Transient deoxyhemoglobin formation as a contrast for perfusion MRI studies in patients with brain tumors: a feasibility study.

Background: Transient hypoxia-induced deoxyhemoglobin (dOHb) has recently been shown to represent a comparable contrast to gadolinium-based contrast agents for generating resting perfusion measures in healthy subjects. Here, we investigate the feasibility of translating this non-invasive approach to patients with brain tumors. Methods: A computer-controlled gas blender was used to induce transient precise isocapnic lung hypoxia and thereby transient arterial dOHb during echo-planar-imaging acquisition in a cohort of patients with different types of brain tumors (n = 9). We calculated relative cerebral blood volume (rCBV), cerebral blood flow (rCBF), and mean transit time (MTT) using a standard model-based analysis. The transient hypoxia induced-dOHb MRI perfusion maps were compared to available clinical DSC-MRI. Results: Transient hypoxia induced-dOHb based maps of resting perfusion displayed perfusion patterns consistent with underlying tumor histology and showed high spatial coherence to gadolinium-based DSC MR perfusion maps. Conclusion: Non-invasive transient hypoxia induced-dOHb was well-tolerated in patients with different types of brain tumors, and the generated rCBV, rCBF and MTT maps appear in good agreement with perfusion maps generated with gadolinium-based DSC MR perfusion.

Assessment of Cerebrovascular Reactivity Using CO2 -BOLD MRI: A 15-Year, Single Center Experience.

BACKGROUND: Cerebrovascular reactivity (CVR) is a measure of the change in cerebral blood flow (CBF) in response to a vasoactive challenge. It is a useful indicator of the brain's vascular health. PURPOSE: To evaluate the factors that influence successful and unsuccessful CVR examinations using precise arterial and end-tidal partial pressure of CO2 control during blood oxygen level-dependent (BOLD) MRI. STUDY TYPE: Retrospective. SUBJECTS: Patients that underwent a CVR between October 2005 and May 2021 were studied (total of 1162 CVR examinations). The mean (±SD) age was 46.1 (±18.8) years, and 352 patients (43%) were female. FIELD STRENGTH/SEQUENCE: 3 T; T1-weighted images, T2*-weighed two-dimensional gradient-echo sequence with standard echo-planar readout. ASSESSMENT: Measurements were obtained following precise hypercapnic stimuli using BOLD MRI as a surrogate of CBF. Successful CVR examinations were defined as those where: 1) patients were able to complete CVR testing, and 2) a clinically useful CVR map was generated. Unsuccessful examinations were defined as those where patients were not able to complete the CVR examination or the CVR maps were judged to be unreliable due to, for example, excessive head motion, and poor PET CO2 targeting. STATISTICAL ANALYSIS: Successful and unsuccessful CVR examinations between hypercapnic stimuli, and between different patterns of stimulus were compared with Chi-Square tests. Interobserver variability was determined by using the intraclass correlation coefficient (P < 0.05 is significant). RESULTS: In total 1115 CVR tests in 662 patients were included in the final analysis. The success rate of generating CVR maps was 90.8% (1012 of 1115). Among the different hypercapnic stimuli, those containing a step plus a ramp protocol was the most successful (95.18%). Among the unsuccessful examinations (9.23%), most were patient related (89.3%), the most common of which was difficulty breathing. DATA CONCLUSION: CO2 -BOLD MRI CVR studies are well tolerated with a high success rate. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 3.

Convolutional Neural Networks to Assess Steno-Occlusive Disease Using Cerebrovascular Reactivity.

