Refining hemodynamic correction in in vivo wide-field fluorescent imaging through linear regression analysis.

Accurate interpretation of in vivo wide-field fluorescent imaging (WFFI) data requires precise separation of raw fluorescence signals into neural and hemodynamic components. The classical Beer-Lambert law-based approach, which uses concurrent 530-nm illumination to estimate relative changes in cerebral blood volume (CBV), fails to account for the scattering and reflection of 530-nm photons from non-neuronal components leading to biased estimates of CBV changes and subsequent misrepresentation of neural activity. This study introduces a novel linear regression approach designed to overcome this limitation. This correction provides a more reliable representation of CBV changes and neural activity in fluorescence data. Our method is validated across multiple datasets, demonstrating its superiority over the classical approach.

Enhanced parameter estimation in multiparametric arterial spin labeling using artificial neural networks.

PURPOSE: Multiparametric arterial spin labeling (MP-ASL) can quantify cerebral blood flow (CBF) and arterial cerebral blood volume (CBVa). However, its accuracy is compromised owing to its intrinsically low SNR, necessitating complex and time-consuming parameter estimation. Deep neural networks (DNNs) offer a solution to these limitations. Therefore, we aimed to develop simulation-based DNNs for MP-ASL and compared the performance of a supervised DNN (DNNSup), physics-informed unsupervised DNN (DNNUns), and the conventional lookup table method (LUT) using simulation and in vivo data. METHODS: MP-ASL was performed twice during resting state and once during the breath-holding task. First, the accuracy and noise immunity were evaluated in the first resting state. Second, CBF and CBVa values were statistically compared between the first resting state and the breath-holding task using the Wilcoxon signed-rank test and Cliff's delta. Finally, reproducibility of the two resting states was assessed. RESULTS: Simulation and first resting-state analyses demonstrated that DNNSup had higher accuracy, noise immunity, and a six-fold faster computation time than LUT. Furthermore, all methods detected task-induced CBF and CBVa elevations, with the effect size being larger with the DNNSup (CBF, p = 0.055, Δ = 0.286; CBVa, p = 0.008, Δ = 0.964) and DNNUns (CBF, p = 0.039, Δ = 0.286; CBVa, p = 0.008, Δ = 1.000) than that with LUT (CBF, p = 0.109, Δ = 0.214; CBVa, p = 0.008, Δ = 0.929). Moreover, all the methods exhibited comparable and satisfactory reproducibility. CONCLUSION: DNNSup outperforms DNNUns and LUT with respect to estimation performance and computation time.

High relative cerebral blood volume is associated with good long term clinical outcomes in acute ischemic stroke: a retrospective cohort study.

BACKGROUND: Endovascular therapy for acute ischemic stroke has been shown to be highly effective in selected patients. However, the ideal criteria for patient selection are still debated. It is well known that collateral flow is an important factor, but the assessment is often subjective and time-consuming. Relative cerebral blood volume (rCBV) is a putative indicator of collateral capacity and can be quickly and easily determined by automated quantitative analysis. We investigated the relationship between rCBV of the affected region and clinical outcome in patients with acute ischemic stroke after endovascular therapy. METHODS: We conducted a retrospective study on consecutive patients between January 2017 and May 2019. Patients with acute ischemic stroke of the anterior circulation who underwent imaging including computed tomography perfusion and were treated with mechanical thrombectomy (MT) were eligible for inclusion. rCBV was calculated automatically with RAPID software by dividing the average cerebral blood volume (CBV) of the affected region (time-to-maximum (Tmax) > 6 s) by the CBV of the unaffected contralateral side. The primary outcome was determined by the modified Rankin Scale (mRS) after 90 days. Good clinical outcome was defined as mRS ≤ 2. We compared means, performed mono- and multivariate logistical regression and calculated a receiver operating characteristic (ROC)-analysis to determine the ideal cutoff value to predict clinical outcomes. RESULTS: 155 patients were enrolled in this study. 66 patients (42.58%) had good clinical outcomes. Higher rCBV was associated with good clinical outcome (p < 0.001), even after adjustment for the patients' status according to mRS and National Institute of Health Stroke Scale (NIHSS) age and Alberta stroke program early computed tomography score (ASPECTS) at baseline (p = 0.006). ROC-analysis revealed 0.650 (confidence interval: 0.616-0.778) as the optimal cutoff value. CONCLUSION: Higher rCBV at baseline is associated with good clinical long-term outcomes in patients with acute ischemic stroke treated by MT. In this study we provide the biggest collective so far that gives evidence that rCBV can be a valuable tool to identify patients who might benefit from MT and are able give a threshold to help to offer patients MT in borderline cases.

