Quantification of blood-brain barrier water exchange and permeability with multidelay diffusion-weighted pseudo-continuous arterial spin labeling.

PURPOSE: To present a pulse sequence and mathematical models for quantification of blood-brain barrier water exchange and permeability. METHODS: Motion-compensated diffusion-weighted (MCDW) gradient-and-spin echo (GRASE) pseudo-continuous arterial spin labeling (pCASL) sequence was proposed to acquire intravascular/extravascular perfusion signals from five postlabeling delays (PLDs, 1590-2790 ms). Experiments were performed on 11 healthy subjects at 3 T. A comprehensive set of perfusion and permeability parameters including cerebral blood flow (CBF), capillary transit time (τc ), and water exchange rate (kw ) were quantified, and permeability surface area product (PSw ), total extraction fraction (Ew ), and capillary volume (Vc ) were derived simultaneously by a three-compartment single-pass approximation (SPA) model on group-averaged data. With information (i.e., Vc and τc ) obtained from three-compartment SPA modeling, a simplified linear regression of logarithm (LRL) approach was proposed for individual kw quantification, and Ew and PSw can be estimated from long PLD (2490/2790 ms) signals. MCDW-pCASL was compared with a previously developed diffusion-prepared (DP) pCASL sequence, which calculates kw by a two-compartment SPA model from PLD = 1800 ms signals, to evaluate the improvements. RESULTS: Using three-compartment SPA modeling, group-averaged CBF = 51.5/36.8 ml/100 g/min, kw = 126.3/106.7 min-1 , PSw = 151.6/93.8 ml/100 g/min, Ew = 94.7/92.2%, τc = 1409.2/1431.8 ms, and Vc = 1.2/0.9 ml/100 g in gray/white matter, respectively. Temporal SNR of MCDW-pCASL perfusion signals increased 3-fold, and individual kw maps calculated by the LRL method achieved higher spatial resolution (3.5 mm3 isotropic) as compared with DP pCASL (3.5 × 3.5 × 8 mm3 ). CONCLUSION: MCDW-pCASL allows visualization of intravascular/extravascular ASL signals across multiple PLDs. The three-compartment SPA model provides a comprehensive measurement of blood-brain barrier water dynamics from group-averaged data, and a simplified LRL method was proposed for individual kw quantification.

Noninvasive Quantification of Cerebral Blood Flow Using Hybrid PET/MR Imaging to Extract the [15 O]H2 O Image-Derived Input Function Free of Partial Volume Errors.

BACKGROUND: Quantification of cerebral blood flow (CBF) with [15 O]H2 O-positron emission tomography (PET) requires arterial sampling to measure the input function. This invasive procedure can be avoided by extracting an image-derived input function (IDIF); however, IDIFs are sensitive to partial volume errors due to the limited spatial resolution of PET. PURPOSE: To present an alternative hybrid PET/MR imaging of CBF (PMRFlowIDIF ) that uses phase-contrast (PC) MRI measurements of whole-brain (WB) CBF to calibrate an IDIF extracted from a WB [15 O]H2 O time-activity curve. STUDY TYPE: Technical development and validation. ANIMAL MODEL: Twelve juvenile Duroc pigs (83% female). POPULATION: Thirteen healthy individuals (38% female). FIELD STRENGTH/SEQUENCES: 3 T; gradient-echo PC-MRI. ASSESSMENT: PMRFlowIDIF was validated against PET-only in a porcine model that included arterial sampling. CBF maps were generated by applying PMRFlowIDIF and two previous PMRFlow methods (PC-PET and double integration method [DIM]) to [15 O]H2 O-PET data acquired from healthy individuals. STATISTICAL TESTS: PMRFlow and PET CBF measurements were compared with regression and correlation analyses. Paired t-tests were performed to evaluate differences. Potential biases were assessed using one-sample t-tests. Reliability was assessed by intraclass correlation coefficients. Statistical significance: α  = 0.05. RESULTS: In the animal study, strong agreement was observed between PMRFlowIDIF (average voxel-wise CBF, 58.0 ± 16.9 mL/100 g/min) and PET (63.0 ± 18.9 mL/100 g/min). In the human study, PMRFlowDIM (y = 1.11x - 5.16, R2  = 0.99 ± 0.01) and PMRFlowPC-PET (y = 0.87x + 3.82, R2  = 0.97 ± 0.02) performed similarly to PMRFlowIDIF, and CBF was within the expected range (eg, 49.7 ± 7.2 mL/100 g/min for gray matter). DATA CONCLUSION: Accuracy of PMRFlowIDIF was confirmed in the animal study with the primary source of error attributed to differences in WB CBF measured by PC MRI and PET. In the human study, differences in CBF from PMRFlowIDIF , PMRFlowDIM , and PMRFlowPC-PET were due to the latter two not accounting for blood-borne activity. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

