Method for measuring cerebrovascular reactivity using hypoxia as a vasoactive factor

Abstract

To provide a technique for measuring cerebrovascular reactivity.SOLUTION: A method for quantitative measurement of cerebrovascular reactivity (CVR) combines sequential gas delivery with Δ R2 * - based perfusion analysis. The sequential gas delivery imposes a first staged reoxygenation 304 after a first hypoxia 302 and a second staged reoxygenation 310 after a second hypoxia 308. MRI gradient echo imaging records the Δ R2 * time course in the target voxel during each reoxygenation. The sigmoid fit yields perfusion indices including relative cerebral blood flow, relative cerebral blood volume, and mean transit time. Comparison of indices derived from two re-oxygenation sessions yields numerical CVR values that are reproducible between sessions and subjects.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 674,732, filed July 23, 2024, entitled "METHOD OF MEASURING CEREBRAL VASCULAR REACTIVITY USING HYPOXIA AS VASOACTIVE AGEN," the entire contents of which are incorporated herein by reference.

[0002] (Field) This specification relates to techniques for hemodynamic assessment, and in particular for measuring cerebrovascular reactivity. [Background technology]

[0003] Cerebrovascular reactivity is most often induced by either intravenous acetazolamide, a carbonic anhydrase inhibitor that acidifies the blood and dilates cerebral vessels over a 10- to 20-minute interval, or hypercapnia, produced by inhaled or endogenously accumulated carbon dioxide, which acts rapidly but is difficult to accurately reproduce between and within subjects. The resulting changes in blood flow are typically estimated by magnetic resonance blood oxygen level-dependent (BOLD) imaging or arterial spin labeling (ASL). While BOLD relies on stable cerebral oxygen consumption and blood volume, ASL suffers from low signal-to-noise ratios, limited spatial and temporal resolution, and sensitivity to variations in arterial transit time. Therefore, the accuracy and reproducibility of assessments of cerebrovascular reactivity are still limited by the characteristics of these stimuli and measurement techniques.

[0004] One study attempted to use hypoxia as a vasoactive stimulant (Hannah R Johnson, Max C Wang, Rachael C Stickland, Yufen Chen, and Molly G Bright, “Toward Reliable quantification of Global Cerebrovascular Reactivity to Hypoxic Hypoxia” (2024) International Society of Magnetic Resonance Medicine, Abstract 2485). The authors used a computer-controlled gas-mixing device to induce baseline, hypoxic (PO2 = 60 mmHg), and hypercapnic respiratory states and measured cerebral blood flow in the extracranial aorta using phase-contrast MRI. Although the authors attempted mathematical correction, unintended changes in CO2 during hypoxia caused significant variations in the measured CVR. Due to an additional limitation that phase contrast can only be performed in large vessels or cardiac valves, capillary blood flow measurements were not performed. Summary of the Invention

[0005] The present disclosure provides an improved method for using hypoxia as a vasoactive stimulus in measuring CVR. According to the method described herein, by utilizing sequential gas delivery to impose a controlled decrease in arterial oxygen saturation followed by acute reoxygenation while independently controlling arterial carbon dioxide concentration, a precisely reproducible vasoactive stimulus can be delivered to a subject for the purpose of cerebrovascular-reactivity mapping. Cerebral blood flow is measured by multi-echo T2 imaging during the reoxygenation event. * It is measured directly from imaging, allowing direct measurement of capillary blood flow within tissue.

[0006] In one aspect, the present disclosure provides a method for measuring cerebrovascular reactivity in a subject, comprising the steps of imposing (applying, implementing, or implementing) a first stepwise reoxygenation from a first hypoxic condition using sequential gas delivery; imposing (implementing, implementing, or implementing) a second stepwise reoxygenation from a second hypoxic condition using sequential gas delivery, the second stepwise reoxygenation being selected to cause greater vasodilation than the first hypoxic condition; and measuring ΔR2 in a target voxel in response to the first stepwise reoxygenation and the second stepwise reoxygenation. * Measuring the time course and ΔR2 measured during the first reoxygenation and the second reoxygenation. * The method includes calculating first and second perfusion metrics based on a time course, and comparing the first perfusion metric to the second perfusion metric to determine cerebrovascular reactivity.

[0007] In one example, the steps of imposing the first stepwise reoxygenation and the second stepwise reoxygenation include restoring normoxia in the subject.

[0008] In one example, the steps of imposing the first stepwise reoxygenation and the second stepwise reoxygenation include restoring the subject's arterial blood oxygen partial pressure to between 90 mmHg and 100 mmHg.

[0009] In one example, the second hypoxic state has a longer duration or a lower arterial oxygen tension than the first hypoxic state.

[0010] In one example, the arterial blood oxygen partial pressure during the first hypoxic state and during the second hypoxic state is less than 60 mmHg.