Whole-brain 3D mapping of oxygen metabolism using constrained quantitative BOLD.

Quantitative BOLD (qBOLD) MRI permits noninvasive evaluation of hemodynamic and metabolic states of the brain by quantifying parametric maps of deoxygenated blood volume (DBV) and hemoglobin oxygen saturation level of venous blood (Yv), and along with a measurement of cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2). The method, thus should have potential to provide important information on many neurological disorders as well as normal cerebral physiology. One major challenge in qBOLD is to separate deoxyhemoglobin's contribution to R2' from other sources modulating the voxel signal, for instance, R2, R2' from non-heme iron (R'2,nh), and macroscopic magnetic field variations. Further, even with successful separation of the several confounders, it is still challenging to extract DBV and Yv from the heme-originated R2' because of limited sensitivity of the qBOLD model. These issues, which have not been fully addressed in currently practiced qBOLD methods, have so far precluded 3D whole-brain implementation of qBOLD. Thus, the purpose of this work was to develop a new 3D MRI oximetry technique that enables robust qBOLD parameter mapping across the entire brain. To achieve this goal, we employed a rapid, R2'-sensitive, steady-state 3D pulse sequence (termed 'AUSFIDE') for data acquisition, and implemented a prior-constrained qBOLD processing pipeline that exploits a plurality of preliminary parameters obtained via AUSFIDE, along with additionally measured cerebral venous blood volume. Numerical simulations and in vivo studies at 3 T were performed to evaluate the performance of the proposed, constrained qBOLD mapping in comparison to the parent qBOLD method. Measured parameters (Yv, DBV, R'2,nh, nonblood magnetic susceptibility) in ten healthy subjects demonstrate the expected contrast across brain territories, while yielding group-averages of 64.0 ± 2.3 % and 62.2 ± 3.1 % for Yv and 2.8 ± 0.5 % and 1.8 ± 0.4 % for DBV in cortical gray and white matter, respectively. Given the Yv measurements, additionally quantified CBF in seven of the ten study subjects enabled whole-brain 3D CMRO2 mapping, yielding group averages of 134.2 ± 21.1 and 79.4 ± 12.6 µmol/100 g/min for cortical gray and white matter, in good agreement with literature values. The results suggest feasibility of the proposed method as a practical and reliable means for measuring neurometabolic parameters over an extended brain coverage.

Validating layer-specific VASO across species.

Cerebral blood volume (CBV) has been shown to be a robust and important physiological parameter for quantitative interpretation of functional (f)MRI, capable of delivering highly localized mapping of neural activity. Indeed, with recent advances in ultra-high-field (≥7T) MRI hardware and associated sequence libraries, it has become possible to capture non-invasive CBV weighted fMRI signals across cortical layers. One of the most widely used approaches to achieve this (in humans) is through vascular-space-occupancy (VASO) fMRI. Unfortunately, the exact contrast mechanisms of layer-dependent VASO fMRI have not been validated for human fMRI and thus interpretation of such data is confounded. Here we validate the signal source of layer-dependent SS-SI VASO fMRI using multi-modal imaging in a rat model in response to neuronal activation (somatosensory cortex) and respiratory challenge (hypercapnia). In particular VASO derived CBV measures are directly compared to concurrent measures of total haemoglobin changes from high resolution intrinsic optical imaging spectroscopy (OIS). Quantified cortical layer profiling is demonstrated to be in agreement between VASO and contrast enhanced fMRI (using monocrystalline iron oxide nanoparticles, MION). Responses show high spatial localisation to layers of cortical processing independent of confounding large draining veins which can hamper BOLD fMRI studies, (depending on slice positioning). Thus, a cross species comparison is enabled using VASO as a common measure. We find increased VASO based CBV reactivity (3.1 ± 1.2 fold increase) in humans compared to rats. Together, our findings confirm that the VASO contrast is indeed a reliable estimate of layer-specific CBV changes. This validation study increases the neuronal interpretability of human layer-dependent VASO fMRI as an appropriate method in neuroscience application studies, in which the presence of large draining intracortical and pial veins limits neuroscientific inference with BOLD fMRI.