Cerebrovascular Reactivity (CVR) is a provocative test used with Blood oxygenation level-dependent (BOLD) Magnetic Resonance Imaging (MRI) studies, where a vasoactive stimulus is applied and the corresponding changes in the cerebral blood flow (CBF) are measured. The most common clinical application is the assessment of cerebral perfusion insufficiency in patients with steno-occlusive disease (SOD). Globally, millions of people suffer from cerebrovascular diseases, and SOD is the most common cause of ischemic stroke. Therefore, CVR analyses can play a vital role in early diagnosis and guiding clinical treatment. This study develops a convolutional neural network (CNN)-based clinical decision support system to facilitate the screening of SOD patients by discriminating between healthy and unhealthy CVR maps. The networks were trained on a confidential CVR dataset with two classes: 68 healthy control subjects, and 163 SOD patients. This original dataset was distributed in a ratio of 80%-10%-10% for training, validation, and testing, respectively, and image augmentations were applied to the training and validation sets. Additionally, some popular pre-trained networks were imported and customized for the objective classification task to conduct transfer learning experiments. Results indicate that a customized CNN with a double-stacked convolution layer architecture produces the best results, consistent with expert clinical readings.

Determining the effects of elevated partial pressure of oxygen on hypercapnia-induced cerebrovascular reactivity.

Evaluation of cerebrovascular reactivity (CVR) to hypo- and hypercapnia is a valuable test for the assessment of vasodilatory reserve. While hypercapnia-induced CVR testing is usually performed at normoxia, mild hyperoxia may increase tolerability of hypercapnia by reducing the ventilatory distress. However, the effects of mild hyperoxia on CVR was unknown. We therefore recruited 21 patients with a range of steno-occlusive diseases and 12 healthy participants who underwent a standardized 13-minute step plus ramp CVR test with a carbon dioxide gas challenge at the subject's resting end-tidal partial pressure of oxygen or at mild hyperoxia (PetO2 = 150 mmHg) depending on to which group they were assigned. In 11 patients, the second CVR test was at normoxia to examine test-retest differences. CVR was defined as % Δ Signal/ΔPetCO2. We found that there was no significant difference between CVR test results conducted at normoxia and at mild hyperoxia for participants in Groups 1 and 2 for the step and ramp portion. We also found no difference between test and retest CVR at normoxia for patients with cerebrovascular pathology (Group 3) for step and ramp portion. We concluded normoxic CVR is repeatable, and that mild hyperoxia does not affect CVR.

DSC MRI in the human brain using deoxyhemoglobin and gadolinium-Simulations and validations at 3T.

Introduction: Dynamic susceptibility contrast (DSC) MRI allows clinicians to determine perfusion parameters in the brain, such as cerebral blood flow, cerebral blood volume, and mean transit time. To enable quantification, susceptibility changes can be induced using gadolinium (Gd) or deoxyhemoglobin (dOHb), the latter just recently introduced as a contrast agent in DSC. Previous investigations found that experimental parameters and analysis choices, such as the susceptibility amplitude and partial volume, affect perfusion quantification. However, the accuracy and precision of DSC MRI has not been systematically investigated, particularly in the lower susceptibility range. Methods: In this study, we compared perfusion values determined using Gd with values determined using a contrast agent with a lower susceptibility-dOHb-under different physiological conditions, such as varying the baseline blood oxygenation and/or magnitude of hypoxic bolus, by utilizing numerical simulations and conducting experiments on healthy subjects at 3T. The simulation framework we developed for DSC incorporates MRI signal contributions from intravascular and extravascular proton spins in arterial, venous, and cerebral tissue voxels. This framework allowed us to model the MRI signal in response to both Gd and dOHb. Results and discussion: We found, both in the experimental results and simulations, that a reduced intravascular volume of the selected arterial voxel, reduced baseline oxygen saturation, greater susceptibility of applied contrast agent (Gd vs. dOHb), and/or larger magnitude of applied hypoxic bolus reduces the overestimation and increases precision of cerebral blood volume and flow. As well, we found that normalizing tissue to venous rather than arterial signal increases the accuracy of perfusion quantification across experimental paradigms. Furthermore, we found that shortening the bolus duration increases the accuracy and reduces the calculated values of mean transit time. In summary, we experimentally uncovered an array of perfusion quantification dependencies, which agreed with the simulation framework predictions, using a wider range of susceptibility values than previously investigated. We argue for caution when comparing absolute and relative perfusion values within and across subjects obtained from a standard DSC MRI analysis, particularly when employing different experimental paradigms and contrast agents.