[0011] In one example, the arterial blood oxygen partial pressure during the first hypoxic state and during the second hypoxic state is less than 40 mmHg.

[0012] In one example, arterial carbon dioxide tension is maintained during the administration of stepwise reoxygenation.

[0013] In one example, the step of calculating the first perfusion index and the second perfusion index includes: * The perfusion index of the target voxel, including fitting to the time course, is further based on a sigmoid function.

[0014] In one example, the first perfusion index and the second perfusion index comprise relative cerebral blood volume, and the first perfusion index and the second perfusion index are calculated as the magnitude of a sigmoid function.

[0015] In one example, the first perfusion index and the second perfusion index comprise relative cerebral blood flow, and the first perfusion index and the second perfusion index are calculated as a maximum rate of decrease of a sigmoid function.

[0016] In one example, the first perfusion index and the second perfusion index include a mean transit time calculated as a ratio of relative cerebral blood volume to relative cerebral blood flow.

[0017] A further aspect herein is a method of measuring cerebrovascular reactivity in a subject, comprising the steps of: imposing a first stepwise reoxygenation from a first hypoxic state using sequential gas delivery, the first stepwise reoxygenation being selected to minimize vasodilation; administering a vasoactive stimulant to the subject; imposing a second stepwise reoxygenation from a second hypoxic state using sequential gas delivery, the second stepwise reoxygenation being selected to minimize vasodilation; and measuring ΔR2 at a target voxel in response to the first stepwise reoxygenation and the second stepwise reoxygenation. * Measuring the time course and ΔR2 measured during the first reoxygenation and during the second reoxygenation. * The method includes calculating a first perfusion index and a second perfusion index based on a time course, and comparing the first perfusion index to the second perfusion index to determine cerebrovascular reactivity.

[0018] In one example, the vasoactive stimulant is carbon dioxide, the first stepwise reoxygenation is imposed under normocapnic conditions, and the carbon dioxide stimulant is administered as hypercapnia.

[0019] In one example, the steps of imposing the first stepwise reoxygenation and the second stepwise reoxygenation include restoring normoxic conditions in the subject.

[0020] In one example, the step of calculating the first perfusion index and the second perfusion index comprises using a sigmoid function ΔR * The perfusion index of the target voxel, including fitting to the time course, is further based on a sigmoid function.

[0021] In one example, the first perfusion index and the second perfusion index comprise relative cerebral blood volume, and the first perfusion index and the second perfusion index are calculated as the magnitude of a sigmoid function.

[0022] In one example, the first perfusion index and the second perfusion index comprise relative cerebral blood flow, and the first perfusion index and the second perfusion index are calculated as a maximum rate of decrease of a sigmoid function.

[0023] In one example, the first perfusion index and the second perfusion index include a mean transit time calculated as a ratio of relative cerebral blood volume to relative cerebral blood flow.

[0024] A still further aspect of the present disclosure provides a system for measuring cerebral vascular reactivity in a subject, the system comprising a sequential gas supply device configured to impose a first stepwise reoxygenation from a first hypoxic state and a second stepwise reoxygenation from a second hypoxic state that causes greater vasodilation than the first hypoxic state. The system is configured to measure ΔR2 in at least one target voxel during the first stepwise reoxygenation and the second stepwise reoxygenation. * A magnetic resonance imaging system that measures the time course and ΔR2 *and a processor that calculates the first perfusion index and the second perfusion index over time and compares the perfusion indexes to determine a value of cerebrovascular reactivity.

[0025] In one example, the sequential gas supply restores normoxic conditions between each step of reoxygenation.

[0026] In one example, normoxia is restored by restoring the subject's arterial oxygen partial pressure to between 90 mmHg and 100 mmHg.

[0027] In one example, the second hypoxic condition results in greater vasodilation than the first hypoxic condition by using a longer exposure, a lower arterial oxygen tension, or a combination of both parameters.

[0028] In one example, the arterial oxygen partial pressure during hypoxia is less than 60 mmHg.

[0029] In one example, the arterial oxygen partial pressure during hypoxia is less than 40 mmHg.

[0030] In one example, the sequential gas delivery device maintains the subject's arterial blood carbon dioxide partial pressure while imposing graded reoxygenation.

[0031] In one example, the processor may use a sigmoid function to calculate each ΔR2 when calculating the first perfusion index and the second perfusion index. * Adapt it over time.

[0032] In one example, each perfusion index includes a relative cerebral blood volume determined from the magnitude of a sigmoid function.

[0033] In one example, each perfusion index includes a relative cerebral blood flow determined from the maximum rate of decline of a sigmoid function.

[0034] In one example, each perfusion index includes a mean transit time calculated as the ratio of relative cerebral blood volume to relative cerebral blood flow.