Integrated VASO and perfusion contrast: A new tool for laminar functional MRI.

Earlier research in cats has shown that both cerebral blood volume (CBV) and cerebral blood flow (CBF) can be used to identify layer-dependent fMRI activation with spatial specificity superior to gradient-echo blood-oxygen-level-dependent (BOLD) contrast (Jin and Kim, 2008a). CBF contrast of perfusion fMRI at ultra-high field has not been widely applied in humans to measure laminar activity due to its low sensitivity, while CBV contrast for fMRI using vascular space occupancy (VASO) has been successfully used. However, VASO can be compromised by interference of blood in-flow effects and a temporally limited acquisition window around the blood-nulling time point. Here, we proposed to use DANTE (Delay Alternating with Nutation for Tailored Excitation) pulse trains combined with 3D-EPI to acquire an integrated VASO and perfusion (VAPER) contrast. The signal origin of the VAPER contrast was theoretically evaluated with respect to its CBV and CBF contributions using a four-compartment simulation model. The feasibility of VAPER to measure layer-dependent activity was empirically investigated in human primary motor cortex at 7 â€‹T. We demonstrated this new tool, with its highly specified functional layer profile, robust reproducibility, and improved sensitivity, to allow investigation of layer-specific cortical functions.

Oxygen extraction fraction mapping with multi-parametric quantitative BOLD MRI: Reduced transverse relaxation bias using 3D-GraSE imaging.

Magnetic resonance imaging (MRI)-based quantification of the blood-oxygenation-level-dependent (BOLD) effect allows oxygen extraction fraction (OEF) mapping. The multi-parametric quantitative BOLD (mq-BOLD) technique facilitates relative OEF (rOEF) measurements with whole brain coverage in clinically applicable scan times. Mq-BOLD requires three separate scans of cerebral blood volume and transverse relaxation rates measured by gradient-echo (1/T2∗) and spin-echo (1/T2). Although the current method is of clinical merit in patients with stroke, glioma and internal carotid artery stenosis (ICAS), there are relaxation measurement artefacts that impede the sensitivity of mq-BOLD and artificially elevate reported rOEF values. We posited that T2-related biases caused by slice refocusing imperfections during rapid 2D-GraSE (Gradient and Spin Echo) imaging can be reduced by applying 3D-GraSE imaging sequences, because the latter requires no slice selective pulses. The removal of T2-related biases would decrease overestimated rOEF values measured by mq-BOLD. We characterized effects of T2-related bias in mq-BOLD by comparing the initially employed 2D-GraSE and two proposed 3D-GraSE sequences to multiple single spin-echo reference measurements, both in vitro and in vivo. A phantom and 25 participants, including young and elderly healthy controls as well as ICAS-patients, were scanned. We additionally proposed a procedure to reliably identify and exclude artefact affected voxels. In the phantom, 3D-GraSE derived T2 values had 57% lower deviation from the reference. For in vivo scans, the formerly overestimated rOEF was reduced by -27% (p â€‹< â€‹0.001). We obtained rOEF â€‹= â€‹0.51, which is much closer to literature values from positron emission tomography (PET) measurements. Furthermore, increased sensitivity to a focal rOEF elevation in an ICAS-patient was demonstrated. In summary, the application of 3D-GraSE improves the mq-BOLD-based rOEF quantification while maintaining clinically feasible scan times. Thus, mq-BOLD with non-slice selective T2 imaging is highly promising to improve clinical diagnostics of cerebrovascular diseases such as ICAS.

Association between perihematomal cerebral blood volume and intracerebral hemorrhage expansion: A computed tomography perfusion study.

We investigated whether computed tomography (CT) perfusion can identify intracerebral hemorrhage patients at high risk of hematoma growth (HG). A total of 155 subjects underwent CT perfusion on admission. Variables associated with log-transformed absolute HG were explored with multivariable linear regression. Perihematomal cerebral blood volume (CBV) was inversely associated with HG (B = -0.20; p < 0.001), independently from blood pressure, hematoma volume, and other confounders. This association was not dose dependent, and only very low CBV (<1.4 ml/100 g) was significantly associated with HG (B = 0.25; p < 0.001). In conclusion, reduced perihematomal CBV is associated with HG, suggesting a potential role of the perihematomal region in the pathophysiology of hematoma enlargement. ANN NEUROL 2019;85:943-947.

