis with Non-Invasive Diffuse Optical Cerebral Hemodynamic Monitoring during Deep Hypothermic Cardiopulmonary Bypass.

Neonates undergoing cardiac surgery involving aortic arch reconstruction are at an increased risk for hypoxic-ischemic brain injury. Deep hypothermia is utilized to help mitigate this risk when periods of circulatory arrest are needed for surgical repair. Here, we investigate correlations between non-invasive optical neuromonitoring of cerebral hemodynamics, which has recently shown promise for the prediction of postoperative white matter injury in this patient population, and invasive cerebral microdialysis biomarkers. We compared cerebral tissue oxygen saturation (StO2), relative total hemoglobin concentration (rTHC), and relative cerebral blood flow (rCBF) measured by optics against the microdialysis biomarkers of metabolic stress and injury (lactate-pyruvate ratio (LPR) and glycerol) in neonatal swine models of deep hypothermic cardiopulmonary bypass (DHCPB), selective antegrade cerebral perfusion (SACP), and deep hypothermic circulatory arrest (DHCA). All three optical parameters were negatively correlated with LPR and glycerol in DHCA animals. Elevation of LPR was found to precede the elevation of glycerol by 30-60 min. From these data, thresholds for the detection of hypoxic-ischemia-associated cerebral metabolic distress and neurological injury are suggested. In total, this work provides insight into the timing and mechanisms of neurological injury following hypoxic-ischemia and reports a quantitative relationship between hypoxic-ischemia severity and neurological injury that may inform DHCA management.

Low frequency power in cerebral blood flow is a biomarker of neurologic injury in the acute period after cardiac arrest.

AIM: Cardiac arrest often results in severe neurologic injury. Improving care for these patients is difficult as few noninvasive biomarkers exist that allow physicians to monitor neurologic health. The amount of low-frequency power (LFP, 0.01-0.1 Hz) in cerebral haemodynamics has been used in functional magnetic resonance imaging as a marker of neuronal activity. Our hypothesis was that increased LFP in cerebral blood flow (CBF) would be correlated with improvements in invasive measures of neurologic health. METHODS: We adapted the use of LFP for to monitoring of CBF with diffuse correlation spectroscopy. We asked whether LFP (or other optical biomarkers) correlated with invasive microdialysis biomarkers (lactate-pyruvate ratio - LPR - and glycerol concentration) of neuronal injury in the 4 h after return of spontaneous circulation in a swine model of paediatric cardiac arrest (Sus scrofa domestica, 8-11 kg, 51% female). Associations were tested using a mixed linear effects model. RESULTS: We found that higher LFP was associated with higher LPR and higher glycerol concentration. No other biomarkers were associated with LPR; cerebral haemoglobin concentration, oxygen extraction fraction, and one EEG metric were associated with glycerol concentration. CONCLUSION: Contrary to expectations, higher LFP in CBF was correlated with worse invasive biomarkers. Higher LFP may represent higher neurologic activity, or disruptions in neurovascular coupling. Either effect may be harmful in the acute period after cardiac arrest. Thus, these results suggest our methodology holds promise for development of new, clinically relevant biomarkers than can guide resuscitation and post-resuscitation care. Institutional protocol number: 19-001327.

Fetal Doppler Echocardiographic Assessment Predicts Severe Postnatal Obstruction in Total Anomalous Pulmonary Venous Connection.