[0035] A further aspect of the present disclosure provides a system for measuring cerebrovascular reactivity in a subject, the system comprising a sequential gas delivery device configured to impose a first stepwise reoxygenation from a first hypoxic condition selected to minimize vasodilation, administer a vasoactive stimulant to the subject, and impose a second stepwise reoxygenation from a second hypoxic condition selected to minimize vasodilation. The system measures ΔR2 in at least one target voxel during the first stepwise reoxygenation and during the second stepwise reoxygenation. * A magnetic resonance imaging system that measures the time course and ΔR2 * and a processor that calculates the first perfusion index and the second perfusion index over time and compares the perfusion indexes to determine a cerebrovascular reactivity value.

[0036] In one example, the vasoactive stimulator is carbon dioxide, and the sequential gas delivery device imposes hypercapnia during stimulation, maintains normoxia, and restores normocapnia during a second stepwise reoxygenation.

[0037] In one example, a sequential gas supply restores normoxic conditions during both stages of reoxygenation.

[0038] In one example, the processor may use a sigmoid function to calculate each ΔR2 when calculating the first perfusion index and the second perfusion index. * Adapt it over time.

[0039] In one example, each perfusion index includes a relative cerebral blood volume determined from the magnitude of a sigmoid function.

[0040] In one example, each perfusion index includes a relative cerebral blood flow determined from the maximum rate of decline of a sigmoid function.

[0041] In one example, each perfusion index includes a mean transit time calculated as the ratio of relative cerebral blood volume to relative cerebral blood flow.

[0042] These, together with other aspects and advantages which will become apparent hereinafter, reside in the details of construction and operation as more particularly described and claimed hereinafter, and reference is made to the accompanying drawings which form a part hereof, and in which like numerals refer to like parts throughout. [Brief explanation of the drawings]

[0043] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0044] The present disclosure will be described with reference to the following drawings:

[0045] [Figure 1] FIG. 1 is a schematic diagram of a system for measuring cerebrovascular reactivity according to one embodiment.

[0046] [Figure 2] FIG. 2 is a schematic diagram of an exemplary method for measuring cerebrovascular reactivity using the system of FIG. 1, according to one embodiment.

[0047] [Figure 3] 3 is a graph illustrating an exemplary implementation of the method of FIG. 2.

[0048] [Figure 4] 3 is a graph illustrating an exemplary implementation of the method of FIG. 2.

[0049] [Figure 5] 1 is a graph showing transcranial Doppler measurements of vascular response to hypoxia.

[0050] [Figure 6] 3 is a graph illustrating an exemplary implementation of the method of FIG. 2.

[0051] [Figure 7] 3 is a graph illustrating an exemplary implementation of the method of FIG. 2.

[0052] [Figure 8A] 3 is a perfusion map illustrating an exemplary implementation of the method of FIG. 2 shown in grayscale. [Figure 8B] 3 is a perfusion map illustrating an exemplary implementation of the method of FIG. 2 shown in grayscale. [Figure 8C] 3 is a perfusion map illustrating an exemplary implementation of the method of FIG. 2 shown in grayscale. [Figure 8D] 3 is a perfusion map illustrating an exemplary implementation of the method of FIG. 2 shown in grayscale.

[0053] [Figure 9] A)-D) are color-coded perfusion maps illustrating an exemplary implementation of the method of FIG. DETAILED DESCRIPTION OF THE INVENTION

[0054] The following abbreviations are used herein: [Table 1]

[0055] The following definitions are used herein:

[0056] As used herein, the term "about" refers to a range of ±20% of the preceding numerical value. In one example, the term "about" refers to a range of ±10% of the preceding numerical value. In another example, the term "about" refers to a range of ±5% of the preceding numerical value.

[0057] As used herein, "hypoxia" refers to blood having an abnormally low oxygen concentration. a O2 is less than about 80 mm Hg.

[0058] As used herein, "normoxia" refers to blood having a normal oxygen concentration. Generally, normoxic P a O2 is approximately 70mmHg to approximately 110mmHg.

