WO2025230985A1

WO2025230985A1 - Non-invasive magnetic resonance oximetry calibration with blood oxygenation modulation

Info

Publication number: WO2025230985A1
Application number: PCT/US2025/026810
Authority: WO
Inventors: Hsin-Jung Yang; Rohan Dharmakumar
Original assignee: Cedars Sinai Medical Center
Current assignee: Cedars Sinai Medical Center
Priority date: 2024-04-29
Filing date: 2025-04-29
Publication date: 2025-11-06
Anticipated expiration: 2026-10-29

Abstract

Methods and systems are provided for calibrating oxygen sensitive imaging techniques and improving accuracy of blood oxygen level measurement therewith, such as via blood oxygen level dependent MRI. In various embodiments, the methods include concurrently or simultaneously acquiring a plurality of T2 or T2* MR images in a pre-determined breathing pattern and measuring corresponding percutaneous O₂ saturation level or end-tidal O₂ partial pressure. The breathing pattern effectuates a varying degree of arterial oxygen saturation level. With the acquired T2 or T2* data and the percutaneous O₂ saturation level or the end-tidal O₂ partial pressure, one can solve for fixed parameters in the Luz-Meiboom (L-M) model for MR oximetry, thereby calibrating these parameters for a target individual, a target organ, or a target MR imaging sequence.

Description

NON-INVASIVE MAGNETIC RESONANCE OXIMETRY CALIBRATION WITH

BLOOD OXYGENATION MODULATION

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application includes a claim of priority under 35 U.S.C. §119(e) to U.S. provisional patent application No. 63/639,798, filed April 29, 2024, and U.S. provisional patent application No. 63/639,796, filed April 29, 2024, the entirety of both of which is hereby incorporated by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with Government support under grant no. HL148788 awarded by National Institutes of Health. The Government has certain rights in the invention.

FIELD OF INVENTION

[0003] This invention relates to magnetic resonance (MR) oximetry.

BACKGROUND

[0004] Accurate measurement of blood oxygenation level in the venous system is also an important tool to investigate the metabolic status of different organs in the human body. To date, most of the measurements still rely on invasive blood draw from the veins and require invasive surgeries for deep organs such as the kidney, liver, brain, and heart, which expose patients to significant risk and are inaccessible to patients. Magnetic resonance (MR) oximetry is a noninvasive way to measure blood oxygenation levels deep in the body. Particularly, its application in the heart can provide important insights into energy consumption of the myocardium and indicate heart health. Cardiac energy consumption plays an important role in patient management across many diseases, such as heart failure, cardiomyopathy, and metabolic syndrome. The transverse relaxation rate of the MR signal (T2* and T2) is blood oxygenation level-dependent (BOLD), which is used in functional MRI in the brain. A

[0005] Recently, the success of this approach has been extended for quantifying the absolute blood oxygenation level utilizing different MRI contrasts (T2*, T2, Tl, and susceptibility), known as MR oximetry, which has propelled studies in different organs in the body. Although quantitative oxygenation level can be derived, MRI signal is strongly dependent on a number of parameters that are subject-dependent (Hematocrit (Het), susceptibility shift of hemoglobin, other proton exchange rate, and etc.), which make the quantification unreliable and has large variability between individuals. To correct for this, timeconsuming in vitro calibrations were used, which require sampling >10 mL of blood and additional in vitro scans that are incompatible with clinical workflow. To address these limitations, recent attempts have been made to allow for self-calibrated MR oximetry. However, the MRI parametric-based calibration methods do not provide sufficient oxygenation dynamic range, are susceptible to physiological noises, and require blood sampling to measure Het. These limitations still compromise the efficacy and accuracy of MR oximetry and their widespread in the clinical environment.

[0006] Therefore, it is an object of the present disclosure to provide a method and a system for reliably measuring blood oxygenation levels in different portions of the heart, preferably in a non-invasive manner.

[0007] It is another object of the present disclosure to provide a method for calibrating MR oximetry specific to each individual (or organ) under a predetermined or defined MR imaging sequence.

[0008] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

SUMMARY OF THE INVENTION

[0009] The following embodiments and aspects thereof are described and illustrated in conjunction with compositions and methods which are meant to be exemplary and illustrative, not limiting in scope.

[0010] Various embodiments provide methods of taking oximetry measurements in a subject or calibrating an oxygen sensitive imaging technique for use in determining blood oxygen saturation (SO2) level in a tissue of the subject, and the methods include: measuring a change or difference in or a time series of imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver; measuring a change or difference in or a time series of peripheral oxygen saturation (SpO2) using a pulse oximeter in response to the breathing maneuver; fitting the measured imaging data and the measured SpO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, wherein the SO2 level in the tissue is approximated in the fitting by the measured SpO2, and solving for one or more fixed parameters of the equation based on the measured imaging data and the measured SpO2, thereby calibrating the fixed parameters in the equation; performing an acquisition of the imaging data in the tissue in the subject using the oxygen sensitive imaging technique; and converting the acquired imaging data into SO2 level using the equation containing the calibrated fixed parameters, thereby taking the oximetry measurements in the subject or determining the SO2 level in the tissue of the subject.

[0011] Embodiments are also provided for methods for calibrating an equation that models a relationship of imaging data and SO2 level, which include: measuring a change or difference in or a time series of imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver; measuring a change or difference in or a time series of peripheral oxygen saturation (SpO2) using a pulse oximeter in response to the breathing maneuver; fitting the measured imaging data and the measured SpO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, wherein the SO2 level in the tissue is approximated in the fitting by the measured SpO2, and solving for one or more fixed parameters of the equation based on the measured imaging data and the measured SpO2, thereby calibrating the fixed parameters in the equation.

[0012] In some embodiments, the breathing maneuver comprises a breath-hold, a period of hyperventilation, or a sequential combination of both.

[0013] In some embodiments, the breath-hold is voluntary.

[0014] In some embodiments, the breathing maneuver is induced by a machine.

[0015] In some embodiments, the breathing maneuver varies the SO2 level in the tissue or the SpO2 by at least 5%.

[0016] In some embodiments, the oxygen sensitive imaging technique comprises blood oxygen level dependent magnetic resonance imaging (BOLD-MRI), nuclear techniques, single-photon emission computed tomography (SPECT), positron emission tomography (PET), computed tomography (CT), echocardiography or other ultrasound, near infrared spectroscopy (NIRS), intravascular blood flow measurements, fractional flow reserve, impedance measurements of the myocardium or other organ, or a combination thereof.

[0017] In some embodiments, the oxygen sensitive imaging technique comprises BOLD-MRI, and wherein the imaging data comprises T2 relaxation time, T2*, T1 relaxation time, or susceptibility contrast.

[0018] In some embodiments, the equation that models the relationship between the imaging data and the SO2 is wherein T2b is the imaging data on the tissue, %SO2 is the SO2 level of the tissue, and T20 and K_eff are fixed parameters of the equation.

[0019] In some embodiments, the approximating in the fitting comprises approximating the SO2 level of the tissue to an SpO2 measured at a time delay At relative to when the imaging data is measured, wherein the fitting comprises fitting to the equation at least two pairs of the measured imaging data and the measured SpO2 at the time delay At, and wherein the solving comprises solving for T20 and K_eir of the equation.

[0020] In some embodiments, the time delay At is a user-selected time delay; and the SpO2(t+At) is obtained/interpolated from a curve that depicts SpO2 level as a function of time, wherein the curve is obtained from fitting a time series of SpO2 level over a course of time.

[0021] In some embodiments, the time delay At is about 15 seconds or between 10 and 20 seconds, when the tissue being imaged is heart or myocardium and the pulse oximeter measures at fingertip, earlobe, lip, or wrist.

[0022] In some embodiments, the time delay At is determined by calculating a lag of time in a SpO2 response to an altered oxygenation or blood flow relative to a SO2 response of the tissue to the altered oxygenation or blood flow. In preferred embodiments, the time lag- corrected SpO2 response and the SO2 response of the tissue has an R-squared value of 0.8 or greater.

[0023] In some embodiments, the method does not include infusion of a vasodilator in the subject, and the method does not include withdrawing blood from the subject.

[0024] Various embodiments provide methods of taking oximetry measurements in a subject or calibrating an oxygen sensitive imaging technique for use in determining blood oxygen saturation (SO2) level in a tissue of the subject, and the methods include: measuring a change or difference in or a time series of imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver; measuring a change or difference in or a time series of end-tidal 02 partial pressure (PETO2) in the tissue using a gas flow controller device in response to the breathing maneuver, and thereby computing a change or difference in or a time series of the SO2 level of the tissue from the PETO2 based on a correlation of SO2

-i nn ^c^^pETO₂)ⁿ , . , 1

= 1UU - - wherein C is an aggregated physiological constant having a pre-

^+C PETO₂) determined value, and n is a correlation parameter for blood pH and has another pre-determined value; fitting the measured imaging data and the computed SO2 level from the PETO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, and solving for one or more fixed parameters of the equation based on the measured imaging data and the computed SO2 level from the PETO2, thereby calibrating the fixed parameters in the equation; performing an acquisition of the imaging data in the tissue in the subject using the oxygen sensitive imaging technique; and converting the acquired imaging data into SO2 level using the equation containing the calibrated fixed parameters, thereby taking the oximetry measurements in the subject or determining the SO2 level in the tissue of the subject.