The functional and structural associations of aberrant microglial activity in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a debilitating mental illness that has been linked to increases in markers of inflammation, as well as to changes in brain functional and structural connectivity, particularly between the insula and the subgenual anterior cingulate cortex (sgACC). In this study, we directly related inflammation and dysconnectivity in treatment-resistant MDD by concurrently measuring the following: microglial activity with [18F]N-2-(fluoroethoxyl)benzyl-N-(4phenoxypyridin-3-yl)acetamide ([18F]FEPPA) positron emission tomography (PET); the severity of MDD; and functional or structural connectivity among insula or sgACC nodes. METHODS: Twelve patients with treatment-resistant MDD (8 female, 4 male; mean age ± standard deviation 54.9 ± 4.5 years and 23 healthy controls (11 female, 12 male; 60.3 ± 8.5 years) completed a hybrid [18F]FEPPA PET and MRI acquisition. From these, we extracted relative standardized uptake values for [18F]FEPPA activity and Pearson r-to-z scores representing functional connectivity from our regions of interest. We extracted diffusion tensor imaging metrics from the cingulum bundle, a key white matter bundle in MDD. We performed regressions to relate microglial activity with functional connectivity, structural connectivity and scores on the 17-item Hamilton Depression Rating Scale. RESULTS: We found significantly increased [18F]FEPPA uptake in the left sgACC in patients with treatment-resistant MDD compared to healthy controls. Patients with MDD also had a reduction in connectivity between the sgACC and the insula. The [18F]FEPPA uptake in the left sgACC was significantly related to functional connectivity with the insula, and to the structural connectivity of the cingulum bundle. [18F]FEPPA uptake also predicted scores on the Hamilton Depression Rating Scale.Limitations: A relatively small sample size, lack of functional task data and concomitant medication use may have affected our findings. CONCLUSION: We present preliminary evidence linking a network-level dysfunction relevant to the pathophysiology of depression and related to increased microglial activity in MDD.

Detection of Brain Hypoxia Based on Noninvasive Optical Monitoring of Cerebral Blood Flow with Diffuse Correlation Spectroscopy.

BACKGROUND: Diffuse correlation spectroscopy (DCS) noninvasively permits continuous, quantitative, bedside measurements of cerebral blood flow (CBF). To test whether optical monitoring (OM) can detect decrements in CBF producing cerebral hypoxia, we applied the OM technique continuously to probe brain-injured patients who also had invasive brain tissue oxygen (PbO2) monitors. METHODS: Comatose patients with a Glasgow Coma Score (GCS) < 8) were enrolled in an IRB-approved protocol after obtaining informed consent from the legally authorized representative. Patients underwent 6-8 h of daily monitoring. Brain PbO2 was measured with a Clark electrode. Absolute CBF was monitored with DCS, calibrated by perfusion measurements based on intravenous indocyanine green bolus administration. Variation of optical CBF and mean arterial pressure (MAP) from baseline was measured during periods of brain hypoxia (defined as a drop in PbO2 below 19 mmHg for more than 6 min from baseline (PbO2 > 21 mmHg). In a secondary analysis, we compared optical CBF and MAP during randomly selected 12-min periods of "normal" (> 21 mmHg) and "low" (< 19 mmHg) PbO2. Receiver operator characteristic (ROC) and logistic regression analysis were employed to assess the utility of optical CBF, MAP, and the two-variable combination, for discrimination of brain hypoxia from normal brain oxygen tension. RESULTS: Seven patients were enrolled and monitored for a total of 17 days. Baseline-normalized MAP and CBF significantly decreased during brain hypoxia events (p < 0.05). Through use of randomly selected, temporally sparse windows of low and high PbO2, we observed that both MAP and optical CBF discriminated between periods of brain hypoxia and normal brain oxygen tension (ROC AUC 0.761, 0.762, respectively). Further, combining these variables using logistic regression analysis markedly improved the ability to distinguish low- and high-PbO2 epochs (AUC 0.876). CONCLUSIONS: The data suggest optical techniques may be able to provide continuous individualized CBF measurement to indicate occurrence of brain hypoxia and guide brain-directed therapy.