Vascular habitat analysis based on dynamic susceptibility contrast perfusion MRI predicts IDH mutation status and prognosis in high-grade gliomas.

OBJECTIVE: The current study aimed to evaluate the clinical practice for hemodynamic tissue signature (HTS) method in IDH genotype prediction in three groups derived from high-grade gliomas. METHODS: Preoperative MRI examinations of 44 patients with known grade and IDH genotype were assigned into three study groups: glioblastoma multiforme, grade III, and high-grade gliomas. Perfusion parameters were analyzed and were used to automatically draw the four reproducible habitats (high-angiogenic enhancing tumor habitats, low-angiogenic enhancing tumor habitats, infiltrated peripheral edema habitats, vasogenic peripheral edema habitats) related to vascular heterogeneity. These four habitats were then compared between inter-patient with IDH mutation and their wild-type counterparts at these three groups, respectively. The discriminating potential for HTS in assessing IDH mutation status prediction was assessed by ROC curves. RESULTS: Compared with IDH wild type, IDH mutation had significantly decreased relative cerebral blood volume (rCBV) at the high-angiogenic enhancing tumor habitats and low-angiogenic enhancing tumor habitats. ROC analysis revealed that the rCBVs in habitats had great ability to discriminate IDH mutation from their wild type in all groups. In addition, the Kaplan-Meier survival analysis yielded significant differences for the survival times observed from the populations dichotomized by low (< 4.31) and high (> 4.31) rCBV in the low-angiogenic enhancing tumor habitat. CONCLUSIONS: The HTS method has been proven to have high prediction capabilities for IDH mutation status in high-grade glioma patients, providing a set of quantifiable habitats associated with tumor vascular heterogeneity. KEY POINTS: • The HTS method has a high accuracy for molecular stratification prediction for all subsets of HGG. • The HTS method can give IDH mutation-related hemodynamic information of tumor-infiltrated and vasogenic edema. • IDH-relevant rCBV difference in habitats will be a great prognosis factor in HGG.

Non-BOLD contrast for laminar fMRI in humans: CBF, CBV, and CMRO2.

Functional magnetic resonance imaging (fMRI) using the blood oxygenation level-dependent (BOLD) contrast indirectly probes neuronal activity changes via evoked cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMRO2) changes. The gradient-echo BOLD signal is mostly sensitive to ascending veins in the tissue and to pial veins. Thereby, the achievable spatial specificity to neuronal activation is limited. Furthermore, the non-linear interaction of CBF, CBV and CMRO2 can hamper quantitative interpretations of the BOLD signal across cortical depths with different baseline physiology. Measuring CBF, CBV or CMRO2 directly on a depth-dependent level has the potential to overcome these limitations. Here, we review these candidates of physiologically well-defined contrasts with the particular focus on arterial spin labeling (ASL), vascular space occupancy (VASO) and calibrated fMRI. These methods are reviewed with respect to their fMRI sequence parameter space and the applicability for neuroscientific studies in humans. We show representative results of depth-dependent 'non-BOLD-fMRI' in humans and their spatiotemporal characteristics. We conclude that non-BOLD methods are promising alternatives compared to conventional fMRI as they can provide improved spatial specificity, quantifiability and, hence, physiological interpretability as a function of cortical depth. At submillimeter resolution with inherently low signal-to-noise ratio (SNR), however, their use is still challenging. Nevertheless, we believe that 'non-BOLD-fMRI' is a useful alternative for depth-dependent investigations, by providing valuable insights into neurovascular coupling models that facilitate the interpretability of fMRI for neuroscientific applications.

Cerebral blood volume changes during the BOLD post-stimulus undershoot measured with a combined normoxia/hyperoxia method.