[0025] Embodiments are also provided for methods for calibrating an equation that models the relationship between imaging data and SO2 level, which include: measuring a change or difference in or a time series of imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver; measuring a change or difference in or a time series of end-tidal 02 partial pressure (PETO2) in the tissue using a gas flow controller device in response to the breathing maneuver, and thereby computing a change or difference in or a time series of the SO2 level of the tissue from the PETO2 based on a correlation of SO2

-i nn ^c^^pET0₂)ⁿ , . , 1

= 1UU - - wherein C is an aggregated physiological constant having a pre-

^+C PETO₂) determined value, and n is a correlation parameter for blood pH and has another pre-determined value; fitting the measured imaging data and the computed SO2 level from the PETO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, and solving for one or more fixed parameters of the equation based on the measured imaging data and the computed SO2 level from the PETO2, thereby calibrating the fixed parameters in the equation.

[0026] In some embodiments, a method for calibrating an oxygen sensitive imaging technique includes:

(a) inducing a breathing pattern effective for varying a blood oxygen saturation (SO2) level in a blood vessel supporting a first organ;

(b) performing the oxygen sensitive imaging technique on the blood vessel in at least two time points ti and t2 within the time course in response to the breathing pattern, and acquiring T2 relaxation time maps and/or observed relaxation time (T2*) maps for each of the at least two time points, thereby obtaining T2 or T2* values for respective time points;

(c) measuring a series of peripheral blood oxygen saturation (SpO2) level of the subject using a pulse oximeter over the time course t; or detecting the SO2 level of the blood vessel supporting the first organ at each of the at least two time points, or reaching predetermined SO2 levels in the blood vessel supporting the first organ while the T2 maps or the T2* maps are being acquired at the at least two time points ti and t?; (d) if step (c) measures the series of the SpO2 level over the time course, estimating a lag of time At in the SpO2 response relative to the varied SO2 level in the blood vessel supporting the first organ, obtaining SpO2 value at each of time points ti+At and t?+At from the series of the SpO2 level over the time course, and fitting the T2 or T2* values at ti and t2 and the SpO2 values at ti+At and t?+At in pairs to a first equation of: wherein T2b(t) is an apparent blood T2 or T2* relaxation time at a time point t, %SpO2(t+At) is the SpO2 level at a time point t+At, and T20 and X^are fixed parameters of the first equation; or if step (c) detects the SO2 level or reaches the predetermined SO2 levels, fitting the T2 or T2* values at ti and t2 and the SO2 levels at ti and t2 in pairs to a second equation: wherein the T2b(t) is the apparent blood T2 or T2* relaxation time at the time point t, the %S02(t) is the SO2 level at the time point t, and the 720 and the X are fixed parameters of the second equation; and

(e) solving for both or one of the T20 and the K_eff of respective equation to obtain calibrated fixed parameters, thereby calibrating for the oxygen sensitive imaging technique.

[0027] In some embodiments, the method is for calibrating blood oxygen level dependent magnetic resonance imaging (BOLD-MRI)-based oximetry in a subject, and the steps (a) through (c) are performed on the subject.

[0028] In some embodiments, the first organ comprises myocardium or heart.

[0029] In some embodiments, the calibration is for use in determining SO2 level in a target organ same as the first organ.

[0030] In some embodiments, the calibration is for use in determining SO2 level in a target organ different from the first organ in the same subject.

[0031] In some embodiments, the calibration is for use in determining SO2 level in a target organ myocardium, heart, brain, kidney, liver, or pancreas.

[0032] In some embodiments, the breathing pattern in step (a) comprises a first time period of hyperventilation and a second time period of breath-hold.

[0033] In some embodiments, inducing the breathing pattern in step (a) comprises operating a gas flow controller device to administer a gas mixture, optionally a mixture of oxygen and carbon dioxide, via inhalation. [0034] In some embodiments, the estimating of the At in step (d) comprises calculating a lag of time in a SpO2 response to an altered oxygenation or blood flow relative to a SO2 response of the tissue to the altered oxygenation or blood flow, wherein the time lag-corrected SpO2 response and the SO2 response of the tissue has an R-squared value of 0.8 or greater.

[0035] In some embodiments, the At is about 15 seconds or between 10 and 20 seconds, when the tissue being imaged is heart or myocardium and the pulse oximeter measures at fingertip, earlobe, lip, or wrist.

[0036] In some embodiments, detecting the SO2 level in step (d) comprises measuring an end-tidal 02 partial pressure (PETO2) in the blood vessel supporting the first organ, thereby obtaining PETO2 values at the two or more time points, and computing the SO2 level as i nn ^c^^pET°2)ⁿ . . . , , . , . , , . ,

1UU - - - — wherein C is an aggregated physiological constant having a pre-determined

1+C(P_£TO₂) value for the subject, and n is a correlation parameter for blood pH and has a pre-determined value.

[0037] In some embodiments, reaching pre-determined SO2 levels in step (c) is performed using a gas flow controller device to deliver an effective amount of gas for modulating the SO2 level in the blood vessel supporting the first organ.

[0038] In some embodiments, the varied SO2 level in the blood vessel supporting the first organ contains at least two different SO2 levels being different by 5% or greater.

[0039] In some embodiments, the breathing pattern in step (a) is effective for varying the SO2 level by 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%, or greater than 100%.

[0040] Other features and advantages of the invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, various features of embodiments of the invention.

BRIEF DESCRIPTION OF THE FIGURES

[0041] FIG. 1 depicts an exemplary flow chart of MR oximetry calibration. A time series of T2 maps from BOLD MRI of the left ventricle (LV) is recorded as a variable parameter, T2b(t). A time series of %SpO2 from pulse oximetry, concurrent with the time series of the T2 maps, is recorded as a variable parameter, %SpO2(t). These two variable parameters are fitted into the equation at the bottom of this figure, to perform regression analysis and solve for fixed parameters, T2b, K_eff, and At. In the exemplary schematic of figure 1, the time series is chosen in a period including a short hyperventilation phase (about 15-20 seconds) followed by a breath-holding phase (about 100-120 seconds). Other breathing patterns may be used in measuring T2b(t) and %SpO2(t) to perform regression analysis and solve for fixed parameters, T_2b, K_eff, and At, in the equation.

[0042] FIG. 2 depicts temporal variation of peripheral artery blood oxygen saturation level (SpO2) and blood T2 during breathing maneuver. Panel A is a plot of SpO2 over time, measured from fingertip pulse oximetry at a 20-second interval. Panel B includes a series of seven T2 maps from BOLD MRI over time, at a 20-second interval, and a breathing pattern at this time period (hyperventilation followed by breath holding). Panels C and D are blood T2 values at the left ventricle (LV) and at the right ventricle (RV), respectively, over time, obtained from the T2 mapping of the myocardium over time of panel B. The trend of SpO2 change (shown in panel A) lags behind the trend of LV T2 change (panel C or B-D) by about 10 seconds (At). Generally, to derive T2 from MRI, a technique called T2 mapping is used, which involves acquiring multiple images with different T2 weighting(TEs) and fitting the signal decay for each pixel to an exponential function, S = So * exp(-TE/T2)) (where S is the signal intensity, So is the initial signal intensity, TE is the echo time, and T2 is the relaxation time), resulting in a T2 map where each pixel represents a T2 value. The slope of this exponential decay curve at each pixel provides the T2 value for that specific location.

[0043] FIG. 3 depicts fitted L-M model and the underlying parameters of the blood signal, which is a predicted arterial and venous blood T2 and SO2 curve from the solved L-M model using the first four T2 and SpO2 measurements. This is a blood T2-blood oxygenation level correspondence model that puts both arterial and venus blood on the curve with calibrated biophysical parameters. The triangular data points are the delay (At)-corrected arterial SO2 (SaO2) during the first four time points. The circular data points are the delay (At)-corrected arterial SO2 (SaO2) of the fifth to the seventh time points. The diamond points are the venous T2 and its derived SO2 (SvO2) under all seven time points. The range of the predicted venous SO2 corresponds nicely to the physiological range of populational normal venous blood. (The equation that models the relationship between venous T2 (e.g., from right ventricle BOLD- MRI images) and venous SO2 (SvO2) is also depicted by the L-M model as in equation [2], same one as that for the arterial T2 (e.g., from left ventricle BOLD-MRI images) - SaO2 relationship.) The x-axis (SO2) is measured SO2 from pulse oximeter.

[0044] FIG. 4 depicts a predicted (theoretical curve from the fitted parameters) SO2 in right and left ventricular blood. It is blood oxygen saturation level measured with CMR through a prolonged breath-hold. Blood oxygen saturation levels are aligned with the physiological range of human subjects. The y-axis (SO2) in figure 4 is derived from the L-M model. [0045] Exemplary embodiments are illustrated in referenced figures. It is intended that the embodiments and figures disclosed herein are to be considered illustrative rather than restrictive.

DESCRIPTION OF THE INVENTION

[0046] All references cited herein are incorporated by reference in their entirety as though fully set forth. Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0047] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. Indeed, the present invention is in no way limited to the methods and materials described. For purposes of the present invention, the following terms are defined below.

[0048] SO2 or SO2 refers to oxygen saturation in general. %SO2, or oxygen saturation, refers to the percentage of hemoglobin in the blood that is carrying oxygen over total hemoglobin in the blood. A normal oxygen saturation level is typically between 95% and 100%. Unless otherwise defined, herein it is also referring to oxygen saturation in a blood vessel, which can be arterial or venous vessel.

[0049] SaO2 or SaO₂ refers to arterial oxygen saturation.

[0050] SpO2 or SpO₂ refers to pulse oximetrically measured oxygen saturation, which is usually peripheral artery blood oxygen saturation measured by applying a pulse oximeter (e.g., via a clip probe; measuring the artery side of the microcirculation) to areas of thin skin such as a fingertip, a lip, an ear lobe, a toe, or a wrist, or a body portion sufficiently perfused with arterial blood.