Broadband NIRS Cerebral Cytochrome-C-Oxidase Response to Anoxia Before and After Hypoxic-Ischaemic Injury in Piglets.

Perinatal hypoxic ischaemic (HI) encephalopathy is associated with severe neurodevelopment problems and mortality. This study uses broadband continuous-wave near-infrared spectroscopy (NIRS) to assess the early changes in cerebral oxygenation and metabolism after HI injury in an animal model using controlled anoxia events. Anoxia was induced before and 1 h after various levels of HI injury to assess the metabolic response via the changes in the oxidation state of cytochrome-c-oxidase (oxCCO), a marker of oxidative metabolism. The oxCCO responses to anoxia were classified into five categories: increase, no change, decrease, biphasic and triphasic responses. The most common response (54%) was a biphasic decrease in oxCCO. A change in the classification of the metabolic response to anoxia after HI injury indicated a severe injury, as determined by proton magnetic resonance spectroscopy, with 86% sensitivity. This shows that broadband NIRS can identify disturbances to cerebral metabolism in the first hours after severe HI injury.

A multi-centre evaluation of eleven clinically feasible brain PET/MRI attenuation correction techniques using a large cohort of patients.

AIM: To accurately quantify the radioactivity concentration measured by PET, emission data need to be corrected for photon attenuation; however, the MRI signal cannot easily be converted into attenuation values, making attenuation correction (AC) in PET/MRI challenging. In order to further improve the current vendor-implemented MR-AC methods for absolute quantification, a number of prototype methods have been proposed in the literature. These can be categorized into three types: template/atlas-based, segmentation-based, and reconstruction-based. These proposed methods in general demonstrated improvements compared to vendor-implemented AC, and many studies report deviations in PET uptake after AC of only a few percent from a gold standard CT-AC. Using a unified quantitative evaluation with identical metrics, subject cohort, and common CT-based reference, the aims of this study were to evaluate a selection of novel methods proposed in the literature, and identify the ones suitable for clinical use. METHODS: In total, 11 AC methods were evaluated: two vendor-implemented (MR-ACDIXON and MR-ACUTE), five based on template/atlas information (MR-ACSEGBONE (Koesters et al., 2016), MR-ACONTARIO (Anazodo et al., 2014), MR-ACBOSTON (Izquierdo-Garcia et al., 2014), MR-ACUCL (Burgos et al., 2014), and MR-ACMAXPROB (Merida et al., 2015)), one based on simultaneous reconstruction of attenuation and emission (MR-ACMLAA (Benoit et al., 2015)), and three based on image-segmentation (MR-ACMUNICH (Cabello et al., 2015), MR-ACCAR-RiDR (Juttukonda et al., 2015), and MR-ACRESOLUTE (Ladefoged et al., 2015)). We selected 359 subjects who were scanned using one of the following radiotracers: [18F]FDG (210), [11C]PiB (51), and [18F]florbetapir (98). The comparison to AC with a gold standard CT was performed both globally and regionally, with a special focus on robustness and outlier analysis. RESULTS: The average performance in PET tracer uptake was within ±5% of CT for all of the proposed methods, with the average±SD global percentage bias in PET FDG uptake for each method being: MR-ACDIXON (-11.3±3.5)%, MR-ACUTE (-5.7±2.0)%, MR-ACONTARIO (-4.3±3.6)%, MR-ACMUNICH (3.7±2.1)%, MR-ACMLAA (-1.9±2.6)%, MR-ACSEGBONE (-1.7±3.6)%, MR-ACUCL (0.8±1.2)%, MR-ACCAR-RiDR (-0.4±1.9)%, MR-ACMAXPROB (-0.4±1.6)%, MR-ACBOSTON (-0.3±1.8)%, and MR-ACRESOLUTE (0.3±1.7)%, ordered by average bias. The overall best performing methods (MR-ACBOSTON, MR-ACMAXPROB, MR-ACRESOLUTE and MR-ACUCL, ordered alphabetically) showed regional average errors within ±3% of PET with CT-AC in all regions of the brain with FDG, and the same four methods, as well as MR-ACCAR-RiDR, showed that for 95% of the patients, 95% of brain voxels had an uptake that deviated by less than 15% from the reference. Comparable performance was obtained with PiB and florbetapir. CONCLUSIONS: All of the proposed novel methods have an average global performance within likely acceptable limits (±5% of CT-based reference), and the main difference among the methods was found in the robustness, outlier analysis, and clinical feasibility. Overall, the best performing methods were MR-ACBOSTON, MR-ACMAXPROB, MR-ACRESOLUTE and MR-ACUCL, ordered alphabetically. These methods all minimized the number of outliers, standard deviation, and average global and local error. The methods MR-ACMUNICH and MR-ACCAR-RiDR were both within acceptable quantitative limits, so these methods should be considered if processing time is a factor. The method MR-ACSEGBONE also demonstrates promising results, and performs well within the likely acceptable quantitative limits. For clinical routine scans where processing time can be a key factor, this vendor-provided solution currently outperforms most methods. With the performance of the methods presented here, it may be concluded that the challenge of improving the accuracy of MR-AC in adult brains with normal anatomy has been solved to a quantitatively acceptable degree, which is smaller than the quantification reproducibility in PET imaging.