Transfer function analysis assesses resting cerebral perfusion metrics using hypoxia-induced deoxyhemoglobin as a contrast agent.

Introduction: Use of contrast in determining hemodynamic measures requires the deconvolution of an arterial input function (AIF) selected over a voxel in the middle cerebral artery to calculate voxel wise perfusion metrics. Transfer function analysis (TFA) offers an alternative analytic approach that does not require identifying an AIF. We hypothesised that TFA metrics Gain, Lag, and their ratio, Gain/Lag, correspond to conventional AIF resting perfusion metrics relative cerebral blood volume (rCBV), mean transit time (MTT) and relative cerebral blood flow (rCBF), respectively. Methods: 24 healthy participants (17 M) and 1 patient with steno-occlusive disease were recruited. We used non-invasive transient hypoxia-induced deoxyhemoglobin as an MRI contrast. TFA and conventional AIF analyses were used to calculate averages of whole brain and smaller regions of interest. Results: Maps of these average metrics had colour scales adjusted to enhance contrast and identify areas of high congruence. Regional gray matter/white matter (GM/WM) ratios for MTT and Lag, rCBF and Gain/Lag, and rCBV and Gain were compared. The GM/WM ratios were greater for TFA metrics compared to those from AIF analysis indicating an improved regional discrimination. Discussion: Resting perfusion measures generated by The BOLD analysis resulting from a transient hypoxia induced variations in deoxyhemoglobin analyzed by TFA are congruent with those analyzed by conventional AIF analysis.

Investigations of hypoxia-induced deoxyhemoglobin as a contrast agent for cerebral perfusion imaging.

The assessment of resting perfusion measures (mean transit time, cerebral blood flow, and cerebral blood volume) with magnetic resonance imaging currently requires the presence of a susceptibility contrast agent such as gadolinium. Here, we present an initial comparison between perfusion measures obtained using hypoxia-induced deoxyhemoglobin and gadolinium in healthy study participants. We hypothesize that resting cerebral perfusion measures obtained using precise changes of deoxyhemoglobin concentration will generate images comparable to those obtained using a clinical standard, gadolinium. Eight healthy study participants were recruited (6F; age 23-60). The study was performed using a 3-Tesla scanner with an eight-channel head coil. The experimental protocol consisted of a high-resolution T1-weighted scan followed by two BOLD sequence scans in which each participant underwent a controlled bolus of transient pulmonary hypoxia, and subsequently received an intravenous bolus of gadolinium. The resting perfusion measures calculated using hypoxia-induced deoxyhemoglobin and gadolinium yielded maps that looked spatially comparable. There was no statistical difference between methods in the average voxel-wise measures of mean transit time, relative cerebral blood flow and relative cerebral blood volume, in the gray matter or white matter within each participant. We conclude that perfusion measures generated with hypoxia-induced deoxyhemoglobin are spatially and quantitatively comparable to those generated from a gadolinium injection in the same healthy participant.

The Choroid Plexus as an Alternative Locus for the Identification of the Arterial Input Function for Calculating Cerebral Perfusion Metrics Using MRI.