[0051] Both SaO2 and SpO2 measure the ratio of oxygen-bound hemoglobin to total hemoglobin in the blood, but they differ in how they are measured and the blood source. SaO2 is measured by analyzing a blood sample drawn from an artery, while SpO2 is measured non- invasively by pulse oximetry using a probe placed on the finger or toe or lip or ear lobe etc. [0052] SvO2 or SvO₂ refers to venous oxygen saturation.

[0053] SzvO2 or SzvO₂ refers to central venous oxygen saturation.

[0054] SvO2 or SvO₂ refers to mixed venous oxygen saturation.

[0055] The term “heart disease” refers to any disease relating to the heart. These include but are not limited to ischemic heart disease or heart disease caused by myocardial infarction, arterial hypertension, diabetes mellitus, hypercholesterolemia, obesity, nonischemic cardiomyopathies, myocardial inflammation, congenital heart disease, valvular heart disease, stress-induced cardiomyopathy, or infiltrative myocardial disorders. The disease may be microvascular disease (for example in hypertension, diabetes, sleep apnea, hypercholesterolemia, “syndrome X”, immunologic and rheumatologic diseases) or macrovascular (stenotic coronary artery disease) disorders. Additional examples of heart disease include but are not limited to cardiomegaly, and stress-induced angina.

[0056] A “subject” or “individual” refers to any human or animal. Non-limiting examples of a subject include humans, non-human mammals, companion mammals, livestock and the like. A subject can further be a healthy human or animal. In various embodiments, a subject is a human. In some embodiments, a subject is a healthy human. In some embodiments, a subject is one at risk of having a heart disease or vasculature disease.

[0057] The term “breathing maneuvers” refers to an alteration to the natural, unconscious control of breathing. Unconscious control of breathing is mediated by specialized centers in the brainstem which automatically regulate the rate and depth of breathing. Thus, breathing maneuvers may include, for example, a change in the rate or the depth of the breath. Breath-holds and hyperventilation are examples of breathing maneuvers. Breathing maneuvers may be voluntary (i.e. in response to conscious control of breathing) or induced mechanically. Certain embodiments use multiple breathing maneuvers or combinations of breathing maneuvers.

[0058] The term “breath-hold,” “breath hold,” or “breath holding” is used interchangeably with “apnea” and refers to the suspension of breathing. The suspension of breathing may be induced mechanically through manipulation of specialized devices (e.g. ventilation bag) or machines such as a ventilator or may be induced naturally and voluntarily without the use of an external machine. In patients with other pre-existing diseases (e.g. pulmonary diseases) the paCCh levels may be different from those naturally defined as physiologic. A person of skill in the art would be able to define the appropriate baseline pCCh levels and baseline respiratory rate for those subjects. Specialized machines may allow for a fine-tuned change of blood carbon dioxide and/or oxygen using simultaneous blood gas analysis and feedback mechanisms to regulate the inhaled gas composition. Examples of suitable machines/devices for regulating inhaled gas composition include but are not limited to a Harvard Apparatus ventilator, but other machines would be known to a person skilled in the art. In one embodiment, breath-holds may be achieved in an anaesthetized ventilated model. In another embodiment standardized voluntary breathing maneuvers is used.

[0059] Breath-holds may be from 5 seconds to 3 minutes in length. In a preferred embodiment a breath-hold is about 1 minute. A breath-hold may be 5 seconds, 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds, 60 seconds, 65 seconds, 70 seconds, 75 seconds, 80 seconds, 85 seconds, 90 seconds, 95 seconds, 100 seconds, 105 seconds, 110 seconds, 115 seconds, 120 seconds, 125 seconds, 130 seconds, 135 seconds, 140 seconds, 145 seconds, 150 seconds, 155 seconds, 160 seconds, 165 seconds, 170 seconds, 175 seconds or 180 seconds. A breath-hold may also be maximal. By maximal it is intended to mean the maximum length of time a subject may voluntarily hold their breath. Multiple breath-holds may be used in the methods described herein.

[0060] The term “hyperventilation” refers to a breathing rate that is faster than the momentary resting breathing rate of the subject or a breathing rate faster than the rate required to maintain physiologic paCCh levels (40±5 mmHg) for ventilated subjects.

[0061] In an embodiment, the breathing maneuver may be a period of hyperventilation. The methods may include multiple periods of hyperventilation or breath-holding or a combination of periods of hyperventilation and breath-holding. For example, one minute of hyperventilation, followed by 60-120 seconds of breath-holding may be used in the methods disclosed herein.

[0062] In an embodiment, the pCCh (arterial, peripheral or end-tidal) and pO2 (arterial, peripheral, inspiratory or expiratory gas concentrations) or SpO2 are adjusted to a baseline level of a target e.g. paO2 of 100 mmHg and a target paCCh of 40 mmHg, SpO2 of 95-98%.

[0063] Changes in oxygenation or blood flow induced by breathing maneuvers may be measured using any diagnostic technique capable of detecting regional or global variations of myocardial perfusion or oxygenation. Examples include but are not limited to oxygenationsensitive cardiac magnetic resonance (CMR) imaging, nuclear cardiology techniques, singlephoton emission computed tomography (SPECT), positron emission tomography (PET), computed tomography (CT), echocardiography, near infrared spectroscopy (NIRS) intravascular blood flow measurements such as fractional flow reserve, or impedance measurements of the myocardium. MRI procedures and various contrasts therewith are described in the literature and patents including U.S. Patent No. 6,603,989, which is herein incorporated by reference in its entirety.

[0064] Typically, breath-holding will lead to an increase in pCCE and thus lead to an increase in blood flow and myocardial oxygenation in healthy myocardial tissue that can be measured with CMR. Hyperventilation will result in the opposite. In an embodiment the method comprises inducing a hyperventilation followed by a breath-hold in a subject; measuring the change in oxygenation-sensitive magnetic resonance signal intensity (e.g., contracts such as T2, T2*, Tl, or susceptibility) in the heart of the subject during breathing maneuvers. The image of the subject may be obtained by CMR and segmented according to procedures that are known to a person skilled in the art.

[0065] Typically, pulse oximetry is a biometric technique that simultaneously measures heart rate and blood oxygenation by estimating oxygen saturation levels in haemoglobin in peripheral arterial blood. Certain pulse oximetry methods are based on non- invasive detection of light reflected, scattered or otherwise transmitted through a peripheral tissue perfused with blood. These methods are generally collectively referred to as photoplethysmography. Accordingly, a photoplethysmographic signal (or, PPG signal) is collected by at least one PPG sensor, and then analyzed. Exemplary components and devices for pulse oximetry are described in U.S. Patent Nos. 12,109,024 and 6,421,549, which are incorporated by reference herein. Although SpO2 is calculated from measured characteristics of a detected light, and is therefore in more appropriate terms only estimated, or calculated, to align with terminology more often used in practice in the present application we refer to the estimation or calculation of the SpO2 parameter as the “measurement” of SpO2.

[0066] The term “monitoring” refers to the activity of repeatedly “measuring” and then saving, displaying or otherwise keeping record of data (e.g., SpO2 data) over a protracted period of time so as to reveal any trends or patterns. In some embodiments, the SpO2 is measured non-invasively using a pulse oximeter preferably at regular and relatively small time intervals, for example many times per second, or every second, every two, three, four, five or ten seconds.

[0067] Conventional types of oximeters include finger oximeters, earlobe oximeters, and fetal oximeters. Typical oximetry systems make use of the fact that the absorption characteristics of different blood components, namely, HbCh and Hb, differ depending on which wavelength of light (e.g., infrared or visible portions of the spectrum) is being used. Accordingly, typical noninvasive oximetric systems impinge at least both visible and infrared light upon a body part, such as a finger, and then estimate the oxygen saturation level using the relative proportions of visible and infrared light transmitted through or reflected by the body tissue. Some systems utilize the pulsatile component of the transmitted or reflected light beam to distinguish variations in the detected intensity of the light beam which are due to changes in blood components from other causes. This approach is generally referred to as pulse oximetry. Using the pulsatile signal modulating the light beams for obtaining an oxygen saturation level estimate provides a significant improvement in accuracy over nonpulse oximetry systems. “Pulsed oximeters” are therefore oximeters which measure the arterial component of the blood perfusion, to yield the arterial oxygen saturation (SaCL) level, using the pulsatile component of a light transmission signal.

[0068] Invasive procedures, such as using an inserted catheter to measure blood pressure and to extract periodic blood samples, measure directly oxygen levels in one or more blood samples, and the corresponding measured parameter is known as “arterial blood oxygen saturation” or “SaO2”. In various embodiments, invasive measurements are avoided or excluded from the methods disclosed herein.

[0069] Here, we introduce a fast, accessible calibration technique to provide a wide dynamic range to derive noise-resistant calibration for MR oximetry. By alternating the arterial blood oxygenation level through breathing maneuvers and/or gas challenging, a wide dynamic range of the arterial blood oxygenation level can be achieved. Combining with dynamically acquired BOLD MRI and peripheral artery blood oxygen saturation level (SpO2), subjectspecific calibration can be derived to estimate the physiological parameters for accurate MR oximetry. Combining accurate estimation of arterial blood oxygenation, sufficient %SO2 and BOLD signal dynamic range, and simultaneously acquired T2 maps with a high temporal resolution, the proposed technique can facilitate accurate MR oximetry with the subjectspecific calibrated BOLD signal. The technique is compatible with clinical workflow and can finally permit MR oximetry’s clinical adoption for various applications (e.g., evaluating cardiac energy consumption for heart failure patients and kidney metabolic efficiency for diabetic patients.)