Investigating the effects of cerebrospinal fluid removal on cerebral blood flow and oxidative metabolism in infants with post-hemorrhagic ventricular dilatation.

BackgroundPost-hemorrhagic ventricular dilatation (PHVD) is predictive of mortality and morbidity among very-low-birth-weight preterm infants. Impaired cerebral blood flow (CBF) due to elevated intracranial pressure (ICP) is believed to be a contributing factor.MethodsA hyperspectral near-infrared spectroscopy (NIRS) method of measuring CBF and the cerebral metabolic rate of oxygen (CMRO2) was used to investigate perfusion and metabolism changes in patients receiving a ventricular tap (VT) based on clinical management. To improve measurement accuracy, the spectral analysis was modified to account for compression of the cortical mantle caused by PHVD and the possible presence of blood breakdown products.ResultsFrom nine patients (27 VTs), a significant CBF increase was measured (15.6%) following VT (14.6±4.2 to 16.9±6.6 ml/100 g/min), but with no corresponding change in CMRO2 (1.02±0.41 ml O2/100 g/min). Post-VT CBF was in good agreement with a control group of 13 patients with patent ductus arteriosus but no major cerebral pathology (16.5±7.7 ml/100 g/min), whereas tissue oxygen saturation (StO2) was significantly lower (58.9±12.1% vs. 70.5±9.1% for controls).ConclusionCBF was impeded in PHVD infants requiring a clinical intervention, but the effect is not large enough to alter CMRO2.

Time-resolved subtraction method for measuring optical properties of turbid media.

Near-infrared spectroscopy is a noninvasive optical method used primarily to monitor tissue oxygenation due to the absorption properties of hemoglobin. Accurate estimation of hemoglobin concentrations and other light absorbers requires techniques that can separate the effect of absorption from the much greater effect of light scattering. One of the most advanced methods is time-resolved near-infrared spectroscopy (TR-NIRS), which measures the absorption and scattering coefficients of a turbid medium by modeling the recorded distribution time of flight of photons. A challenge with TR-NIRS is that it requires accurate characterization of the dispersion caused by the system. In this study, we present a method for circumventing this problem by applying statistical moment analysis to two time-of-flight distributions measured at separated source-detector distances. Simulations based on analytical models and Monte Carlo code, and tissue-mimicking phantoms, were used to demonstrate its accuracy for source-detector distances typically used in neuroimaging applications. The simplicity of the approach is well suited to real-time applications requiring accurate quantification of the optical properties of a turbid medium.