[0059] FIG. 1 illustrates a system 100 for measuring cerebrovascular reactivity using sequential gas delivery. The system 100 includes a respiratory device. Generally, the respiratory device includes a means for delivering a hypoxic gas to a subject and then delivering an oxygen-containing gas to the subject. In one example, the respiratory device includes an inspiratory tube with a three-way valve for delivering the gas to the subject and an expiratory tube for receiving the expiratory gas. The inspiratory tube is configured to deliver the hypoxic gas to the subject. After inducing hypoxia in the subject, the three-way valve is activated to deliver oxygen-only or oxygen-enriched gas to the subject, thereby producing higher hemoglobin saturation. In the example described herein, the respiratory device is a sequential gas delivery (SGD) device 101 configured to deliver gas to the subject 130 and target an arterial blood partial pressure of a gas, such as CO or O. The SGD device 101 allows for the subject to achieve a target P while maintaining normocapnia. a The system 100 further comprises a magnetic resonance imaging (MRI) system 102. The SGD device 101 comprises a gas supply device 103, a gas mixing device 104, a mask 108, a processor 110, a memory 112, and a user interface 114. The SGD device 101 estimates the subject's end-tidal CO2 partial pressure (P) by performing a gas flow prediction. ET CO2) and the subject's end-tidal O2 partial pressure (P ET The SGD device 101 may be configured to control the saturation of the saturation gas (O2) to activate a target end-tidal value. The SGD device 101 may be a RespirAct™ device (Thornhill Medical™, Toronto, Canada) specially configured to implement the techniques described herein. For more information regarding sequential gas delivery, see U.S. Pat. No. 8,844,528, U.S. Patent Application Publication No. 2018 / 0043117, and U.S. Pat. No. 10,850,052, which are incorporated herein by reference.

[0060] The gas supply 103 may supply, for example, carbon dioxide, oxygen, nitrogen, and air at controllable rates defined by the processor 110. Non-limiting examples of gas mixtures provided by the gas supply 103 are: a. Gas A: 4% O2, 96% N2; b. Gas B: 4% O2, 96% CO2; c. Gas C: 100% O2; and d. Calibration gas: 10% O2, 9% CO2, 81% N2.

[0061] The gas mixer 104 is connected to the gas supply device 103, receives gases from the gas supply device 103, and mixes the received gases as controlled by the processor 110 to obtain a gas mixture such as a first gas (G1) and a second gas (G2) for sequential gas supply.

[0062] The second gas (G2) is a neutral gas in the sense that it has approximately the same composition as the gas exhaled by the subject 130, which contains approximately 4% to 5% carbon dioxide. In some examples, the second gas (G2) may contain the gas actually exhaled by the subject 130. The first gas (G1) is a neutral gas that contains approximately 4% to 5% carbon dioxide. ET It has an oxygen composition equivalent to O2 and preferably does not have a significant amount of carbon dioxide. For example, the first gas (G1) may be air (typically having about 0.04% carbon dioxide), or may be composed of 21% oxygen and 79% nitrogen, or a gas of similar composition, preferably without appreciable CO2.

[0063] The processor 110 can control the gas mixer 104, such as by electronic valves, to deliver the gas mixture in a controlled manner. ET O2 and target P ETThe processor 410 may be configured to calculate the compositions of the first gas (G1) and the second gas (G2) required to achieve CO2. The processor 410 may calculate the compositions of the first gas (G1) and the second gas (G2) according to a predicted targeting algorithm. The processor 410 may further calculate the compositions of the first gas (G1) and the second gas (G2) according to feedback received from one or more sensors 132. In particular, the sensor 132 may measure the composition of exhaled gas.

[0064] The mask 108 is connected to the gas mixing device 104 and supplies gas to the subject 130. The mask 108 can be sealed to the subject's face to ensure that the subject 130 only inhales the gas supplied to the mask 108 by the gas mixing device 104. In some examples, the mask is sealed to the subject's face with skin tape, such as Tegaderm™ (3M™; Saint Paul, Minnesota). A valve arrangement 106 can be provided in the SGD device 101 to restrict the subject's inhalation to the gas supplied by the gas mixing device 104 and their exhalation to the chamber. In the example shown, the valve arrangement 106 includes an inhalation one-way valve from the gas mixing device 104 to the mask 108, a branch between the inhalation one-way valve and the mask 108, and an exhalation one-way valve at the branch. Thus, the subject 130 inhales gas from the gas mixing device 104 and exhales gas into the chamber.

[0065] The subject 130 may be spontaneously breathing or may be ventilated.

[0066] The gas supply 103, gas mixing device 104, and mask 108 may be physically connectable by conduits 109, such as tubing, for carrying gas. Any suitable number of sensors 132 may be positioned in the gas mixing device 104, mask 408, and / or conduits 409 to sense gas flow, pressure, temperature, and / or similar properties and provide this information to the processor 110. Gas properties may be sensed at any suitable location to measure properties of gases inhaled and / or exhaled by the subject 130.

[0067] The processor 110 may comprise a central processing unit (CPU), microcontroller, microprocessor, processing core, field programmable gate array (FPGA), application specific integrated circuit (ASIC), or similar device capable of executing instructions. The processor 110 may be connected to and cooperate with memory 112 that stores instructions and data.

[0068] The memory 112 comprises a non-transitory machine-readable medium, such as an electronic, magnetic, optical, or other physical storage device that encodes instructions. This medium may include, for example, random access memory (RAM), read-only memory (ROM), electrically erasable programmable read-only memory (EEPROM), flash memory, storage drives, optical devices, or the like.

[0069] The user interface 114 may include a display device, a touch screen, a keyboard, a speaker, a microphone, indicators, buttons, etc., or combinations thereof, to allow for operator input and / or output.