BACKGROUND: Obstructed total anomalous pulmonary venous connection (TAPVC) is a form of critical congenital heart disease that usually requires urgent postnatal intervention. Knowing which patients have severe obstruction can aid delivery planning. The authors previously developed a novel quantitative metric of pulmonary venous flow, the pulmonary venous variability index (PVVI). The aim of this study was to test the hypothesis that fetal PVVI and vertical vein Doppler velocities are associated with severe pulmonary vein obstruction postnatally. METHODS: A retrospective cohort study of neonates with prenatally diagnosed TAPVC was performed. Patients who underwent fetal echocardiography at the Children's Hospital of Philadelphia with Doppler interrogation of the vertical vein were included for analysis. Twenty-nine patients met criteria (21 with heterotaxy, 18 with supracardiac TAPVC). The latest gestation fetal echocardiogram was used. Severe pulmonary vein obstruction was defined as preoperative death or urgent surgery or catheter-based intervention (first day of life). Measurements of PVVI, defined as (maximum velocity - minimum velocity)/mean velocity, were made offline. Wilcoxon rank sum models were used to assess the associations of severe obstruction and PVVI and maximum, mean, and minimum velocities. RESULTS: The mean gestational age at the latest fetal echocardiographic examination was 35 weeks (range, 30-39 weeks). Twelve of the 29 patients (41%) met criteria for severe pulmonary vein obstruction. Lower PVVI was associated with greater risk for severe pulmonary venous obstruction (P = .008). The maximum, mean, and minimum velocities in the vertical vein were all significantly associated with severe pulmonary venous obstruction (P = .03, P = .03, and P = .007, respectively). Qualitative assessment of obstruction was not significantly associated with the outcome. Interobserver reliability for all vertical vein Doppler metrics was high (intraclass correlation coefficient > 0.9). CONCLUSIONS: Fetal PVVI and maximum, mean, and minimum velocities are associated with severe postnatal pulmonary vein obstruction in TAPVC. Accurate prediction of obstructed TAPVC could allow safer delivery planning. Further research with larger sample sizes is needed to identify the ideal cutoff values for these Doppler measures.

Statistical approaches to temporal and spatial autocorrelation in resting-state functional connectivity in mice measured with optical intrinsic signal imaging.

Significance: Resting-state functional connectivity imaging in mice with optical intrinsic signal (OIS) imaging could provide a powerful translational tool for developing imaging biomarkers in preclinical disease models. However, statistical interpretation of correlation coefficients is hampered by autocorrelations in the data. Aim: We sought to better understand temporal and spatial autocorrelations in optical resting-state data. We then adapted statistical methods from functional magnetic resonance imaging to improve statistical inference. Approach: Resting-state data were obtained from mice using a custom-built OSI system. The autocorrelation time was calculated at each pixel, and z scores for correlation coefficients were calculated using Fisher transforms and variance derived from either Bartlett's method or xDF. The significance of each correlation coefficient was determined through control of the false discovery rate (FDR). Results: Autocorrelation was generally even across the cortex and parcellation reduced variance. Correcting variance with Bartlett's method resulted in a uniform reduction in z scores, with xDF preserving high z scores for highly correlated data. Control of the FDR resulted in reasonable thresholding of the correlation coefficient matrices. The use of Bartlett's method compared with xDF results in more conservative thresholding and fewer false positives under null hypothesis conditions. Conclusions: We developed streamlined methods for control of autocorrelation in OIS functional connectivity data in mice, and Bartlett's method is a reasonable compromise and simplification that allows for accurate autocorrelation correction. These results improve the rigor and reproducibility of functional neuroimaging in mice.

Sustained improvement in fellows' echocardiographic completeness through the coronavirus pandemic with a standardised imaging protocol.

First-year cardiology fellows must quickly learn basic competency in echocardiography during fellowship orientation. This educational process was disrupted in 2020 due to the coronavirus pandemic, as our hands-on echocardiography teaching transitioned from practice on paediatric volunteers to simulation-based training. We previously described an improvement in echocardiographic completeness after implementation of a standardised imaging protocol for the performance of acute assessments of ventricular function. Herein, we assessed whether this improvement could be sustained over the two subsequent years, including the fellowship year affected by the pandemic. Echocardiograms performed by first-year paediatric cardiology fellows to assess ventricular function were reviewed for completeness. The frequency with which each requested component was included was measured. A total demographic score (out of 7) and total imaging score (out of 23) were calculated. The pre-protocol years (2015-2017) were compared to the post-protocol years (2018-2020), and the pre-COVID years (2018-2019) were compared to the year affected by COVID (2020). There was a sustained improvement in completeness after protocol implementation with improvement in the demographic score (median increasing from 6 to 7, p < 0.001) and imaging score (median increasing from 13 to 16, p < 0.001). More individual components showed a statistically significant increase in frequency compared to our prior publication. The COVID pandemic resulted in very few differences in completeness. Demographic reporting improved modestly (p = 0.04); the imaging score was unchanged (p = 0.59). The only view obtained less frequently was the apical two-chamber view. A standardised imaging protocol allowed sustained improvements in echocardiographic completeness despite the disruption of fellowship orientation by COVID-19.

Effects of circulatory arrest and cardiopulmonary bypass on cerebral autoregulation in neonatal swine.