Quantitative retinal blood flow mapping from fluorescein videoangiography using tracer kinetic modeling.

Abnormal retinal blood flow (RBF) has been associated with numerous retinal pathologies, yet existing methods for measuring RBF predominantly provide only relative measures of blood flow and are unable to quantify volumetric blood flow, which could allow direct patient to patient comparison. This work presents a methodology based on linear systems theory and an image-based arterial input function to quantitatively map volumetric blood flow from standard fluorescein videoangiography data, and is therefore directly translatable to the clinic. Application of the approach to fluorescein retinal videoangiography in rats (4 control, 4 diabetic) demonstrated significantly higher RBF in 4-5 week diabetic rats as expected from the literature.

Quantifying cerebral blood flow in an adult pig ischemia model by a depth-resolved dynamic contrast-enhanced optical method.

Dynamic contrast-enhanced (DCE) near-infrared (NIR) methods have been proposed for bedside monitoring of cerebral blood flow (CBF). These methods have primarily focused on qualitative approaches since scalp contamination hinders quantification. In this study, we demonstrate that accurate CBF measurements can be obtained by analyzing multi-distance time-resolved DCE data with a combined kinetic deconvolution optical reconstruction (KDOR) method. Multi-distance time-resolved DCE-NIR measurements were made in adult pigs (n=8) during normocapnia, hypocapnia and ischemia. The KDOR method was used to calculate CBF from the DCE-NIR measurements. For validation, CBF was measured independently by CT under each condition. The mean CBF difference between the techniques was -1.7 mL/100 g/min with 95% confidence intervals of -16.3 and 12.9 mL/100 g/min; group regression analysis revealed a strong agreement between the two techniques (slope=1.06±0.08, y-intercept=-4.37±4.33 mL/100 g/min, p<0.001). The results of an error analysis suggest that little a priori information is needed to recover CBF, due to the robustness of the analytical method and the ability of time-resolved NIR to directly characterize the optical properties of the extracerebral tissue (where model mismatch is deleterious). The findings of this study suggest that the DCE-NIR approach presented is a minimally invasive and portable means of determining absolute hemodynamics in neurocritical care patients.

Frugal and Translatable [15O]O2 Production for Human Inhalation with Direct Delivery from the Cyclotron to a Hybrid PET/MR.

Oxygen-15 (ß+, t1/2 = 122 s) radiolabeled diatomic oxygen, in conjunction with positron emission tomography, is the gold standard to quantitatively measure the metabolic rate of oxygen consumption in the living human brain. We present herein a protocol for safe and effective delivery of [15O]O2 over 200 m to a human subject for inhalation. A frugal quality control testing procedure was devised and validated. This protocol can act as a blueprint for other sites seeking to implement similar imaging programs.

Assessing changes in regional cerebral hemodynamics in adults with a high-density full-head coverage time-resolved near-infrared spectroscopy device.

Significance: Cerebral oximeters have the potential to detect abnormal cerebral blood oxygenation to allow for early intervention. However, current commercial systems have two major limitations: (1) spatial coverage of only the frontal region, assuming that surgery-related hemodynamic effects are global and (2) susceptibility to extracerebral signal contamination inherent to continuous-wave near-infrared spectroscopy (NIRS). Aim: This work aimed to assess the feasibility of a high-density, time-resolved (tr) NIRS device (Kernel Flow) to monitor regional oxygenation changes across the cerebral cortex during surgery. Approach: The Flow system was assessed using two protocols. First, digital carotid compression was applied to healthy volunteers to cause a rapid oxygenation decrease across the ipsilateral hemisphere without affecting the contralateral side. Next, the system was used on patients undergoing shoulder surgery to provide continuous monitoring of cerebral oxygenation. In both protocols, the improved depth sensitivity of trNIRS was investigated by applying moment analysis. A dynamic wavelet filtering approach was also developed to remove observed temperature-induced signal drifts. Results: In the first protocol (28±5 years; five females, five males), hair significantly impacted regional sensitivity; however, the enhanced depth sensitivity of trNIRS was able to separate brain and scalp responses in the frontal region. Regional sensitivity was improved in the clinical study given the age-related reduction in hair density of the patients (65±15 years; 14 females, 13 males). In five patients who received phenylephrine to treat hypotension, different scalp and brain oxygenation responses were apparent, although no regional differences were observed. Conclusions: The Kernel Flow has promise as an intraoperative neuromonitoring device. Although regional sensitivity was affected by hair color and density, enhanced depth sensitivity of trNIRS was able to resolve differences in scalp and brain oxygenation responses in both protocols.