Cerebral blood flow (CBF) and blood oxygenation level dependent (BOLD) signal measurements make it possible to estimate steady-state changes in the cerebral metabolic rate of oxygen (CMRO2) with a calibrated BOLD method. However, extending this approach to measure the dynamics of CMRO2 requires an additional assumption: that deoxygenated cerebral blood volume (CBVdHb) follows CBF in a predictable way. A test-case for this assumption is the BOLD post-stimulus undershoot, for which one proposed explanation is a strong uncoupling of flow and blood volume with an elevated level of CBVdHb during the post-stimulus period compared to baseline due to slow blood volume recovery (Balloon Model). A challenge in testing this model is that CBVdHb differs from total blood volume, which can be measured with other techniques. In this study, the basic hypothesis of elevated CBVdHb during the undershoot was tested, based on the idea that the BOLD signal change when a subject switches from breathing a normoxic gas to breathing a hyperoxic gas is proportional to the absolute CBVdHb. In 19 subjects (8F), dual-echo BOLD responses were measured in primary visual cortex during a flickering radial checkerboard stimulus in normoxia, and the identical experiment was repeated in hyperoxia (50% O2/balance N2). The BOLD signal differences between normoxia and hyperoxia for the pre-stimulus baseline, stimulus, and post-stimulus periods were compared using an equivalent BOLD signal calculated from measured R2* changes to eliminate signal drifts. Relative to the pre-stimulus baseline, the average BOLD signal change from normoxia to hyperoxia was negative during the undershoot period (p = 0.0251), consistent with a reduction of CBVdHb and contrary to the prediction of the Balloon Model. Based on these results, the BOLD post-stimulus undershoot does not represent a case of strong uncoupling of CBVdHb and CBF, supporting the extension of current calibrated BOLD methods to estimate the dynamics of CMRO2.

Cerebral blood volume mapping using Fourier-transform-based velocity-selective saturation pulse trains.

PURPOSE: Velocity-selective saturation (VSS) pulse trains provide a viable alternative to the spatially selective methods for measuring cerebral blood volume (CBV) by reducing the sensitivity to arterial transit time. This study is to compare the Fourier-transform-based velocity-selective saturation (FT-VSS) pulse trains with the conventional flow-dephasing VSS techniques for CBV quantification. METHODS: The proposed FT-VSS label and control modules were compared with VSS pulse trains utilizing double refocused hyperbolic tangent (DRHT) and 8-segment B1-insensitive rotation (BIR-8). This was done using both numerical simulations and phantom studies to evaluate their sensitivities to gradient imperfections such as eddy currents. DRHT, BIR-8, and FT-VSS prepared CBV mapping was further compared for velocity-encoding gradients along 3 orthogonal directions in healthy subjects at 3T. RESULTS: The phantom studies exhibited more consistent immunity to gradient imperfections for the utilized FT-VSS pulse trains. Compared to DRHT and BIR-8, FT-VSS delivered more robust CBV results across the 3 VS encoding directions with significantly reduced artifacts along the superior-inferior direction and improved temporal signal-to-noise ratio (SNR) values. Average CBV values obtained from FT-VSS based sequences were 5.3 mL/100 g for gray matter and 2.3 mL/100 g for white matter, comparable to literature expectations. CONCLUSION: Absolute CBV quantification utilizing advanced FT-VSS pulse trains had several advantages over the existing approaches using flow-dephasing VSS modules. A greater immunity to gradient imperfections and the concurrent tissue background suppression of FT-VSS pulse trains enabled more robust CBV measurements and higher SNR than the conventional VSS pulse trains.

Measurement of microvascular cerebral blood volume changes over the cardiac cycle with ferumoxytol-enhanced T2* MRI.

PURPOSE: This feasibility study investigates the non-invasive measurement of microvascular cerebral blood volume (BV) changes over the cardiac cycle using cardiac-gated, ferumoxytol-enhanced T2∗ MRI. METHODS: Institutional review board approval was obtained and all subjects provided written informed consent. Cardiac gated MR scans were prospectively acquired on a 3.0T scanner in 22 healthy subjects using T2∗ -weighted sequences with 2D-EPI and 3D spiral trajectories. Images were collected before and after the intravenous administration of 2 doses of ferumoxytol (1 mg FE/kg and 4 mg FE/kg). Cardiac cycle-induced R2∗ (1/ T2∗ ) changes (Δ R2∗ ) and BV changes (ΔBV) throughout the cardiac cycle in gray matter (GM) and white matter (WM) were quantified and differences assessed using ANOVA followed by post hoc analysis. RESULTS: Δ R2∗ was found to increase in a dose-dependent fashion. A significantly larger increase was observed in GM compared to WM in both 2D and 3D acquisitions (P < 0.050). In addition, Δ R2∗ increased significantly (P < 0.001) post versus pre-contrast injection in GM in both T2∗ MRI acquisitions. Mean GM Δ R2∗ derived from 2D-EPI images was 0.14 ± 0.06 s-1 pre-contrast and 0.33 ± 0.13 s-1 after 5 mg FE/kg. In WM, Δ R2∗ was 0.19 ± 0.06 s-1 pre-contrast, and 0.23 ± 0.06 s-1 after 5 mg FE/kg. The fractional changes in BV throughout the cardiac cycle were 0.031 ± 0.019% in GM and 0.011 ± 0.008% in WM (P < 0.001) after 5 mg FE/kg. CONCLUSION: Cardiac-gated, ferumoxytol-enhanced T2∗ MRI enables characterization of microvascular BV changes throughout the cardiac cycle in GM and WM tissue of healthy subjects.