[0070] In this study, we tested the feasibility of the method in healthy volunteers with an exemplary breathing maneuver pattern (hyperventilation followed by a prolonged breathhold), and showed the MR oximetry can provide an accurate estimation of human blood without invasive blood sampling.

[0071] T2 values of the blood are known to be sensitive to blood oxygen saturation (SO2). In the past decade, extensive studies have been performed to extract the relationship between T2 and SO2. Notably, the Luz-Meiboom (L-M) chemical exchange model was proposed to mathematically characterize the relation emulating the proton exchange between red blood cell (RBC) and free-water in the blood. Wright et al. adopted the model and for the first time showed in 1991 that the SO2 can be quantitatively estimated using in-vivo blood T2 with the L- M model as described in equation [1]: wherein 7 b is the apparent blood T2, Pa is the proton fraction in the plasma, a is the susceptibility calibration parameter between deoxy- and oxyhemoglobin, 00 is the resonance frequency, T_ezis the proton exchange time, TI₈₀ is the time between refocusing pulses, and T20 is the base T2 with fully oxygenated blood.

[0072] When images were acquired under a fixed imaging protocol and physiological parameters, equation [1] can be simplified into a concise form, equation [2], wherein K_e/f is an aggregated parameter based on a fixed set of Pa, a, 00, T_ex, and T₁₈₀. [0073] For in vivo MR oximetry, T20 and need to be accurately calibrated and determined to determine the relationship between T2b and %SO2. Utilizing the closed formulation of equation [2], T20 and K_eff can be calculated with a set of blood T2 measured under different %SO2 levels. However, because measuring accurate %SO2 in the heart non- invasively is not a trivial task, the calibration usually requires multiple blood draw and ex-vivo blood scans prior to the in-vivo studies. The extra procedures strongly hinder the application of MR oximetry in the clinical environment.

[0074] Here, we propose a new method to accurately calibrate the arterial %SO2 with the MRI signal without blood draw and extra scan time. Instead of measuring %SO2 in ex-vivo blood, we used other surrogates to derive the %SO2 under a range of blood oxygen saturation levels. Examples of the surrogates are described below.

[0075] Various embodiments provide methods for calibrating an oxygen sensitive imaging technique and determining blood oxygen saturation (SO2) level in a tissue. Various embodiments provide methods for calibrating an oxygen sensitive imaging technique for use in determining blood oxygen saturation (SO2) level in a tissue. Various embodiments provide methods for calibrating BOLD-MRI and determining blood oxygen saturation (SO2) level therewith after the calibration. Various embodiments provide for methods of taking oximetry measurements.

[0076] In various embodiments, a method of taking oximetry measurements, or calibrating an oxygen sensitive imaging technique for use in determining blood oxygen saturation (SO2) level, or calibrating BOLD-MRI and determining SO2 level therewith in a tissue, includes: measuring a change in imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver; measuring a change in peripheral oxygen saturation (SpO2) using a pulse oximeter in response to the breathing maneuver; fitting the measured imaging data and the measured SpO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, wherein the SO2 level in the tissue is approximated in the fitting by the measured SpO2, and solving for one or more fixed parameters of the equation based on the measured imaging data and the measured SpO2, thereby calibrating the fixed parameters in the equation; acquiring the imaging data in the tissue in the subject using the oxygen sensitive imaging technique; and converting the acquired imaging data into SO2 level using the equation containing the calibrated fixed parameters.

[0077] In various embodiments, a method of taking oximetry measurements, or calibrating an oxygen sensitive imaging technique for use in determining blood oxygen saturation (SO2) level, or calibrating BOLD-MRI and determining SO2 level therewith in a tissue, includes: measuring a difference in imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver; measuring a difference in peripheral oxygen saturation (SpO2) using a pulse oximeter in response to the breathing maneuver; fitting the measured imaging data and the measured SpO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, wherein the SO2 level in the tissue is approximated in the fitting by the measured SpO2, and solving for one or more fixed parameters of the equation based on the measured imaging data and the measured SpO2, thereby calibrating the fixed parameters in the equation; acquiring the imaging data in the tissue in the subject using the oxygen sensitive imaging technique; and converting the acquired imaging data into SO2 level using the equation containing the calibrated fixed parameters.

[0078] In various embodiments, a method of taking oximetry measurements, or calibrating an oxygen sensitive imaging technique for use in determining blood oxygen saturation (SO2) level, or calibrating BOLD-MRI and determining SO2 level therewith in a tissue, includes: measuring a time series of two or more imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver over the time course; measuring a time series of two or more peripheral oxygen saturation (SpO2) levels using a pulse oximeter in response to the breathing maneuver over the time course; fitting the measured imaging data and the measured SpO2 levels to an equation that models a relationship between the imaging data and the SO2 level in the tissue, wherein the SO2 level in the tissue is approximated in the fitting by the measured SpO2, and solving for one or more fixed parameters of the equation based on the measured imaging data and the measured SpO2, thereby calibrating the fixed parameters in the equation; acquiring the imaging data in the tissue in the subject using the oxygen sensitive imaging technique; and converting the acquired imaging data into SO2 level using the equation containing the calibrated fixed parameters.

[0079] Various embodiments provide a method of taking oximetry measurements or calibrating an oxygen sensitive imaging technique for use in determining blood oxygen saturation (SO2) level in a tissue of a subject, which includes: measuring a change in imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver; measuring a change in end-tidal 02 partial pressure (PETO2) in the tissue using a gas flow controller device in response to the breathing maneuver, and thereby computing a change in the SO2 level of the tissue from the PETO2 based on a correlation of SO2 = mn ^c(^pErO2)ⁿ . . . , , . , . , , . , . ,

1 - - wherein C is an aggregated physiological constant having a pre-determined

^ + C PETO₂) value, and n is a correlation parameter for blood pH and has another pre-determined value; fitting the measured imaging data and the computed SO2 level from the PETO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, and solving for one or more fixed parameters of the equation based on the measured imaging data and the computed SO2 level from the PETO2, thereby calibrating the fixed parameters in the equation; acquiring a further imaging data in the tissue in the subject using the oxygen sensitive imaging technique; and converting the acquired imaging data into SO2 level using the equation containing the calibrated fixed parameters, thereby taking the oximetry measurements in the subject or determining the SO2 level in the tissue of the subject.

[0080] In other embodiments, a method of taking oximetry measurements or calibrating an oxygen sensitive imaging technique for use in determining blood oxygen saturation (SO2) level in a tissue of a subject, which includes: measuring a difference in imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver; measuring a difference in end-tidal 02 partial pressure (PETO2) in the tissue using a gas flow controller device in response to the breathing maneuver, and thereby computing a difference in the SO2 level of the tissue from the PETO2 based on a correlation of

SO2 = 100 - - wherein C is an aggregated physiological constant having a pre- l+C P_ETO₂)ⁿ determined value, and n is a correlation parameter for blood pH and has another pre-determined value; fitting the measured imaging data and the computed SO2 level from the PETO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, and solving for one or more fixed parameters of the equation based on the measured imaging data and the computed SO2 level from the PETO2, thereby calibrating the fixed parameters in the equation; acquiring a further imaging data in the tissue in the subject using the oxygen sensitive imaging technique; and converting the acquired imaging data into SO2 level using the equation containing the calibrated fixed parameters, thereby taking the oximetry measurements in the subject or determining the SO2 level in the tissue of the subject.

[0081] In other embodiments, a method of taking oximetry measurements or calibrating an oxygen sensitive imaging technique for use in determining blood oxygen saturation (SO2) level in a tissue of a subject, which includes: measuring a time series of two or more imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver over a time course; measuring a time series of two or more end-tidal 02 partial pressure (PETO2) in the tissue using a gas flow controller device in response to the breathing maneuver over the time course, and thereby two or more of SO2 levels of the tissue from the PETO2 based on a correlation of SO2 = 100 - - - — , wherein C is an aggregated

1+C(P_£TO₂) physiological constant having a pre-determined value, and n is a correlation parameter for blood pH and has another pre-determined value; fitting the measured imaging data and the computed SO2 level from the PETO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, and solving for one or more fixed parameters of the equation based on the measured imaging data and the computed SO2 level from the PETO2, thereby calibrating the fixed parameters in the equation; acquiring a further imaging data in the tissue in the subject using the oxygen sensitive imaging technique; and converting the acquired imaging data into SO2 level using the equation containing the calibrated fixed parameters, thereby taking the oximetry measurements in the subject or determining the SO2 level in the tissue of the subject.

[0082] In various aspects, the equation that models a relationship between the imaging data and the SO2 level is wherein T2b is the imaging data, %SO2 is the SO2 level, and T20 and Keff are fixed parameters of the equation.

[0083] In some embodiments, the oxygen sensitive imaging technique comprises BOLD-MRI, and the imaging data comprises T2 relaxation time. In some embodiments, the oxygen sensitive imaging technique is BOLD-MRI, the imaging data is T2 relaxation time, and the equation that models a relationship between the T2 relaxation time and the SO2 level is wherein T2b is the T2 relaxation time, %SO2 is the SO2 level, and T20 and K_efr are fixed parameters of the equation.

[0084] In some embodiments, the oxygen sensitive imaging technique comprises BOLD-MRI, and the imaging data comprises T2*. In some embodiments, the equation that models a relationship between T2* and the SO2 level is described by Zhao et al. in Magnetic Resonance inMedicine, 58:592-596 (2007), which is herein incorporated by reference.