Altered resting-state functional connectivity in newborns with hypoxic ischemic encephalopathy assessed using high-density functional near-infrared spectroscopy.

Hypoxic-ischemic encephalopathy (HIE) results from a lack of oxygen to the brain during the perinatal period. HIE can lead to mortality and various acute and long-term morbidities. Improved bedside monitoring methods are needed to identify biomarkers of brain health. Functional near-infrared spectroscopy (fNIRS) can assess resting-state functional connectivity (RSFC) at the bedside. We acquired resting-state fNIRS data from 21 neonates with HIE (postmenstrual age [PMA] = 39.96), in 19 neonates the scans were acquired post-therapeutic hypothermia (TH), and from 20 term-born healthy newborns (PMA = 39.93). Twelve HIE neonates also underwent resting-state functional magnetic resonance imaging (fMRI) post-TH. RSFC was calculated as correlation coefficients amongst the time courses for fNIRS and fMRI data, respectively. The fNIRS and fMRI RSFC maps were comparable. RSFC patterns were then measured with graph theory metrics and compared between HIE infants and healthy controls. HIE newborns showed significantly increased clustering coefficients, network efficiency and modularity compared to controls. Using a support vector machine algorithm, RSFC features demonstrated good performance in classifying the HIE and healthy newborns in separate groups. Our results indicate the utility of fNIRS-connectivity patterns as potential biomarkers for HIE and fNIRS as a new bedside tool for newborns with HIE.

Preservation of the metabolic rate of oxygen in preterm infants during indomethacin therapy for closure of the ductus arteriosus.

BACKGROUND: The aim of this study was to assess and quantify the effects of indomethacin on cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) in preterm infants undergoing treatment for a patent ductus arteriosus (PDA). METHODS: CBF and CMRO2 were measured before and after the first dose of a 3-d course of indomethacin to close hemodynamically significant PDA in preterm neonates. Indocyanine-green (ICG) concentration curves were acquired before and after indomethacin injection to quantify CBF and CMRO2. RESULTS: Eight preterm neonates (gestational age, 27.6 ± 0.5 wk; birth weight, 992 ± 109 g; 6 males:2 females) were treated at a median age of 4.5 d (range, 4-21 d). Indomethacin resulted in an average CBF decrease of 18% (pre- and post-CBF = 12.9 ± 1.3 and 10.6 ± 0.8 ml/100 g/min, respectively) and an OEF increase of 11% (pre- and post-OEF = 0.38 ± 0.02 and 0.42 ± 0.02, respectively) but no significant change in CMRO2 (pre- and post-CMRO2 = 0.83 ± 0.07 and 0.76 ± 0.07 ml O2/100 g/min, respectively). Corresponding mean blood pressure (BP), arterial oxygen saturation (SaO2), heart rate, and end-tidal carbon dioxide tension levels remained unchanged. CONCLUSION: Indomethacin resulted in significant reduction in CBF but did not alter CMRO2 because of a compensatory increase in OEF.

Using depth-enhanced diffuse correlation spectroscopy and near-infrared spectroscopy to isolate cerebral hemodynamics during transient hypotension.