Coupling between cerebral blood flow and cerebral blood volume: Contributions of different vascular compartments.

A better understanding of the coupling between changes in cerebral blood flow (CBF) and cerebral blood volume (CBV) is vital for furthering our understanding of the BOLD response. The aim of this study was to measure CBF-CBV coupling in different vascular compartments during neural activation. Three haemodynamic parameters were measured during a visual stimulus. Look-Locker flow-sensitive alternating inversion recovery was used to measure changes in CBF and arterial CBV (CBVa ) using sequence parameters optimized for each contrast. Changes in total CBV (CBVtot ) were measured using a gadolinium-based contrast agent technique. Haemodynamic changes were extracted from a region of interest based on voxels that were activated in the CBF experiments. The CBF-CBVtot coupling constant αtot was measured as 0.16 ± 0.14 and the CBF-CBVa coupling constant αa was measured as 0.65 ± 0.24. Using a two-compartment model of the vasculature (arterial and venous), the change in venous CBV (CBVv ) was predicted for an assumed value of baseline arterial and venous blood volume. These results will enhance the accuracy and reliability of applications that rely on models of the BOLD response, such as calibrated BOLD.

Permeability measurement using dynamic susceptibility contrast magnetic resonance imaging enhances differential diagnosis of primary central nervous system lymphoma from glioblastoma.

OBJECTIVES: To test if adding permeability measurement to perfusion obtained from dynamic susceptibility contrast MRI (DSC-MRI) improves diagnostic performance in the differentiation of primary central nervous system lymphoma (PCNSL) from glioblastoma. MATERIALS AND METHODS: DSC-MRI was acquired in 145 patients with pathologically proven glioblastoma (n = 89) or PCNSL (n = 56). The permeability metrics of contrast agent extraction fraction (Ex), apparent permeability (Ka), and leakage-corrected perfusion of normalized cerebral blood volume (nCBVres) and cerebral blood flow (nCBFres) were derived from a tissue residue function. For comparison purposes, the leakage-corrected normalized CBV (nCBV) and relative permeability constant (K2) were also obtained using the established Weisskoff-Boxerman leakage correction method. The area under the receiver operating characteristics curve (AUC) and cross-validation were used to compare the diagnostic performance of the single DSC-MRI parameters with the performance obtained with the addition of permeability metrics. RESULTS: PCNSL demonstrated significantly higher permeability (Ex, p < .001) and lower perfusion (nCBVres, nCBFres, and nCBV, all p < .001) than glioblastoma. The combination of Ex and nCBVres showed the highest performance (AUC, 0.96; 95% confidence interval, 0.92-0.99) for differentiating PCNSL from glioblastoma, which was a significant improvement over the single perfusion (nCBV: AUC, 0.84; nCBVres: AUC, 0.84; nCBFres: AUC, 0.82; all p < .001) or Ex (AUC, 0.80; p < .001) parameters. CONCLUSIONS: Analysis of the combined permeability and perfusion metrics obtained from a single DSC-MRI acquisition improves the diagnostic value for differentiating PCNSL from glioblastoma in comparison with single-parameter nCBV analysis. KEY POINTS: • Permeability measurement can be calculated from DSC-MRI with a tissue residue function-based leakage correction. • Adding Exto CBV aids in the differentiation of PCNSL from glioblastoma. • CBV and Exmeasurements from DSC-MRI were highly reproducible.

Non-invasive Cerebrovascular Autoregulation Assessment Using the Volumetric Reactivity Index: Prospective Study.