BACKGROUND AND PURPOSE: MR imaging-based cerebral perfusion metrics can be obtained by tracing the passage of a bolus of contrast through the microvasculature of the brain parenchyma. Thus, the temporal signal pattern of the contrast agent is typically measured over a large artery such as the MCA to generate the arterial input function. The largest intracranial arteries in the brain may not always be suitable for selecting the arterial input function due to skull base susceptibility artifacts or reduced size from steno-occlusive disease. Therefore, a suitable alternative arterial input function window would be useful. The choroid plexus is a highly vascular tissue composed essentially of arterialized blood vessels and acellular stroma with low metabolic requirements relative to its blood flow and may be a suitable alternative to identify the arterial input function. MATERIALS AND METHODS: We studied 8 healthy participants and 7 patients with gliomas who were administered a bolus of gadolinium. We selected an arterial input function from both the left and right M1 segments of the MCA and both lateral ventricles of the choroid plexus for each participant. We compared the changes in the T2* signal and the calculated resting perfusion metrics using the arterial input functions selected from the MCA and choroid plexus. RESULTS: We found no systematic difference between resting perfusion metrics in GM and WM when calculated using an arterial input function from the MCA or choroid plexus in the same participant. CONCLUSIONS: The choroid plexus provides an alternative location from which an arterial input function may be sampled when a suitable measure over an MCA is not available.

Assessing Perfusion in Steno-Occlusive Cerebrovascular Disease Using Transient Hypoxia-Induced Deoxyhemoglobin as a Dynamic Susceptibility Contrast Agent.

BACKGROUND AND PURPOSE: Resting brain tissue perfusion in cerebral steno-occlusive vascular disease can be assessed by MR imaging using gadolinium-based susceptibility contrast agents. Recently, transient hypoxia-induced deoxyhemoglobin has been investigated as a noninvasive MR imaging contrast agent. Here we present a comparison of resting perfusion metrics using transient hypoxia-induced deoxyhemoglobin and gadolinium-based contrast agents in patients with known cerebrovascular steno-occlusive disease. MATERIALS AND METHODS: Twelve patients with steno-occlusive disease underwent DSC MR imaging using a standard bolus of gadolinium-based contrast agent compared with transient hypoxia-induced deoxyhemoglobin generated in the lungs using an automated gas blender. A conventional multi-slice 2D gradient echo sequence was used to acquire the perfusion data and analyzed using a standard tracer kinetic model. MTT, relative CBF, and relative CBV maps were generated and compared between contrast agents. RESULTS: The spatial distributions of the perfusion metrics generated with both contrast agents were consistent. Perfusion metrics in GM and WM were not statistically different except for WM MTT. CONCLUSIONS: Cerebral perfusion metrics generated with noninvasive transient hypoxia-induced changes in deoxyhemoglobin are very similar to those generated using a gadolinium-based contrast agent in patients with cerebrovascular steno-occlusive disease.

Assessment of cerebrovascular function in patients with sickle cell disease using transfer function analysis.

In patients with sickle cell disease (SCD), the delivery of oxygen to the brain is compromised by anemia, abnormal rheology, and steno-occlusive vascular disease. Successful compensation depends on an increase in oxygen supply such as that provided by an increase in cerebral blood flow (CBF). We used magnetic resonance imaging to provide a high-resolution assessment of the ability of SCD patients to respond to a vasoactive stimulus in middle, anterior, and posterior cerebral artery territories for both white and gray matter. Cerebrovascular reactivity (CVR) was measured as the blood oxygen level dependent signal (a surrogate for CBF) response to an increase in the end tidal partial pressure of CO2 (PET CO2 ). The dynamic aspect of the response was measured as the time constant of the first order response kinetics (tau). To confirm and support these findings we used an alternative examination of the response, transfer function analysis (TFA), to measure the responsiveness (gain), the speed of response (phase), and the consistency of the response over time (coherence). We tested 34 patients with SCD and compared the results to those of 24 healthy controls participants. The results from a three-way ANOVA showed that patients with SCD have reduced CVR (p < 0.001) and lower coherence (p < 0.001) in gray matter and white matter and reduced gain in gray matter only (p < 0.001). In terms of the speed of the response to CO2 , tau (p < 0.001) and TFA phase (p < 0.001) were increased in SCD patients compared to healthy control subjects. These findings show that the cerebrovascular responsiveness to CO2 in patients with SCD is both decreased and slowed compared to healthy controls.

Quantifying cerebral blood arrival times using hypoxia-mediated arterial BOLD contrast.