[0085] In some embodiments, the oxygen sensitive imaging technique comprises BOLD-MRI, and the imaging data comprises T1 relaxation time. In some embodiments, the equation that models a relationship between T1 and the SO2 level is described by Portnoy et al. in Magnetic Resonance in Medicine, 78:2352-2359 (2017).

[0086] In some embodiments, the oxygen sensitive imaging technique comprises BOLD-MRI, and the imaging data comprises susceptibility contrast. In some embodiments, the equation that models a relationship between susceptibility and the SO2 level is described by Wen et al. in Journal of Cardiovascular Magnetic Resonance, (2019) 21 :70.

[0087] In some aspects, the imaged tissue is an internal organ, e.g., left ventricle of the heart, and the SO2 level thereof is arterial blood oxygen saturation level. In some aspects, the imaged tissue is right ventricle of the heart, and the SO2 level thereof is venous blood oxygen saturation level; so as to calibrate fixed parameters (e.g., K_eff, T20 in the L-M model). The calibrated fixed parameters based on either artery or venous blood oxygen saturation level may be used for converting either arterial imaging data into arterial blood oxygen saturation level or venous imaging data into venous blood oxygen saturation level. That is, the calibrated fixed parameters based on artery blood oxygen saturation level may be used for converting arterial imaging data into arterial blood oxygen saturation level. The calibrated fixed parameters based on artery blood oxygen saturation level may be used for converting venous imaging data into venous blood oxygen saturation level. The calibrated fixed parameters based on venous blood oxygen saturation level may be used for converting venous imaging data into venous blood oxygen saturation level. The calibrated fixed parameters based on venous blood oxygen saturation level may be used for converting arterial imaging data into arterial blood oxygen saturation level.

[0088] In some aspects, the SO2 level of a tissue is approximated by SpO2 level. In some aspects, the SO2 level of a tissue is approximated by SpO2 level measured at a time delay At (also called a time lag) relative to when the imaging data is obtained. In further aspects, the methods include measuring SpO2 level over the course of the breathing maneuver, thereby obtaining SpO2 level as a function of time. The function of SpO2 level over time may be used to estimate a lag of time in SpO2 changes compared to the SO2 changes in the blood of the internal organ.

[0089] In some aspects, the time delay At is a user-selected time delay. In some aspects, the time delay At is about 15 seconds or 10-20 seconds between the heart or myocardium and the fingertip, earlobe, lip, or toe etc.

[0090] In other aspects, the time delay At is determined by calculating a lag of time in a SpO2 response to an altered oxygenation or blood flow relative to a SO2 response of the tissue to the altered oxygenation or blood flow. In further aspects, the time lag-corrected SpO2 response and the SO2 response of the tissue has an R-squared value of 0.7, 0.75, or 0.8 or greater. For example, At is found/identified/determined when it provides for an R-squared value of at least 0.8 when SpO2(t+At) and S02(t) are regressed. That is, when the time lag is corrected, i.e., u = t+At, then a large proportion of variance in SpO2(u) correlates with or is mathematically explained by S02(t).

[0091] In various aspects, the breathing maneuver varies the SO2 level in the tissue or the SpO2 by at least 5%. In various aspects, the breathing maneuver varies the SO2 level in the tissue or the SpO2 by at least 10%. In various aspects, the breathing maneuver varies the SO2 level in the tissue or the SpO2 by at least 20%. In various aspects, the breathing maneuver varies the SO2 level in the tissue or the SpO2 by at least 30%. In various aspects, the breathing maneuver varies the SO2 level in the tissue or the SpO2 by at least 40%. In various aspects, the breathing maneuver varies the SO2 level in the tissue or the SpO2 by at least 3% and no greater than 50%.

[0092] Additional embodiments provide for methods of calibrating an oxygen sensitive imaging technique or calibrating an equation that models a relationship between a parameter obtained from the oxygen sensitive imaging technique and SO2 level of a tissue thus imaged. In some embodiments, a calibration method includes measuring a change in imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver; measuring a change in peripheral oxygen saturation (SpO2) using a pulse oximeter in response to the breathing maneuver; fitting the measured imaging data and the measured SpO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, wherein the SO2 level in the tissue is approximated in the fitting by the measured SpO2, and solving for one or more fixed parameters of the equation based on the measured imaging data and the measured SpO2, thereby calibrating the fixed parameters in the equation.

[0093] In some embodiments, a calibration method includes measuring a difference in imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver; measuring a difference in peripheral oxygen saturation (SpO2) using a pulse oximeter in response to the breathing maneuver; fitting the measured imaging data and the measured SpO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, wherein the SO2 level in the tissue is approximated in the fitting by the measured SpO2, and solving for one or more fixed parameters of the equation based on the measured imaging data and the measured SpO2, thereby calibrating the fixed parameters in the equation.

[0094] In some embodiments, a calibration method includes measuring a time series of imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver over a time course; measuring a time series of peripheral oxygen saturation (SpO2) using a pulse oximeter in response to the breathing maneuver over the time course; fitting the measured imaging data and the measured SpO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, wherein the SO2 level in the tissue is approximated in the fitting by the measured SpO2, and solving for one or more fixed parameters of the equation based on the measured imaging data and the measured SpO2, thereby calibrating the fixed parameters in the equation.

[0095] In other embodiments, a calibration method includes measuring a change in imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver; measuring a change in end-tidal 02 partial pressure (PETO2) in the tissue using a gas flow controller device in response to the breathing maneuver, and thereby computing a change in the SO2 level of the tissue from the PETO2 based on a correlation of

SO2 = 100 - - wherein C is an aggregated physiological constant having a pre- l+C P_ETO₂)ⁿ determined value, and n is a correlation parameter for blood pH and has another pre-determined value; fitting the measured imaging data and the computed SO2 level from the PETO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, and solving for one or more fixed parameters of the equation based on the measured imaging data and the computed SO2 level from the PETO2, thereby calibrating the fixed parameters in the equation. [0096] In other embodiments, a calibration method includes measuring a difference in imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver; measuring a difference in end-tidal 02 partial pressure (PETO2) in the tissue using a gas flow controller device in response to the breathing maneuver, and thereby computing a change in the SO2 level of the tissue from the PETO2 based on a correlation of

SO2 = 100 - - wherein C is an aggregated physiological constant having a pre- l+C P_ETO₂)ⁿ determined value, and n is a correlation parameter for blood pH and has another pre-determined value; fitting the measured imaging data and the computed SO2 level from the PETO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, and solving for one or more fixed parameters of the equation based on the measured imaging data and the computed SO2 level from the PETO2, thereby calibrating the fixed parameters in the equation.

[0097] In other embodiments, a calibration method includes measuring a time series of imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver over a time course; measuring a time series of end-tidal 02 partial pressure (PETO2) in the tissue using a gas flow controller device in response to the breathing maneuver over the time course, and thereby computing a series of corresponding SO2 levels of the tissue from the PETO2 based on a correlation of SO2 = 100 - - - — , wherein C is an aggregated

1+C(P_£TO₂) physiological constant having a pre-determined value, and n is a correlation parameter for blood pH and has another pre-determined value; fitting the measured imaging data and the computed SO2 level from the PETO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, and solving for one or more fixed parameters of the equation based on the measured imaging data and the computed SO2 level from the PETO2, thereby calibrating the fixed parameters in the equation.

[0098] In various aspects, a time series’ measurement includes two or more time points of measurement. In some embodiments, a time series’ measurement includes two time points of measurement. In some embodiments, a time series’ measurement includes three time points of measurement. In some embodiments, a time series’ measurement includes four time points of measurement. In some embodiments, a time series’ measurement includes more than four time points of measurement.

[0099] In various embodiments, %SO2 in the left ventricle (%SLVO2) is assumed to be same or substantially the same as arterial oxygen saturation, and thus is denoted as the SaO2 level. In some implementations, %SO2 in the left ventricle (%SLVO2) is estimated through the measurement of peripheral blood oxygen saturation level (SpO2), although with a lag in time (At) in most instances wherein changes in SpO2 lag behind changes in %SO2 in the left ventricle, also known as a response delay from myocardium to peripheral skin of a subject. Because the arterial blood oxygen saturation (SaO2) level is highly associated with the peripheral blood oxygen saturation level, the arterial SO2 in the left ventricle (SLVCL) can be estimated with equation [3] and be adopted to calibrate the L-M model and derive accurate T20 and K_eff.

%SaO₂ = %S/vO2(t) ~ %SpO₂(t + At) [3]

[0100] In some implementations, %SaO2 is derived by measuring the end-tidal 02 partial pressure (PETO2) and be modulated through gas challenging procedures. With accurately controlled inhalation gas composition (e.g., oxygen partial pressure), PETO2 can be modulated and the %SO2 can be targeted and estimated using equation [4]:

%SaO₂ = 100 wherein n is a correlation parameter for blood pH, having a pre-determined value, and C is an aggregated physiological constant, having a pre-determined value, based on assumed conditions for physiological parameters comprising hematocrit, blood pH and others. Determination of C and n is described by Balaban, D. Y, in Respir. Physiol. NeurobioL 186, 45-52 (2013), which is incorporated by reference herein. In some embodiments, n = -4.4921*pH + 36.365; C = 5x l0^A(-142x(pH¹⁵⁷³¹)) in healthy adults. By targeting a wide range of PETO2, the BOLD signal can be modulated through a wide dynamic range to minimize noise contamination for the calibration process and achieve accurate %SO2 estimation.

[0101] Methods are provided for calibrating magnetic resonance (MR)-based oximetry, or more specifically calibrating parameters in the Luz-Meiboom model for computing blood oxygen saturation (SO2) level based on results of T2 or T2*-weighted, BOLD MRI.