[0070] Instructions 120 may be provided to perform the functions and methods described herein. The instructions 120 may be directly executable, such as a binary file, and / or may include interpretable code, bytecode, source code, or similar instructions that may undergo further processing to be executed. The instructions 120 may be stored in memory 112.

[0071] The system 100 further includes an MRI system 102 for performing magnetic resonance imaging on the subject 130. Suitable MRI equipment may include a scanner 118, such as a 3-Tesla (3T) MRI scanner or a 7-Tesla (7T) MRI scanner. A suitable example of a 3T MRI scanner is the Signa HDxt 3.0T™ offered by GE Healthcare (Milwaukee, USA). A suitable example of a 7-Tesla MRI scanner is the MAGNETOM™ 7T MRI offered by Siemens (Munich, Germany). In addition to the scanner 418, the MRI system 402 may further include a processor 126, a memory 128, and a user interface 124.

[0072] Any description of processor 126 may also apply to processor 110, and vice versa. Similarly, any description of memory 128 may also apply to memory 112, and vice versa. Similarly, any description of instructions 122 may also apply to instructions 120, and vice versa. Also, any description of user interface 124 may also apply to user interface 114, and vice versa. In some embodiments, MRI system 102 and SGD device 101 share one or more of memory, processor, user interface, and instructions, but in this disclosure, MRI system 102 and SGD device 101 are described as having their own processors, user interfaces, memory, and instructions. Processor 410 of SGD device 101 may send data and instructions to processor 126 of MRI system 102. Processor 126 of MRI system 102 may send data and instructions to processor 110 of SGD device 101. The system 100 may be configured to synchronize MRI images acquired by the MRI system 102 with measurements acquired by the SGD device 101 .

[0073] The processor 126 can retrieve the operating instructions 122 from the memory 128 or the user interface 124. The operating instructions 122 can include image acquisition parameters. The parameters can include a predetermined number of contiguous slices, a defined isotropic resolution, a diameter of the field of view, a repetition time (TR), and an echo time. Multi-echo T2 * A variety of protocols, such as imaging, can be utilized.

number

[0074] The user interface 124 may include a display device, a touch screen, a keyboard, a speaker, indicators, a microphone, buttons, etc., or a combination thereof, to allow for operator input and / or output. Data generated and images acquired by the processor 126 may be displayed on the user interface 124.

[0075] 2 illustrates an exemplary method 200 for measuring cerebrovascular reactivity in a subject. Method 200 may be performed using system 100, but method 200 is not particularly limited.

[0076] Block 204 includes imposing a first staged reoxygenation using sequential gas delivery. In system 100, block 204 is performed by SGD device 101, which delivers gas to a subject to create a first hypoxic state and then reoxygenates the subject's arterial blood.

[0077] The first hypoxic state is imposed by controlling the subject's arterial oxygen partial pressure (PaO2), particularly by lowering the subject's PaO2 below normoxia. In a specific, non-limiting example, the PaO2 of the first hypoxic state is less than 60 mmHg, more specifically between about 40 mmHg and about 50 mmHg. In a further, non-limiting example, the PaO2 of the first hypoxic state is less than or about 40 mmHg. By lowering the subject's PaO2 below 60 mmHg, block 204 can induce a measurable degree of vasodilation in the tissue. Notably, 40 mmHg is adjacent to the steepest portion of the oxyhemoglobin dissociation curve; therefore, the closer the PaO2 is to 40 mmHg, the stronger the signal will be.

[0078] Once the first hypoxic condition has been imposed for a selected period of time, a first stepwise reoxygenation is imposed. The first stepwise reoxygenation includes an increase in the subject's PaO2 sufficient to cause a measurable magnetic signal. In some examples, the first stepwise reoxygenation restores normoxia to the subject. In further examples, the first stepwise reoxygenation restores PaO2 to approximately 80 mmHg. In further examples, the first stepwise reoxygenation restores PaO2 to approximately 85 mmHg. In further examples, the first stepwise reoxygenation restores PaO2 to approximately 90 mmHg. In further examples, the first stepwise reoxygenation restores PaO2 to approximately 95 mmHg. In further examples, the first stepwise reoxygenation restores PaO2 to approximately 100 mmHg. In further examples, the first stepwise reoxygenation restores PaO2 to approximately 105 mmHg. In still other examples, the first stepwise reoxygenation restores PaO2 to about 90 mmHg to about 100 mmHg. In some examples, the stepwise reoxygenation is rapid, and in certain examples, the stepwise reoxygenation occurs during a single inspiration. The duration of inspiration is typically about 0.5 seconds to about 2.0 seconds. Generally, restoring to normoxia is more rapid and reproducible than targeting a hyperoxic PaO2, and therefore, this step is better tolerated by the subject, especially when blocks 204 through 212 are repeated to obtain multiple measurements.