Cerebral blood arrival and tissue transit times are sensitive measures of the efficiency of tissue perfusion and can provide clinically meaningful information on collateral blood flow status. We exploit the arterial blood oxygen level dependent (BOLD) signal contrast established by precisely decreasing, and then increasing, arterial hemoglobin saturation using respiratory re-oxygenation challenges to quantify arterial blood arrival times throughout the brain. We term this approach the Step Hemoglobin re-Oxygenation Contrast Stimulus (SHOCS). Carpet plot analysis yielded measures of signal onset (blood arrival), global transit time (gTT) and calculations of relative total blood volume. Onset times averaged across 12 healthy subjects were 1.1 ± 0.4 and 1.9 ± 0.6 for cortical gray and deep white matter, respectively. The average whole brain gTT was 4.5 ± 0.9 s. The SHOCS response was 1.7 fold higher in grey versus white matter; in line with known differences in tissue-specific blood volume fraction. SHOCS was also applied in a patient with unilateral carotid artery occlusion revealing ipsilateral prolonged signal onset with normal perfusion in the unaffected hemisphere. We anticipate that SHOCS will further inform on the extent of collateral blood flow in patients with upstream steno-occlusive vascular disease, including those already known to manifest reductions in vasodilatory reserve capacity or vascular steal.

Assessing Cerebrovascular Resistance in Patients With Sickle Cell Disease.

In patients with sickle cell disease (SCD) the delivery of oxygen to the brain is compromised by anemia, abnormal rheology, and steno-occlusive vascular disease. Meeting demands for oxygen delivery requires compensatory features of brain perfusion. The cerebral vasculature's regulatory function and reserves can be assessed by observing the flow response to a vasoactive stimulus. In a traditional approach we measured voxel-wise change in Blood Oxygen-Level Dependent (BOLD) MRI signal as a surrogate of cerebral blood flow (CBF) in response to a linear progressive ramping of end-tidal partial pressure of carbon dioxide (PETCO2). Cerebrovascular reactivity (CVR) was defined as ΔBOLD/ΔPETCO2. We used a computer model to fit a virtual sigmoid resistance curve to the progressive CBF response to the stimulus, enabling the calculation of resistance parameters: amplitude, midpoint, range response, resistance sensitivity and vasodilatory reserve. The quality of the resistance sigmoid fit was expressed as the r 2 of the fit. We tested 35 patients with SCD, as well as 24 healthy subjects to provide an indication of the normal ranges of the resistance parameters. We found that gray matter CVR and resistance amplitude, range, reserve, and sensitivity are reduced in patients with SCD compared to healthy controls, while resistance midpoint was increased. This study is the first to document resistance measures in adult patients with SCD. It is also the first to score these vascular resistance measures in comparison to the normal range. We anticipate these data will complement the current understanding of the cerebral vascular pathophysiology of SCD, identify paths for therapeutic interventions, and provide biomarkers for monitoring the progress of the disease.

Does breathing pattern affect cerebrovascular reactivity?

NEW FINDINGS: What is the central question of this study? Is cerebrovascular reactivity affected by isocapnic changes in breathing pattern? What is the main finding and its importance? Cerebrovascular reactivity does not change with isocapnic variations in tidal volume and frequency. ABSTRACT: Deviations of arterial carbon dioxide tension from resting values affect cerebral blood vessel tone and thereby cerebral blood flow. Arterial carbon dioxide tension also affects central respiratory chemoreceptors, adjusting respiratory drive. This coincidence raises the question: does respiratory drive also affect the cerebral blood flow response to carbon dioxide? A change in cerebral blood flow for a given change in the arterial carbon dioxide tension is defined as cerebrovascular reactivity (CVR). Two studies have reached conflicting conclusions on this question, using voluntary control of breathing as a disturbing factor during measurements of CVR. Here, we address some of the methodological limitations of both studies by using sequential gas delivery and targeted control of carbon dioxide and oxygen to enable a separation of the effects of carbon dioxide on CVR from breathing vigour. We confirm that there is no detectable superimposed effect of breathing efforts on CVR.