BACKGROUND: Cerebral autoregulation mechanisms help maintain adequate cerebral blood flow (CBF) despite changes in cerebral perfusion pressure. Impairment of cerebral autoregulation, during and after cardiopulmonary bypass (CPB), may increase risk of neurologic injury in neonates undergoing surgery. In this study, alterations of cerebral autoregulation were assessed in a neonatal swine model probing four perfusion strategies. METHODS: Neonatal swine (n = 25) were randomized to continuous deep hypothermic cardiopulmonary bypass (DH-CPB, n = 7), deep hypothermic circulatory arrest (DHCA, n = 7), selective cerebral perfusion (SCP, n = 7) at deep hypothermia, or normothermic cardiopulmonary bypass (control, n = 4). The correlation coefficient (LDx) between laser Doppler measurements of CBF and mean arterial blood pressure was computed at initiation and conclusion of CPB. Alterations in cerebral autoregulation were assessed by the change between initial and final LDx measurements. RESULTS: Cerebral autoregulation became more impaired (LDx increased) in piglets that underwent DH-CPB (initial LDx: median 0.15, IQR [0.03, 0.26]; final: 0.45, [0.27, 0.74]; p = 0.02). LDx was not altered in those undergoing DHCA (p > 0.99) or SCP (p = 0.13). These differences were not explained by other risk factors. CONCLUSIONS: In a validated swine model of cardiac surgery, DH-CPB had a significant effect on cerebral autoregulation, whereas DHCA and SCP did not. IMPACT: Approximately half of the patients who survive neonatal heart surgery with cardiopulmonary bypass (CPB) experience neurodevelopmental delays. This preclinical investigation takes steps to elucidate and isolate potential perioperative risk factors of neurologic injury, such as impairment of cerebral autoregulation, associated with cardiac surgical procedures involving CPB. We demonstrate a method to characterize cerebral autoregulation during CPB pump flow changes in a neonatal swine model of cardiac surgery. Cerebral autoregulation was not altered in piglets that underwent deep hypothermic circulatory arrest (DHCA) or selective cerebral perfusion (SCP), but it was altered in piglets that underwent deep hypothermic CBP.

Optical Detection of Intracranial Pressure and Perfusion Changes in Neonates With Hydrocephalus.

OBJECTIVE: To demonstrate that a novel noninvasive index of intracranial pressure (ICP) derived from diffuse optics-based techniques is associated with intracranial hypertension. STUDY DESIGN: We compared noninvasive and invasive ICP measurements in infants with hydrocephalus. Infants born term and preterm were eligible for inclusion if clinically determined to require cerebrospinal fluid (CSF) diversion. Ventricular size was assessed preoperatively via ultrasound measurement of the fronto-occipital (FOR) and frontotemporal (FTHR) horn ratios. Invasive ICP was obtained at the time of surgical intervention with a manometer. Intracranial hypertension was defined as invasive ICP ≥15 mmHg. Diffuse optical measurements of cerebral perfusion, oxygen extraction, and noninvasive ICP were performed preoperatively, intraoperatively, and postoperatively. Optical and ultrasound measures were compared with invasive ICP measurements, and their change in values after CSF diversion were obtained. RESULTS: We included 39 infants, 23 with intracranial hypertension. No group difference in ventricular size was found by FOR (P = .93) or FTHR (P = .76). Infants with intracranial hypertension had significantly higher noninvasive ICP (P = .02) and oxygen extraction fraction (OEF) (P = .01) compared with infants without intracranial hypertension. Increased cerebral blood flow (P = .005) and improved OEF (P < .001) after CSF diversion were observed only in infants with intracranial hypertension. CONCLUSIONS: Noninvasive diffuse optical measures (including a noninvasive ICP index) were associated with intracranial hypertension. The findings suggest that impaired perfusion from intracranial hypertension was independent of ventricular size. Hemodynamic evidence of the benefits of CSF diversion was seen in infants with intracranial hypertension. Noninvasive optical techniques hold promise for aiding the assessment of CSF diversion timing.

Variability in atlas registration of optical intrinsic signal imaging and its effect on functional connectivity analysis.

To compare neuroimaging data between subjects, images from individual sessions need to be aligned to a common reference or "atlas." Atlas registration of optical intrinsic signal imaging of mice, for example, is commonly performed using affine transforms with parameters determined by manual selection of canonical skull landmarks. Errors introduced by such procedures have not previously been investigated. We quantify the variability that arises from this process and consequent errors from misalignment that affect interpretation of functional neuroimaging data. We propose an improved method, using separately acquired high-resolution images and demonstrate improvements in variability and alignment using this method.