[0102] In various implementations, the parameters for calibration are fixed parameters, i.e., those that do not vary or do not depend from blood oxygen level or T2 or T2*-weighted MRI. In various implementations, the parameters for calibration are both of T20 and K_eff in equation [2], In some embodiments, the parameter(s) for calibration is at least one of 720 and T in equation [2], In some embodiments, the parameter(s) for calibration is T20 in equation [2], In some embodiments, the parameter(s) for calibration is T in equation [2], [0103] In some implementations, a method is provided for calibrating and measuring blood oxygen saturation (SO2) level of an internal organ with magnetic resonance (MR) oximetry (e.g., based on the Luz-Meiboom model), wherein the method includes steps of:

(a) inducing in a subject a breathing pattern effective for varying (e.g., increasing, decreasing, or increasing followed by decreasing, or decreasing followed by increasing) tissue oxygenation or the SO2 level of an internal organ within a period of time, preferably the varying resulting in a difference (compared to baseline) of 3% or greater, 4% or greater, 5% or greater, 6% or greater, 7% or greater, 8% or greater, 9% or greater, or 10% or greater;

(b) performing a blood oxygenation level-dependent (BOLD) MR imaging (e.g., T2 or T2* - weighted or maps) of the tissue or the internal organ of the subject at three or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10 or more) time points within the period of time, thereby obtaining T2 or T2* values of the three or more time points; pulse-oxymetrically measuring a peripheral blood oxygen saturation (SpO2) level of the subject concurrently including or at the three or more time points, thereby obtaining SpO2 values of the three or more time points corresponding (in time) to the T2 or T2* values;

(d) applying the T2 or T2* values and the SpO2 values of corresponding time points in a model of: wherein the T2 or T2* values at a time point tz and the SpO2 values at a time point of (tz+At) (z = 1, 2, 3, 4, . . .) are applied as data points of T2b(t) and %SpO2(t+At) in the model (1), respectively, and said application is done for each of the three or more time points; and solving for one or both of T20 and K_eff in the model (1) based on the application of the T2 or T2* values and the SpO2 values for each of the three or more time points, thereby obtaining one or both of calibrated T20 and calibrated K_eff for the T2 or T2* weighted, BOLD MR-based oximetry; and (e) measuring an S02 level of an internal organ of a test subject by: performing the T2 or T2* maps, BOLD MR imaging of the internal organ of the test subject, thereby obtaining a T2 or T2* value for the test subject, applying the T2 or T2* value for the test subject in a model of: wherein the T2 or T2* value for the test subject is applied as T2b in the model (2), and the one or both of the calibrated T20 and the calibrated K_efr of step (d) are applied as T20 and K_eff, respectively, in the model (2), and solving for %SO2 in the model (2) based on the application of the T2 or T2* value for the test subject and the one or both of the calibrated T20 and the calibrated K_eff, (and a known value of K_eff or T20 if unsolved for in step (d),) thereby obtaining the SO2 level of the internal organ of the test subject.

[0104] In some implementations, a method is for calibrating the Luz-Meiboom model in an MR-based oximetry and measuring blood oxygen saturation (SO2) level of an internal organ based on a calibrated Luz-Meiboom model, wherein the method includes steps of:

(a) inducing in a subject a breathing pattern comprising a first time period of hyperventilation and a second time period of breath holding,

(b) performing a T2 or T2* weighted, blood oxygenation level-dependent (BOLD)- weighted MR imaging of the internal organ of the subject at three or more time points selected within the first time period and/or the second time period, thereby obtaining T2 or T2* values of the three or more time points;

(c) pulsoxymetrically measuring a peripheral blood oxygen saturation (SpO2) level of the subject concurrently at the three or more time points, thereby obtaining SpO2 values of the three or more time points corresponding to the T2 or T2* values;

(d) applying the T2 or T2* values and the SpO2 values of corresponding time points in a model of: wherein the T2 or T2* values and the SpO2 values at time points considering the delay of response are applied as T2b(t) and %SpO2(t+At) in the model (1), respectively, and said application is repeated for each of the rest of the three or more time points; and solving for both or one of T20 and K_eff in the model (1) based on the application of the T2 or T2* values and the SpO2 values for each of the three or more time points, thereby obtaining both or one of calibrated T20 and calibrated K_eff for T2 or T2* weighted, BOLD- weighted MR-based oximetry, thereby obtaining the calibrated Luz-Meiboom model; and

(e) measuring an SO2 level of an internal organ of a test subject based on the calibrated

Luz-Meiboom model: performing the T2 or T2* weighted, BOLD-weighted MR imaging of the internal organ of the test subject, thereby obtaining a T2 or T2* value for the test subject, applying the T2 or T2* value for the test subject in a model of wherein the T2 or T2* value for the test subject is applied as T2b in the model (2), and the both or one of the calibrated T20 and the calibrated K_eff are applied as T20 and K_eff, respectively, in the model (2), and solving for %SO2 in the model (2) based on the application of the T2 or T2* values for the test subject and the both or one of the calibrated T20 and the calibrated K_eff, thereby obtaining the SO2 level of the internal organ of the test subject.

[0105] In some embodiments, the test subject in step (e) is the same as the subject in steps (a)-(c). In some embodiments, the test subject in step (e) is not the same as the subject in steps (a)-(c). In some embodiments, the test subject in step (e) is of a same mammalian species as the subject in steps (a)-(c). In some embodiments, the test subject in step (e) and the subject in steps (a)-(c) are human subjects.

[0106] In various aspects, the breathing pattern in step (a) is effective for varying the SO2 level of the internal organ by about 10% or at least 10%. In further aspects, the breathing pattern in step (a) is effective for varying the pulse-oximetrically measured SpO2 level in step (c) by about 10% or at least 10%.

[0107] In some aspects, the time point is one in a period with modulations.

[0108] In some aspects, the breathing pattern is effective for varying the SO2 level of the internal organ or the SpO2 level between 40% and 100%. In some aspects, the breathing pattern is effective for varying the SO2 level of the internal organ or the SpO2 level between 50% and 100%. In some aspects, the breathing pattern is effective for varying the SO2 level of the internal organ or the SpO2 level between 60% and 100%. In some aspects, the breathing pattern is effective for varying the SO2 level of the internal organ or the SpO2 level between 70% and 100%. In some aspects, the breathing pattern is effective for varying the SO2 level of the internal organ or the SpO2 level between 80% and 100%. In some aspects, the breathing pattern is effective for varying the SO2 level of the internal organ or the SpO2 level between 90% and 100%. In some aspects, the breathing pattern is effective for varying the SO2 of the internal organ or the SpO2 at levels of 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 105%, and any range in between any two of these levels.

[0109] In some aspects, the breathing pattern is effective for varying (inducing to reach and vary in between) the SO2 level of the internal organ or the SpO2 level: at about 40%, at about 100%, and between 40% and 100%. In some aspects, the breathing pattern is effective for varying (inducing to reach and vary in between) the SO2 level of the internal organ or the SpO2 level: at about 50%, at about 100%, and between 50% and 100%. In some aspects, the breathing pattern is effective for varying (inducing to reach and vary in between) the SO2 level of the internal organ or the SpO2 level: at about 60%, at about 100%, and between 60% and 100%. In some aspects, the breathing pattern is effective for varying (inducing to reach and vary in between) the SO2 level of the internal organ or the SpO2 level: at about 70%, at about 100%, and between 70% and 100%. In some aspects, the breathing pattern is effective for varying (inducing to reach and vary in between) the SO2 level of the internal organ or the SpO2 level: at about 80%, at about 100%, and between 80% and 100%. In some aspects, the breathing pattern is effective for varying (inducing to reach and vary in between) the SO2 level of the internal organ or the SpO2 level: at about 90%, at about 100%, and between 90% and 100%.

[0110] In various aspects, the three or more time points in steps (b) and (c) correspond to three or more different SO2 levels of the internal organ, or three or more different SpO2 levels pulsoxymetrically measured at extremities or thin skin of the subject. In further aspects, the three or more different levels have a difference in two closest levels of at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10%.

[OHl] An exemplary breathing pattern is hyperventilation for a first period of time followed by breath holding for a second period of time. Hyperventilation can induce the SO2 or the SpO2 to close to 100%. In some aspects, the breathing pattern is achieved via the subject’s own conscious effort/control of breathing frequency and without a gas controlling device. For example, a fast breathing (i.e., shortened breath-to-breath time gap) will induce a hyperventilation pattern (or a hyperventilation phase); whereas breath-holding is another pattern (or another phase). Alternatively, changes in SO2 level of the subject are actively induced by challenging the subject with gas (with different oxygen partial volume, e.g., 1-5%, 5-10%, 10-15%, 15-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%), or prospectively targeted by using a gas flow controller device with a re-breathing circuit.

[0112] In some implementations, the T2 or T2*-weighted, BOLD MR imaging is sequentially performed, so that MR images are obtained at least about 1 seconds, 3 seconds, 5 seconds, 10 seconds apart, 15 seconds apart, 20 seconds apart, 30 seconds apart, 40 seconds apart, 50 seconds apart, or 1 minute apart, or a combination thereof. In various aspects, the MR images correspond (in time) to SO2, or SpO2, of varying levels. In some implementations, the obtained MR images corresponding to the varying levels of SO2 or SpO2 do not span over 10 minutes.

[0113] In various implementations, T2 and T2* maps are obtained of ‘blood’ (or vessel in an internal organ) with a temporal resolution of 1 heartbeat to catch the underlying blood T2 and T2* change during the SPO2 modulation. T2 and T2* are sensitive to BOLD.