Perfusion MRI using endogenous deoxyhemoglobin as a contrast agent: Preliminary data.

PURPOSE: To demonstrate the feasibility of mapping cerebral perfusion metrics with BOLD MRI during modulation of pulmonary venous oxygen saturation. METHODS: A gas blender with a sequential gas delivery breathing circuit was used to implement rapid isocapnic changes in the partial pressure of oxygen of the arterial blood. Partial pressure of oxygen was initially lowered to a baseline of 40 mmHg. It was then rapidly raised to 95 mmHg for 20 s before rapidly returning to baseline. The induced cerebral changes in deoxyhemoglobin concentration were tracked over time using BOLD MRI in 6 healthy subjects and 1 patient with cerebral steno-occlusive disease. BOLD signal change, contrast-to-noise ratio, and time delay metrics were calculated. Perfusion metrics such as mean transit time, relative cerebral blood volume, and relative cerebral blood flow were calculated using a parametrized method with a mono-exponential residue function. An arterial input function from within the middle cerebral artery was used to scale relative cerebral blood volume and calculate absolute cerebral blood volume and cerebral blood flow. RESULTS: In normal subjects, average gray and white matter were: BOLD change = 6.3 ± 1.2% and 2.5 ± 0.6%, contrast-to-noise ratio = 4.3 ± 1.3 and 2.6 ± 0.7, time delay = 2.3 ± 0.6 s and 3.6 ± 0.7 s, mean transit time = 3.9 ± 0.6 s and 5.5 ± 0.6 s, relative cerebral blood volume = 3.7 ± 0.9 and 1.6 ± 0.4, relative cerebral blood flow = 70.1 ± 8.3 and 20.6 ± 4.0, cerebral blood flow volume = 4.1 ± 0.9 mL/100 g and 1.8 ± 0.5 mL/100 g, and cerebral blood flow = 97.2 ± 18.7 mL/100 g/min and 28.7 ± 5.9 mL/100 g/min. CONCLUSION: This study demonstrates that induced abrupt changes in deoxyhemoglobin can function as a noninvasive vascular contrast agent that may be used for cerebral perfusion imaging.

The Reproducibility of Cerebrovascular Reactivity Across MRI Scanners.

Cerebrovascular reactivity (CVR) is defined as the ratio of the cerebral blood flow (CBF) response to an increase in a vasoactive stimulus. We used changes in blood oxygenation level-dependent (BOLD) MRI as surrogates for changes of CBF, and standardized quantitative changes in arterial partial pressure of carbon dioxide as the stimulus. Despite uniform stimulus and test conditions, differences in voxel-wise BOLD changes between testing sites may remain, attributable to physiologic and machine variability. We generated a reference atlas of normal CVR metrics (voxel-wise mean and SD) for each of two sites. We hypothesized that there would be no significant differences in CVR between the two atlases enabling each atlas to be used at any site. A total of 69 healthy subjects were tested to create site-specific atlases, with 20 of those individuals tested at both sites. 38 subjects were scanned at Site 1 (17F, 37.5 ± 16.8 y) and 51 subjects were tested at Site 2 (22F, 40.9 ± 17.4 y). MRI platforms were: Site 1, 3T Magnetom Skyra Siemens scanner with 20-channel head and neck coil; and Site 2, 3T HDx Signa GE scanner with 8-channel head coil. To construct the atlases, test results of individual subjects were co-registered into a standard space and voxel-wise mean and SD CVR metrics were calculated. Map comparisons of z scores found no significant differences between white matter or gray matter in the 20 subjects scanned at both sites when analyzed with either atlas. We conclude that individual CVR testing, and atlas generation are compatible across sites provided that standardized respiratory stimuli and BOLD MRI scan parameters are used. This enables the use of a single atlas to score the normality of CVR metrics across multiple sites.