Significance: Combining diffuse correlation spectroscopy (DCS) and near-infrared spectroscopy (NIRS) permits simultaneous monitoring of multiple cerebral hemodynamic parameters related to cerebral autoregulation; however, interpreting these optical measurements can be confounded by signal contamination from extracerebral tissue. Aim: We aimed to evaluate extracerebral signal contamination in NIRS/DCS data acquired during transient hypotension and assess suitable means of separating scalp and brain signals. Approach: A hybrid time-resolved NIRS/multidistance DCS system was used to simultaneously acquire cerebral oxygenation and blood flow data during transient orthostatic hypotension induced by rapid-onset lower body negative pressure (LBNP) in nine young, healthy adults. Changes in microvascular flow were verified against changes in middle cerebral artery velocity (MCAv) measured by transcranial Doppler ultrasound. Results: LBNP significantly decreased arterial blood pressure (-18%±14%), scalp blood flow (>30%), and scalp tissue oxygenation (all p≤0.04 versus baseline). However, implementing depth-sensitive techniques for both DCS and time-resolved NIRS indicated that LBNP did not significantly alter microvascular cerebral blood flow and oxygenation relative to their baseline values (all p≥0.14). In agreement, there was no significant reduction in MCAv (8%±16%; p=0.09). Conclusion: Transient hypotension caused significantly larger blood flow and oxygenation changes in the extracerebral tissue compared to the brain. We demonstrate the importance of accounting for extracerebral signal contamination within optical measures of cerebral hemodynamics during physiological paradigms designed to test cerebral autoregulation.

Three-dimensional cranial ultrasound and functional near-infrared spectroscopy for bedside monitoring of intraventricular hemorrhage in preterm neonates.

Germinal Matrix-Intraventricular Hemorrhage (GMH-IVH) remains a significant cause of adverse neurodevelopment in preterm infants. Current management relies on 2-dimensional cranial ultrasound (2D cUS) ventricular measurements. Reliable biomarkers are needed to aid in the early detection of posthemorrhagic ventricular dilatation (PHVD) and subsequent neurodevelopment. In a prospective cohort study, we incorporated 3-dimensional (3D) cUS and functional near-infrared spectroscopy (fNIRS) to monitor neonates with GMH-IVH. Preterm neonates (≤ 32 weeks' gestation) were enrolled following a GMH-IVH diagnosis. Neonates underwent sequential measurements: 3D cUS images were manually segmented using in-house software, and the ventricle volumes (VV) were extracted. Multichannel fNIRS data were acquired using a high-density system, and spontaneous functional connectivity (sFC) was calculated. Of the 30 neonates enrolled in the study, 19 (63.3%) had grade I-II and 11 (36.7%) grade III-IV GMH-IVH; of these, 7 neonates (23%) underwent surgical interventions to divert cerebrospinal fluid (CSF). In infants with severe GMH-IVH, larger VV were significantly associated with decreased |sFC|. Our findings of increased VV and reduced sFC suggest that regional disruptions of ventricular size may impact the development of the underlying white matter. Hence, 3D cUS and fNIRS are promising bedside tools for monitoring the progression of GMH-IVH in preterm neonates.

Development of a minimally invasive simultaneous estimation method for quantifying translocator protein binding with [18F]FEPPA positron emission tomography.

BACKGROUND: The purpose of this study was to assess the feasibility of using a minimally invasive simultaneous estimation method (SIME) to quantify the binding of the 18-kDa translocator protein tracer [18F]FEPPA. Arterial sampling was avoided by extracting an image-derived input function (IDIF) that was metabolite-corrected using venous blood samples. The possibility of reducing scan duration to 90 min from the recommended 2-3 h was investigated by assuming a uniform non-displaceable distribution volume (VND) to simplify the SIME fitting. RESULTS: SIME was applied to retrospective data from healthy volunteers and was comprised of both high-affinity binders (HABs) and mixed-affinity binders (MABs). Estimates of global VND and regional total distribution volume (VT) from SIME were not significantly different from values obtained using a two-tissue compartment model (2CTM). Regional VT estimates were greater for HABs compared to MABs for both the 2TCM and SIME, while the SIME estimates had lower inter-subject variability (41 ± 17% reduction). Binding potential (BPND) values calculated from regional VT and brain-wide VND estimates were also greater for HABs, and reducing the scan time from 120 to 90 min had no significant effect on BPND. The feasibility of using venous metabolite correction was evaluated in a large animal model involving a simultaneous collection of arterial and venous samples. Strong linear correlations were found between venous and arterial measurements of the blood-to-plasma ratio and the remaining [18F]FEPPA fraction. Lastly, estimates of BPND and the specific distribution volume (i.e., VS = VT - VND) from a separate group of healthy volunteers (90 min scan time, venous-scaled IDIFs) agreed with estimates from the retrospective data for both genotypes. CONCLUSIONS: The results of this study demonstrate that accurate estimates of regional VT, BPND and VS can be obtained by applying SIME to [18F]FEPPA data. Furthermore, the application of SIME enabled the scan time to be reduced to 90 min, and the approach worked well with IDIFs that were scaled and metabolite-corrected using venous blood samples.