[0114] In various embodiments, the methods do not include blood sampling of either the subject (for calibrating the L-M model) or the test subject. That is, the methods preferably do not require drawing blood samples from the subject to obtain SpO2 or SO2 for the calibration.

[0115] T2 or T2*-weighted, BOLD-weighted MR imaging is described in patent application publications such as US-2018-0271375, WO2020/163783 and U.S. Patent No. 11,129,911, which are incorporated herein by reference in the entirety.

[0116] Exemplary internal organs suitable for the MR-based oximetry include but are not limited to heart, myocardium, brain, kidney, or liver. In some embodiments, the MR-based oximetry is performed on the heart. In some embodiments, the MR-based oximetry is performed on the left ventricle. In some embodiments, the MR-based oximetry is performed on the myocardium including the left ventricle.

[0117] Exemplary pulse oximeters for pulsoxymetrical measurement can detect SpO2 at a fingertip, an ear lobe, or a lip. In some embodiments, pulse oximetry is performed at a fingertip of a subject. In some embodiments, pulse oximetry is performed at an ear lobe o the subject. In some embodiments, pulse oximetry is performed at a lip of a subject. Breathing patterns can be set or controlled by a gas controller device for inhalation by a subject.

[0118] Another method for calibrating magnetic resonance (MR)-based oximetry and measuring blood oxygen saturation (SO2) level of myocardium is provided, which includes:

(a) inducing in a subject a breathing pattern effective for varying the SO2 level of the myocardium within a period of time (e.g., by a difference (compared to baseline) of at least 5%), wherein the breathing pattern can be induced by gas challenging the subject with a gas flow controller device, or by a gas flow controller device adapted for reaching a targeted (predetermined) SO2 level in the left ventricle of a subject; (b) performing a T2 or T2* weighted, blood oxygenation level-dependent (BOLD)- weighted MR imaging of the myocardium of the subject at two or more time points within the period of time, thereby obtaining T2 or T2* values of the two or more time points;

(c) measuring an end-tidal 02 partial pressure (PETO2) of the subject concurrently at each of the two or more time points, thereby obtaining PETO2 values of the two or more time points corresponding in time to the T2 or T2* values;

(d) applying the T2 or T2* values and the PETO2 values of corresponding time points in a model of: wherein %S02 is mathematically (4), and wherein C is an aggregated physiological constant, which includes hematocrit, blood pH and other physiological assumptions on the subject, having a pre-determined value; n is a correlation parameter for blood, which has a pre-determined value; and the T2 or T2* values and the PETO2 value of a corresponding time point are applied as T2b and PETO₂ in models (3) and (4), respectively, and said application is repeated for each of the rest of the two or more time points; solving for both or one of T20 and K_eff in the model (3) based on the application of the T2 or T2* values and the PETO2 values for each of the two or more time points, thereby obtaining both or one of calibrated T20 and calibrated K_eff for T2 or T2* weighted, BOLD- weighted MR-based oximetry; and

(e) measuring an S02 level of a myocardium of a test subject by: performing the T2 or T2* weighted, BOLD-weighted MR imaging of the myocardium of the test subject, thereby obtaining a T2 or T2* value for the test subject, applying the T2 or T2* value for the test subject as T2b and the both or one of the calibrated T20 and the calibrated K_eff as T20 and K_efr, respectively, in the model (3), and solving for %S02 value in the model (3) based on the application of the T2 or T2* value for the test subject and the both or one of the calibrated T20 and the calibrated Keff, and a known value of K_eff or T20 if unsolved for in step (d), thereby obtaining the S02 level of the myocardium of the test subject. [0119] Some embodiments provide for methods for providing calibrated parameters for the L-M model in MR-based oximetry, which includes steps (a)-(d) in a method disclosed above.

[0120] Methods are also provided for performing blood oxygenation level-dependent (BOLD)-weighted MR imaging of an internal organ of a subject and pulse-oxymetrically measuring a peripheral artery blood oxygen saturation (SpO2) of the subject, in which the method include:

(a) inducing in the subj ect a breathing pattern effective for varying blood oxygen saturation (SO2) level of the internal organ (e.g., by at least 5%) within a duration of time, or inducing in the subject a breathing pattern comprising a first time period of hyperventilation and a second time period of breath holding,

(b) performing a T2 or T2* weighted, BOLD-weighted MR imaging of the internal organ of the subject at three or more time points within the duration of time or within the breathing pattern; and

(c) pulse-oximetrically measuring a peripheral artery blood oxygen saturation (SpO2) level of the subject concurrently at the three or more time points.

EXAMPLES

[0121] The following examples are provided to better illustrate the claimed invention and are not to be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention.

Example 1.

[0122] We adopted equation [3] and performed the proposed calibration with SpO2 acquired during image acquisition. We acquired short-axis T2 maps of the heart under a designated breathing maneuver routine (hyperventilation for 10 seconds and breath holding for 2 minutes) to reach different levels of %SO2 in the LV. (Breath holding can be achieved by the subject’s conscious effort. Alternatively, changes in SaO2 level of the subject can be actively induced by challenging the subject with gas (with different 02 partial volume, e.g., 1- 5%, 5-10%, 10-15%, 15-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%), or prospectively targeted by using a gas flow controller device with a re-breathing circuit. T2 maps were acquired with 20 seconds intervals to sample the temporal evolution of blood T2. SpO2 through a fingertip pulse sat monitor was recorded simultaneously during the image acquisition. T2 of the LV blood and SpO2 from the first minute were used to fit the L-M model using equation [5] (combing equations [2] and [3]), and thereby T20, K_eff, and Af were determined.

[0123] In some embodiments, a separate function depicting SpO2 levels as a function of time is obtained. So, AMs solved for by another step of estimating the lag of time in changes compared to the function of SO2 over time, or is solved for from equation [5] where 3 parameters are derived: Keff, T20, and A

[0124] LV blood T2 and SpO2 at 80 seconds, 100 sec, and 120 sec into the breath-hold were used to validate the calibration. RV blood throughout the period was also calculated based on the fitted parameters to determine whether they are in the physiological range reported from previous studies. A flow chart of the image acquisition and post-processing procedure is presented in figure 1.

[0125] Blood oxygenation-sensitive images (T2map) and SpO2 acquired during the breathing maneuver are presented in figure 2. SpO2 throughout the breathing maneuver period is presented in panel A. As expected SpO2 increases to near 100% after hyperventilation and start decreasing after 10 seconds into the breath-hold. The SpO2 reduced to 76% after 2 minutes of holding breath. A similar trend is observed in the T2 values of the blood pool (panel B). T2 values of blood are measured with manually drawn ROI in the blood pool on the T2 maps. Elevated T2 values after hyperventilation and strongly decreased blood T2 after prolonged breath-hold is observed. T2 values of the LV and RV blood are measured and presented in panel C and D, respectively. In contrast to the LV blood, RV blood T2 was flat throughout the hyperventilation period. During the breath-hold, RV blood T2 dropped significantly after 80 seconds, which reflects nicely to the deficient oxygen supply. LV are representative of arterial blood and RV are representative of venous blood.

[0126] The fitted parameters for the L-M model and measured T2 values are presented in figure 3. Both LV and RV blood regressed well to the model. L-M parameters ( T =152.8 ms and T20M 10 ms, t=15 sec) are comparable to the previously reported in vitro values. Both arterial and venous blood T2 regressed nicely to the theoretical L-M model for SO2 derivation (Fig.3). The triangular points are the delay(At)-corrected arterial SO2 (SaO2) during the first 4 time points. The circular points are the delay(At)-corrected arterial SO2 (SaO2) of time point 5-7. The diamond points are the venous T2 and its derived SO2 under all 7 time points. The range of the predicted venous SO2 corresponds nicely to the physiological range of populational normal venous blood.

[0127] Temporally resolved blood oxygenation saturation level (SO2) derived based on the MRI signal (cardiovascular MR, CMR) and the calibrated model are presented in figure 4. Both RV CMR-SO2 (“SVO2”) and LV CMR-SO2 (“SaO2”) are within the physiological range reported in the literature.

[0128] Techniques for breathing maneuver and prospective control of arterial blood have been developed for other purposes. However, individuals can have different responses and tolerance to an underlying %SaO2 modulation. Based on our study, a reduction of %SaO2 to 90%, which is in the range of normoxia, can provide sufficient variation in the BOLD signals to calibrate the underlying parameters. Intermittent hypoxia has been reported to be tolerable in most of the subjects, while minimum complications and side effects were reported in both human volunteers and patients.

[0129] Therefore, MR oximetry can be accurately calibrated with breathing maneuvers and combined blood oxygenation level monitoring. The combination of innovative dynamic measurement of SpO2 and MR BOLD signal during PaO2 modulation can serve as a risk-free platform to accurately measure blood oxygenation levels in all vessels in the human body. We also conceive the feasibility in patients and through other means of SaO2 manipulation, such as gas challenging and different breathing patterns.

[0130] Various embodiments of the invention are described above in the Detailed Description. While these descriptions directly describe the above embodiments, it is understood that those skilled in the art may conceive modifications and/or variations to the specific embodiments shown and described herein. Any such modifications or variations that fall within the purview of this description are intended to be included therein as well. Unless specifically noted, it is the intention of the inventors that the words and phrases in the specification and claims be given the ordinary and accustomed meanings to those of ordinary skill in the applicable art(s).

[0131] The foregoing description of various embodiments of the invention known to the applicant at this time of filing the application has been presented and is intended for the purposes of illustration and description. The present description is not intended to be exhaustive nor limit the invention to the precise form disclosed and many modifications and variations are possible in the light of the above teachings. The embodiments described serve to explain the principles of the invention and its practical application and to enable others skilled in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. Therefore, it is intended that the invention not be limited to the particular embodiments disclosed for carrying out the invention.