[0079] As part of block 204, the SGD device 101 may maintain the subject's arterial blood carbon dioxide partial pressure (PaCO2) while imposing the first hypoxic condition and the first stepwise reoxygenation.

[0080] Block 208 includes imposing a second staged reoxygenation using sequential gas delivery. In system 100, block 208 is performed by SGD device 101, which delivers gas to the subject to create a second hypoxic state and then reoxygenates the subject's arterial blood.

[0081] Once the second hypoxic condition has been imposed for a selected period of time, a first stepwise reoxygenation is imposed. The second stepwise reoxygenation includes an increase in the subject's PaO2 sufficient to cause a measurable magnetic signal. In some examples, the second stepwise reoxygenation restores normoxia to the subject. In further examples, the second stepwise reoxygenation restores the PaO2 to approximately 80 mmHg. In further examples, the second stepwise reoxygenation restores the PaO2 to approximately 85 mmHg. In further examples, the second stepwise reoxygenation restores the PaO2 to approximately 90 mmHg. In further examples, the second stepwise reoxygenation restores the PaO2 to approximately 95 mmHg. In further examples, the second stepwise reoxygenation restores the PaO2 to approximately 100 mmHg. In further examples, the second stepwise reoxygenation restores the PaO2 to approximately 105 mmHg. In still other instances, a second stepwise reoxygenation restores PaO2 to about 90 to about 100 mmHg. In some instances, the stepwise reoxygenation is rapid, and in certain instances, the stepwise reoxygenation occurs during a single inspiration. The inspiration duration is typically about 0.5 seconds to about 2.0 seconds. Restoring normoxia is generally more rapid and reproducible than targeting a hyperoxic PaO2, and therefore, this step is better tolerated by the subject, especially when blocks 204 through 212 are repeated to obtain multiple measurements.

[0082] To measure the subject's CVR, the second hypoxic condition is selected to induce greater vasodilation than the first hypoxic condition. In particular, the duration or oxygen concentration, or a combination of both parameters, is selected in block 208 to induce a greater vasodilation response than in block 204. Generally, a shorter duration minimizes vasodilation, and vice versa. Similarly, a higher PaO2 minimizes vasodilation, and vice versa. The first hypoxic condition may be selected to minimize vasodilation, while the second hypoxic condition may be selected to induce vasodilation. It should be understood that blocks 204 and 208 can be performed in either order, and in some instances, the first hypoxic condition is selected to induce vasodilation, while the second hypoxic condition is selected to minimize vasodilation.

[0083] In some instances, the duration of the second hypoxic condition is the same as or longer than the duration of the first hypoxic condition.

[0084] In specific, non-limiting examples, the duration of the first hypoxic state is less than 6 breaths. In even more non-limiting examples, the duration of the first hypoxic state is 4-5 breaths. In even more non-limiting examples, the duration of the first hypoxic state is less than 60 seconds. In even more non-limiting examples, the duration of the first hypoxic state is less than 30 seconds. In even more non-limiting examples, the duration of the first hypoxic state is less than 20 seconds. In even more non-limiting examples, the duration of the first hypoxic state is less than 10 seconds. In even more non-limiting examples, the duration of the first hypoxic state is about 5 seconds to about 30 seconds.

[0085] In a particularly non-limiting example, the duration of the second hypoxic state is greater than 6 breaths. In a further non-limiting example, the duration of the second hypoxic state is between about 12 breaths and about 20 breaths. In a further non-limiting example, the duration of the second hypoxic state is between about 60 seconds and 120 seconds. In a further non-limiting example, the duration of the second hypoxic state is about 60 seconds. In a further non-limiting example, the duration of the second hypoxic state is about 90 seconds. In a further non-limiting example, the duration of the second hypoxic state is about 120 seconds.

[0086] In some instances, the PaO2 of the second hypoxic state is the same as or less than the PaO2 of the first hypoxic state.

[0087] In a particularly non-limiting example, the PaO2 in the first hypoxic state is less than 60 mmHg. In a further non-limiting example, the PaO2 in the first hypoxic state is less than 50 mmHg. In a further non-limiting example, the PaO2 in the first hypoxic state is between about 40 mmHg and about 50 mmHg. In a further non-limiting example, the PaO2 in the first hypoxic state is less than or about 40 mmHg. By lowering the subject's PaO2 to less than 60 mmHg, block 208 can cause a measurable degree of vasodilation in the tissue. Notably, 40 mmHg is adjacent to the steepest portion of the oxyhemoglobin dissociation curve; therefore, the closer the PaO2 is to 40 mmHg, the stronger the signal will be.