A two-stage approach for measuring vascular water exchange and arterial transit time by diffusion-weighted perfusion MRI.

Changes in the exchange rate of water across the blood-brain barrier, denoted k(w), may indicate blood-brain barrier dysfunction before the leakage of large-molecule contrast agents is observable. A previously proposed approach for measuring k(w) is to use diffusion-weighted arterial spin labeling to measure the vascular and tissue fractions of labeled water, because the vascular-to-tissue ratio is related to k(w). However, the accuracy of diffusion-weighted arterial spin labeling is affected by arterial blood contributions and the arterial transit time (τ(a)). To address these issues, a two-stage method is proposed that uses combinations of diffusion-weighted gradient strengths and post-labeling delays to measure both τ(a) and k(w). The feasibility of this method was assessed by acquiring diffusion-weighted arterial spin labeling data from seven healthy volunteers. Repeat measurements and Monte Carlo simulations were conducted to determine the precision and accuracy of the k(w) estimates. Average grey and white matter k(w) values were 110 ± 18 and 126 ± 18 min(-1), respectively, which compare favorably to blood-brain barrier permeability measurements obtained with positron emission tomography. The intrasubject coefficient of variation was 26% ± 23% in grey matter and 21% ± 17% in white matter, indicating that reproducible k(w) measurements can be obtained.

Deconvolution method for recovering the photon time-of-flight distribution from time-resolved measurements.

A nonparametric deconvolution algorithm for recovering the photon time-of-flight distribution (TOFD) from time-resolved (TR) measurements is described. The algorithm combines wavelet denoising and a two-stage deconvolution method based on generalized singular value decomposition and Tikhonov regularization. The efficacy of the algorithm was tested on simulated and experimental TR data and the results show that it can recover the photon TOFD with high fidelity. Combined with the microscopic Beer-Lambert law, the algorithm enables accurate quantification of absorption changes from arbitrary time-of-flight windows, thereby optimizing the depth sensitivity provided by TR measurements.

Measuring the neural response to continuous intramuscular infusion of hypertonic saline by perfusion MRI.

PURPOSE: To determine the extent to which arterial spin labeling (ASL), a functional magnetic resonance imaging technique that directly measures cerebral blood flow (CBF), is able to measure the neural activation associated with prolonged experimental muscle pain. MATERIALS AND METHODS: Hypertonic saline (HS) (5% NaCl) was infused into the brachioradialis muscle of 19 healthy volunteers for 15 min. The imaging volume extended from the dorsal side of the pons to the primary somatosensory cortices, covering most of the cortical and subcortical regions associated with pain perception. RESULTS: Using a numerical scale from 0 to 10, ratings of pain intensity peaked at 5.9 ± 0.5 (mean ± SE). Group activation maps showed that the slow infusion of HS evoked CBF increases primarily in bilateral insula, with additional activation in right frontal regions. In the activated areas, CBF gradually increased at the onset of HS infusion and was maintained at relatively constant levels throughout the remainder of the infusion period. However, the level and extent of activation were smaller than observed in previous studies involving acute muscle pain. CONCLUSION: This study demonstrates the ability of ASL to measure changes in CBF over extended periods of time and that the neural activation caused by muscle pain is paradigm specific.