BACKGROUND: This prospective study of an innovative non-invasive ultrasonic cerebrovascular autoregulation (CA) monitoring method is based on real-time measurements of intracranial blood volume (IBV) reactions following changes in arterial blood pressure. In this study, we aimed to determine the clinical applicability of a non-invasive CA monitoring method by performing a prospective comparative clinical study of simultaneous invasive and non-invasive CA monitoring on intensive care patients. METHODS: CA was monitored in 61 patients with severe traumatic brain injuries invasively by calculating the pressure reactivity index (PRx) and non-invasively by calculating the volumetric reactivity index (VRx) simultaneously. The PRx was calculated as a moving correlation coefficient between intracranial pressure and arterial blood pressure slow waves. The VRx was calculated as a moving correlation coefficient between arterial blood pressure and non-invasively-measured IBV slow waves. RESULTS: A linear regression between VRx and PRx averaged per patients' monitoring session showed a significant correlation (r = 0.843, p < 0.001; 95% confidence interval 0.751 - 0.903). The standard deviation of the difference between VRx and PRx was 0.192; bias was - 0.065. CONCLUSIONS: This prospective clinical study of the non-invasive ultrasonic volumetric reactivity index VRx monitoring, based on ultrasonic time-of-flight measurements of IBV dynamics, showed significant coincidence of non-invasive VRx index with invasive PRx index. The ultrasonic time-of-flight method reflects blood volume changes inside the acoustic path, which crosses both hemispheres of the brain. This method does not reflect locally and invasively-recorded intracranial pressure slow waves, but the autoregulatory reactions of both hemispheres of the brain. Therefore, VRx can be used as a non-invasive cerebrovascular autoregulation index in the same way as PRx and can also provide information about the CA status encompassing all intracranial hemodynamics.

Estimation of Ischemic Core Volume Using Computed Tomographic Perfusion.

Background and Purpose- Estimation of infarction based on computed tomographic perfusion (CTP) has been challenging, mainly because of noise associated with CTP data. The Bayesian method is a robust probabilistic method that minimizes effects of oscillation, tracer delay, and noise during residue function estimation compared with other deconvolution methods. This study compares CTP-estimated ischemic core volume calculated by the Bayesian method and by the commonly used block-circulant singular value deconvolution technique. Methods- Patients were included if they had (1) anterior circulation ischemic stroke, (2) baseline CTP, (3) successful recanalization defined by thrombolysis in cerebral infarction ≥IIb, and (4) minimum infarction volume of >5 mL on follow-up magnetic resonance imaging (MRI). CTP data were processed with circulant singular value deconvolution and Bayesian methods. Two established CTP methods for estimation of ischemic core volume were applied: cerebral blood flow (CBF) method (relative CBF, <30% within the region of delay >2 seconds) and cerebral blood volume method (<2 mL per 100 g within the region of relative mean transit time >145%). Final infarct volume was determined on MRI (fluid-attenuated inversion recovery images). CTP and MRI-derived ischemic core volumes were compared by univariate and Bland-Altman analysis. Results- Among 35 patients included, the mean/median (mL) difference for CTP-estimated ischemic core volume against MRI was -4/-7 for Bayesian CBF ( P=0.770), 20/12 for Bayesian cerebral blood volume ( P=0.041), 21/10 for circulant singular value deconvolution CBF ( P=0.006), and 35/18 for circulant singular value deconvolution cerebral blood volume ( P<0.001). Among all methods, Bayesian CBF provided the narrowest limits of agreement (-28 to 19 mL) in comparison with MRI. Conclusions- Despite existing variabilities between CTP postprocessing methods, Bayesian postprocessing increases accuracy and limits variability in CTP estimation of ischemic core.

Ultra-high resolution blood volume fMRI and BOLD fMRI in humans at 9.4 T: Capabilities and challenges.

Functional mapping of cerebral blood volume (CBV) changes has the potential to reveal brain activity with high localization specificity at the level of cortical layers and columns. Non-invasive CBV imaging using Vascular Space Occupancy (VASO) at ultra-high magnetic field strengths promises high spatial specificity but poses unique challenges in human applications. As such, 9.4 T B1+ and B0 inhomogeneities limit efficient blood tagging, while the specific absorption rate (SAR) constraints limit the application of VASO-specific RF pulses. Moreover, short T2* values at 9.4 T require short readout duration, and long T1 values at 9.4 T can cause blood-inflow contaminations. In this study, we investigated the applicability of layer-dependent CBV-fMRI at 9.4 T in humans. We addressed the aforementioned challenges by combining multiple technical advancements: temporally alternating pTx B1+ shimming parameters, advanced adiabatic RF-pulses, 3D-EPI signal readout, optimized GRAPPA acquisition and reconstruction, and stability-optimized RF channel combination. We found that a combination of suitable advanced methodology alleviates the challenges and potential artifacts, and that VASO fMRI provides reliable measures of CBV change across cortical layers in humans at 9.4 T. The localization specificity of CBV-fMRI, combined with the high sensitivity of 9.4 T, makes this method an important tool for future studies investigating cortical micro-circuitry in humans.