[0088] In a particularly non-limiting example, the PaO2 in the second hypoxic state is less than 60 mmHg. In a further non-limiting example, the PaO2 in the second hypoxic state is less than 50 mmHg. In a further non-limiting example, the PaO2 in the second hypoxic state is between about 40 mmHg and about 50 mmHg. In a further non-limiting example, the PaO2 in the second hypoxic state is less than about 40 mmHg or about 40 mmHg.

[0089] In general, the parameters of the first hypoxic condition and the second hypoxic condition are not particularly limited, so long as the first hypoxic condition and the second hypoxic condition cause contrasting degrees of vasodilation that can be compared to determine the subject's CVR.

[0090] FIG. 3 is a graph illustrating an exemplary implementation of blocks 204 and 208. In FIG. 3, the subject's PaO2 is plotted against time. In block 204, the SGD device 101 imposes a first hypoxic state 302, followed by a first stepwise reoxygenation 304. In this example, the first hypoxic state 302 is brief, while in other examples, the first hypoxic state 302 is characterized by a higher PaO2 selected to minimize vasodilation. In this example, the first stepwise reoxygenation 304 is selected to restore normoxia 306, and more specifically, the first stepwise reoxygenation 304 restores PaO2 to 100 mmHg. In block 210, the SGD device 101 imposes a second hypoxic state 308, followed by a second stepwise reoxygenation 310. In this example, the second hypoxic state 308 is extended relative to the duration of the first hypoxic state 302, while in other examples, the second hypoxic state 308 is characterized by a lower PaO2 selected to cause vasodilation.

[0091] As part of block 208, the SGD device 101 may maintain the subject's arterial blood carbon dioxide partial pressure (PaCO2) while imposing the second hypoxic condition and the second stepwise reoxygenation.

[0092] Block 212 calculates ΔR2 at the target voxel in response to the first stepwise reoxygenation and the second stepwise reoxygenation. * In system 100, block 212 is performed by MRI system 102 measuring magnetic signals in subject 130 while SGD device 101 controls the subject's PaO2.

[0093] As part of block 212, the MRI system 102 measures T2 * Susceptibility imaging was used to measure weighted signals, and each T2 * First ΔR2 based on the weighted signal * and the second ΔR2 * For illustrative purposes, the method 200 herein calculates the T2 * Although it may be described in terms of weighted signals, the MRI system 102 generally uses multiple T2 * It should be understood that the MRI system 102 measures T2 weighted signals for the subject 130. * By performing a T2 weighted scan * The weighted signal can be measured. T2 * The parameters for the weighted scan may include TR = 1500 ms, TE = 30 ms, flip angle = 73°, 29 slices, voxel size = 3 mm in a 64 × 64 matrix, isotropic, but T2 * The parameters of the weighted scan are not particularly limited, and other parameters may be suitable. Because block 212 applies magnetic susceptibility imaging, measurements can be obtained from both blood vessels and tissue within the region of interest.

[0094] As a further part of block 212, processor 126 * The weighted signal can be pre-processed. Pre-processing is done by T2 * Pre-processing may include volume registration of weighted signals. * The pre-processing may further include slice time correction of the weighted signals. * The pre-processing may further include co-registering the weighted signals to an anatomical image. * The preprocessing may further include removing noise from the weighted signal. *The method may further include applying a spatial blur to the weighted signal. In a particular example, the processor 126 applies AFNI software to * Superimpose the weighted signal onto the anatomical image (National Institutes of Health, Bethesda, Maryland, Version AFNI_24.0.12 'Caracalla' URL https: / / afni.nimh.nih.gov).

[0095] As a further part of block 212, processor 126 * ΔR2 based on weighted signals * Derive T2 * The weighted signal is calculated as ΔR2 using Equation 1 * can be calculated to:

number

[0096] Block 508 calculates ΔR2 for the selected voxel as the MRI system 402 measures the magnetic signal while the respiratory device is causing the step change. * Generates a value over time.

[0097] Block 216 calculates the respective ΔR2 * In system 100, block 216 is performed by processor 126, which retrieves a sigmoid function from memory and optimizes parameters of the sigmoid function to calculate a first perfusion index and a second perfusion index based on the value of ΔR2. * Reduce the error between the values.

[0098] The sigmoid function may include one or more parameters that define its amplitude, inflection point, slope, and offset. Optimization may be performed using a curve-fitting algorithm such as least-squares minimization.

[0099] In some examples, the sigmoid function is symmetric. In particular examples, the sigmoid function is a Gompertz fitting function. The Gompertz fitting function may be defined using Equation 2:

number

[0100] In some examples, the sigmoid function is the ΔR2 derived in block 212. * As part of block 216, processor 126 calculates a ΔR2 value that corresponds to a stepwise increase in PaO2. * The value can be selected. * Some of the values ​​may be selected based on user input received at the user interface 124 .