[0132] While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that, based upon the teachings herein, changes and modifications may be made without departing from this invention and its broader aspects and, therefore, the appended claims are to encompass within their scope all such changes and modifications as are within the true spirit and scope of this invention. It will be understood by those within the art that, in general, terms used herein are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.).

[0133] As used herein the term “comprising” or “comprises” is used in reference to compositions, methods, and respective component(s) thereof, that are useful to an embodiment, yet open to the inclusion of unspecified elements, whether useful or not. It will be understood by those within the art that, in general, terms used herein are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). Although the open-ended term “comprising,” as a synonym of terms such as including, containing, or having, is used herein to describe and claim the invention, the present invention, or embodiments thereof, may alternatively be described using alternative terms such as “consisting of’ or “consisting essentially of.”

Claims

CLAIMS WE CLAIM:

1. A method of taking oximetry measurements in a subject or calibrating an oxygen sensitive imaging technique for use in determining blood oxygen saturation (SO2) level in a tissue of the subject, the method comprising: measuring a change in imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver; measuring a change in peripheral oxygen saturation (SpO2) using a pulse oximeter in response to the breathing maneuver; fitting the measured imaging data and the measured SpO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, wherein the SO2 level in the tissue is approximated in the fitting by the measured SpO2, and solving for one or more fixed parameters of the equation based on the measured imaging data and the measured SpO2, thereby calibrating the fixed parameters in the equation; performing an acquisition of the imaging data in the tissue in the subject using the oxygen sensitive imaging technique; and converting the acquired imaging data into SO2 level using the equation containing the calibrated fixed parameters, thereby taking the oximetry measurements in the subject or determining the SO2 level in the tissue of the subject.

2. The method of claim 1, wherein the breathing maneuver comprises a breath-hold, a period of hyperventilation, or a sequential combination of both.

3. The method of claim 2, wherein the breath-hold is voluntary.

4. The method of claim 2, wherein the breathing maneuver is induced by a machine.

5. The method of claim 1, wherein the breathing maneuver varies the SO2 level in the tissue or the SpO2 by at least 5%.

6. The method of claim 1, wherein the oxygen sensitive imaging technique comprises blood oxygen level dependent magnetic resonance imaging (BOLD-MRI), nuclear techniques, single-photon emission computed tomography (SPECT), positron emission tomography (PET), computed tomography (CT), echocardiography or other ultrasound, near infrared spectroscopy (NIRS), intravascular blood flow measurements, fractional flow reserve, impedance measurements of the myocardium or other organ, or a combination thereof.

7. The method of claim 1, wherein the oxygen sensitive imaging technique comprises BOLD-MRI, and wherein the imaging data comprises T2 relaxation time, T2*, T1 relaxation time, or susceptibility contrast.

8. The method of claim 1, wherein the equation is wherein T2b is the imaging data on the tissue, %SO2 is the SO2 level of the tissue, and T20 and K_eff are fixed parameters of the equation.

9. The method of claim 8, wherein the approximating in the fitting comprises approximating the SO2 level of the tissue to an SpO2 measured at a time delay At relative to when the imaging data is measured, wherein the fitting comprises fitting to the equation at least two pairs of the measured imaging data and the measured SpO2 at the time delay At, and wherein the solving comprises solving for T20 and K_eir of the equation.

10. The method of claim 9, wherein the time delay At is a user-selected time delay.

11. The method of claim 9, wherein the time delay At is about 15 seconds or between 10 and 20 seconds, when the tissue being imaged is heart or myocardium and the pulse oximeter measures at fingertip, earlobe, lip, or wrist.

12. The method of claim 9, wherein the time delay At is determined by calculating a lag of time in a SpO2 response to an altered oxygenation or blood flow relative to a SO2 response of the tissue to the altered oxygenation or blood flow, wherein the time lag-corrected SpO2 response and the SO2 response of the tissue has an R-squared value of 0.8 or greater.

13. The method of claim 1, wherein the method does not include infusion of a vasodilator in the subject, and the method does not include withdrawing blood from the subject.

14. A method of taking oximetry measurements in a subject or calibrating an oxygen sensitive imaging technique for use in determining blood oxygen saturation (SO2) level in a tissue of the subject, the method comprising: measuring a change in imaging data in the tissue using an oxygen sensitive imaging technique in response to a breathing maneuver; measuring a change in end-tidal 02 partial pressure (PETO2) in the tissue using a gas flow controller device in response to the breathing maneuver, and thereby computing a change in the SO2 level of the tissue from the PETO2 based on a correlation of SO2 = mn ^c^^pET0₂')ⁿ . . . , , . , . , , . ,

TUU - - wherein C is an aggregated physiological constant having a pre-determined

^ + C PETO₂) value, and n is a correlation parameter for blood pH and has another pre-determined value; fitting the measured imaging data and the computed SO2 level from the PETO2 to an equation that models a relationship between the imaging data and the SO2 level in the tissue, and solving for one or more fixed parameters of the equation based on the measured imaging data and the computed SO2 level from the PETO2, thereby calibrating the fixed parameters in the equation; performing an acquisition of the imaging data in the tissue in the subject using the oxygen sensitive imaging technique; and converting the acquired imaging data into SO2 level using the equation containing the calibrated fixed parameters, thereby taking the oximetry measurements in the subject or determining the SO2 level in the tissue of the subject.

15. The method of claim 14, wherein the oxygen sensitive imaging technique comprises BOLD-MRI, wherein the imaging data comprises T2 relaxation time, wherein the equation is wherein T2b is the T2 relaxation time on the tissue, %SO2 is the SO2 level of the tissue, and T20 and K_eff are fixed parameters of the equation.

16. A method for calibrating an oxygen sensitive imaging technique, comprising:

(c) measuring a series of peripheral blood oxygen saturation (SpO2) level of the subject using a pulse oximeter over the time course t; or detecting the SO2 level of the blood vessel supporting the first organ at each of the at least two time points, or reaching predetermined SO2 levels in the blood vessel supporting the first organ while the T2 maps or the T2* maps are being acquired at the at least two time points ti and t2;

(d) if step (c) measures the series of the SpO2 level over the time course, estimating a lag of time At in the SpO2 response relative to the varied SO2 level in the blood vessel supporting the first organ, obtaining SpO2 value at each of time points ti+At and t2+At from the series of the SpO2 level over the time course, and fitting the T2 or T2* values at ti and t2 and the SpO2 values at ti+At and t?+At in pairs to a first equation of wherein T2b(t) is an apparent blood T2 or T2* relaxation time at a time point t, %SpO2(t+At) is the SpO2 level at a time point t+At, and T20 and Keff are fixed parameters of the first equation; or if step (c) detects the SO2 level or reaches the predetermined SO2 levels, fitting the T2 or T2* values at ti and t2 and the SO2 levels at ti and t2 in pairs to a second equation: wherein the T2b(t) is the apparent blood T2 or T2* relaxation time at the time point t, the %S02(t) is the SO2 level at the time point t, and the 720 and the K_eff are fixed parameters of the second equation; and

17. The method of claim 16, wherein the method is for calibrating blood oxygen level dependent magnetic resonance imaging (BOLD-MRI)-based oximetry in a subject, and the steps (a) through (c) are performed on the subject.

18. The method of claim 16, wherein the first organ comprises myocardium or heart.

19. The method of claim 16, wherein the calibration is for use in determining SO2 level in a target organ same as the first organ.

20. The method of claim 17, wherein the calibration is for use in determining SO2 level in a target organ different from the first organ in the same subject.

21. The method of claim 16, wherein the calibration is for use in determining SO2 level in a target organ myocardium, heart, brain, kidney, liver, or pancreas.

22. The method of claim 16, wherein the breathing pattern in step (a) comprises a first time period of hyperventilation and a second time period of breath-hold.

23. The method of claim 16, wherein inducing the breathing pattern in step (a) comprises operating a gas flow controller device to administer a gas mixture, optionally a mixture of oxygen and carbon dioxide, via inhalation.

24. The method of claim 16, wherein the estimating of the At in step (d) comprises calculating a lag of time in a SpO2 response to an altered oxygenation or blood flow relative to a SO2 response of the tissue to the altered oxygenation or blood flow, wherein the time lag- corrected SpO2 response and the SO2 response of the tissue has an R-squared value of 0.8 or greater.

25. The method of claim 16, wherein the At is about 15 seconds or between 10 and 20 seconds, when the tissue being imaged is heart or myocardium and the pulse oximeter measures at fingertip, earlobe, lip, or wrist.

26. The method of claim 16, wherein detecting the SO2 level in step (d) comprises measuring an end-tidal 02 partial pressure (PETO2) in the blood vessel supporting the first organ, thereby obtaining PETO2 values at the two or more time points, and computing the SO2 1 1 level aggregated , p ,hysi .o ,logi .ca ,l constant , havi .ng a pre- determined value for the subject, and n is a correlation parameter for blood pH and has a predetermined value.

27. The method of claim 16, wherein reaching pre-determined SO2 levels in step (c) is performed using a gas flow controller device to deliver an effective amount of gas for modulating the SO2 level in the blood vessel supporting the first organ.

28. The method of claim 16, wherein the varied SO2 level in the blood vessel supporting the first organ contains at least two different SO2 levels being different by 5% or greater.

29. The method of claim 16, wherein the breathing pattern in step (a) is effective for varying the SO2 level by 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, 80-90%, or 90-100%, or greater than 100%.