Venous Flow Variation Predicts Preoperative Pulmonary Venous Obstruction in Children with Total Anomalous Pulmonary Venous Connection.

BACKGROUND: Identifying preoperative pulmonary venous obstruction in total anomalous pulmonary venous connection is important to guide treatment planning and risk prognostication. No standardized echocardiographic definition of obstruction exists in the literature. Definitions based on absolute velocities are affected by technical limitations and variations in pulmonary venous return. The authors developed a metric to quantify pulmonary venous blood flow variation: pulmonary venous variability index (PVVI). The aim of this study was to demonstrate its accuracy in defining obstruction. METHODS: All patients with total anomalous pulmonary venous connection at a single institution were identified. Echocardiograms were reviewed, and maximum (Vmax), mean (Vmean), and minimum (Vmin) velocities along the pulmonary venous pathway were measured. PVVI was defined as (Vmax - Vmin)/Vmean. These metrics were compared with pressures measured on cardiac catheterization. Echocardiographic measures were then compared between patients with and without clinical preoperative obstruction (defined as a need for preoperative intubation, catheter-based intervention, or surgery within 1 day of diagnosis), as well as pulmonary edema by chest radiography and markers of lactic acidosis. One hundred thirty-seven patients were included, with 22 having catheterization pressure recordings. RESULTS: Vmax and Vmean were not different between patients with catheter gradients ≥ 4 and < 4 mm Hg, while PVVI was significantly lower and Vmin higher in those with gradients ≥ 4 mm Hg. The composite outcome of preoperative obstruction occurred in 51 patients (37%). Absolute velocities were not different between patients with and without clinical obstruction, while PVVI was significantly lower in patients with obstruction. All metrics except Vmax were associated with pulmonary edema; none were associated with blood gas metrics. CONCLUSIONS: The authors developed a novel quantitative metric of pulmonary venous flow, which was superior to traditional echocardiographic metrics. Decreased PVVI was highly associated with elevated gradients measured by catheterization and clinical preoperative obstruction. These results should aid risk assessment and diagnosis preoperatively in patients with total anomalous pulmonary venous connection.

Wavelength censoring for spectroscopy in optical functional neuroimaging.

Optical neuromonitoring provides insight into neurovascular physiology and brain structure and function. These methods rely on spectroscopy to relate light absorption changes to variation of concentrations of physiologic chromophores such as oxy- and deoxyhemoglobin. In clinical or preclinical practice, data quality can vary significantly across wavelengths. In such situations, standard spectroscopic methods may perform poorly, resulting in data loss and limiting field-of-view. To address this issue, and thereby improve the robustness of optical neuromonitoring, we develop, in this manuscript, novel methods to perform spectroscopy even when data quality exhibits wavelength-dependent spatial variation. We sought to understand the impact of spatial, wavelength-based censoring on the physiologic accuracy and utility of hemoglobin spectroscopy. The principles of our analysis are quite general, but to make the methodology tangible we focused on optical intrinsic signal imaging of resting-state functional connectivity in mice. Starting with spectroscopy using four sources, all possible subset spectroscopy matrices were assessed theoretically, using simulated data, and using experimental data. These results were compared against the use of the full spectroscopy matrix to determine which subsets yielded robust results. Our results demonstrated that accurate calculation of changes in hemoglobin concentrations and the resulting functional connectivity network maps was possible even with censoring of some wavelengths. Additionally, we found that the use of changes in total hemoglobin (rather than oxy- or deoxyhemoglobin) yielded results more robust to experimental noise and allowed for the preservation of more data. This new and rigorous image processing method should improve the fidelity of clinical and preclinical functional neuroimaging studies.

Brain segmentation, spatial censoring, and averaging techniques for optical functional connectivity imaging in mice.

Resting-state functional connectivity analysis using optical neuroimaging holds the potential to be a powerful bridge between mouse models of disease and clinical neurologic monitoring. However, analysis techniques specific to optical methods are rudimentary, and algorithms from magnetic resonance imaging are not always applicable to optics. We have developed visual processing tools to increase data quality, improve brain segmentation, and average across sessions with better field-of-view. We demonstrate improved performance using resting-state optical intrinsic signal from normal mice. The proposed methods increase the amount of usable data from neuroimaging studies, improve image fidelity, and should be translatable to human optical neuroimaging systems.