Linking brain vascular physiology to hemodynamic response in ultra-high field MRI.

Functional MRI using blood oxygenation level-dependent (BOLD) contrast indirectly probes neuronal activity via evoked cerebral blood volume (CBV) and oxygenation changes. Thus, its spatio-temporal characteristics are determined by vascular physiology and MRI parameters. In this paper, we focus on the spatial distribution and time course of the fMRI signal and their magnetic field strength dependence. Even though much is still unknown, the following consistent picture is emerging: a) For high spatial resolution imaging, fMRI contrast-to-noise increases supra-linearly with field strength. b) The location and spacing of penetrating arteries and ascending veins in the cortical tissue are not correlated to cortical columns, imposing limitations on achievable point-spread function (PSF) in fMRI. c) Baseline CBV distribution may vary over cortical layers biasing fMRI signal to layers with high CBV values. d) The largest CBV change is in the tissue microvasculature, less in surface arteries and even less in pial veins. e) Venous CBV changes are only relevant for longer stimuli, and oxygenation changes are largest in post-capillary blood vessels. f) The balloon effect (i.e. slow recovery of CBV to baseline) is located in the tissue, consistent with the fact that the post-stimulus undershoot has narrower spatial PSF than the positive BOLD response. g) The onset time following stimulation has been found to be shortest in middle/lower layers, both in optical imaging and high-resolution fMRI, but we argue and demonstrate with simulations that varying signal latencies can also be caused by vascular properties and, therefore, may potentially not be interpreted as neural latencies. With simulations, we illustrate the field strength dependency of fMRI signal transients, such as the adaptation during stimulation, initial dip and the post-stimulus undershoot. In sum, vascular structure and function impose limitations on the achievable PSF of fMRI and give rise to complex fMRI transients, which contain time-varying amount of excitatory and inhibitory neuronal information. Nevertheless, non-invasive fMRI at ultra-high magnetic fields not only provides high contrast-to-noise but also an unprecedented detailed view on cognitive processes in the human brain.

Impulse response timing differences in BOLD and CBV weighted fMRI.

Recent advances in BOLD fMRI scan techniques have substantially improved spatial and temporal resolution, currently reaching to sub-millimeter and sub-second levels respectively. Unfortunately, there remain physiological barriers that prevent achieving this resolution in practice. BOLD contrast relies on the hemodynamic response to neuronal activity, whose associated cerebral blood oxygenation (CBO) changes may spread over several millimeters and last several seconds. Recent reports have suggested that significant improvements may be possible with cerebral blood volume (CBV)-weighted fMRI, which highlights the CBV changes rather than the BOLD changes associated with the hemodynamic response. Nevertheless, quantitative comparisons between CBV and BOLD are sparse, in particular regarding their temporal characteristics in human brain. To address this, we studied a cohort of subjects that received injection of ferumoxytol, an intravascular iron-oxide based contrast agent that introduces strong CBV contrast. An event-related visual stimulus paradigm was used to compare the impulse response (IR) for CBV and BOLD contrast, obtained with and without ferumoxytol, respectively. Experiments performed at 7 T (n = 5) at 1.2-1.5 mm spatial and 1 s temporal resolution showed that the onset time and time-to-peak of the CBV IR averaged 0.8 and 3.5 s respectively, both 0.6 s shorter than the BOLD IR. While significant, these improvements are relatively small and not expected to lead to practical advantages for the extraction of temporal information about neural activity. Nonlinearities in the observed IR were also compared and found to be similar between the CBV and BOLD, indicating that these are likely not caused by a 'ceiling' effect in the CBO response, but rather support a previously proposed model of vascular compliance, in which changes in vascular tone elicited by a preceding stimulus affect the IR.