[0101] Block 216 further includes calculating a perfusion index based on a sigmoid function. The perfusion index may include one or more of rCBV, rCBF, MTT, and rBAT, but is not limited to these.

[0102] 4 is a graph illustrating an exemplary implementation of blocks 204 through 212. In FIG. * is plotted against time. The solid line shows the sigmoid function, ΔR2 in this example. *The amplitude of the Gompertz fitted function is defined by lines A and B. Line CD is the tangent to the sigmoid function at the inflection point, and the slope of line CD is the maximum rate of decrease of the sigmoid function. The mean transit time (MTT) can be calculated as the time range of the tangent. Relative cerebral blood volume (rCBV) can be calculated as the amplitude of the sigmoid function. Relative cerebral blood flow (rCBF) can be calculated as the slope of the tangent or the maximum rate of decrease of the sigmoid function. The reference time (a) is the time period during which ΔR2 * The starting time (b) corresponds to the time when ΔR2 * indicates the point at which a 2% decrease in rCBV begins. The relative blood arrival time (rBAT) can be calculated as the difference between the onset time (b) and the reference time (a), with negative values ​​indicating earlier arrival.

[0103] ΔR2 * The maximum rate of decrease in SaO2 can be calculated from the S-fit(t) parameters as a × c / e to measure rCBF, where e is the base of the natural logarithm. A tangent line with this slope is drawn through the time point of maximum slope, ln(b) / c (Fig. 4, C-D). This tangent line defines three time regions, as indicated by the arrows in Fig. 4. First, the ΔR2 from the time the step change in SaO2 reaches the voxel until the change is contained within the voxel in all capillaries. * Second, the exponential increase in the rate of decrease of SaO2 until all vessels are filled with the change in SaO2 and the change begins to leave the voxel. * the linear part of the decline; and third, the ΔR2 as the SaO2 change moves away from the voxel. * The MTT is the sum of the first and third time domain time constants plus the second linear ΔR2 * The MTT is calculated by adding the time required for the reduced time region. Therefore, as the ratio of CBV / CBF, MTT satisfies the central volume theorem. The rCBV and rCBF values ​​were multiplied by 2 and 200, respectively, to obtain readable values ​​within the range of absolute measurements.

[0104] Block 220 includes comparing the first perfusion index to the second perfusion index to determine cerebrovascular reactivity (CVR). In system 100, block 220 is performed by processor 126, which compares the first perfusion index to the second perfusion index.

[0105] An example of a suitable calculation is shown in Equation 3. In the example shown in Equation 3, the perfusion index is CBF, but it should be understood that any suitable perfusion index can be used to calculate CVR. In Equation 3, CBF ベースライン is the ΔR2 measured during the first step of reoxygenation * represents the CBF calculated in block 216 from stim is the ΔR2 measured during the second stepwise reoxygenation * represents the CBF calculated in block 216 from CVR=CBF stim -CBF ベースライン (3)

[0106] As part of block 220, processor 126 may generate one or more perfusion maps including CVRs for multiple voxels. In certain embodiments, processor 126 transforms the perfusion maps to Montreal Neurological Institute (MNI) coordinates and overlays the perfusion maps onto respective anatomical images.

[0107] As a further part of block 220, the processor 126 may compare the subject's CVR to statistics of a reference population.

[0108] In some examples, the reference population includes a group of selected healthy subjects who do not exhibit a chronic illness or disease. In a further example, the reference population includes a group of subjects who exhibit a health condition or disease. In yet a further example, the reference population includes a group of subjects receiving treatment. In some examples, the comparison can be repeated by comparing the subject to two or more reference populations, for example, a diseased population and a healthy population. It should be understood that the statistical value for the reference population is generated by performing blocks 204 to 216 on a group of subjects in the reference population, and then combining the CVRs generated for the reference population to obtain the statistical value. In a non-limiting example, the statistical value is the average value of the CVRs generated for the reference population. Furthermore, it should be understood that the comparison is most effective when the same or similar parameters are used to generate the statistical value. For example, the CVRs of the subject and the statistical value for the reference population should be obtained from measurements at corresponding voxels.

[0109] As a further part of block 220, the processor 126 can calculate z-scores that represent a comparison of the perfusion index of the subject to a statistical value of a reference population. The z-scores of multiple voxels can be mapped to an anatomical image to obtain a z-score map.

[0110] In some examples, the method 200 further includes mapping the interference based on a comparison of the subject to a reference population. The processor 126 may be configured to evaluate a health condition or a treatment based on the comparison to the reference population.

[0111] The health condition may include, but is not limited to, a cardiovascular or neurological disease selected from Parkinson's disease, stroke, hemangioma, vascular tumor or cyst, coronary heart disease, moyamoya disease, cerebral venous thrombosis, arteriovenous malformation, arteriovenous fistula, hemangioma formation, carotid artery disease, elevated intracranial pressure, stenotic-occlusive disease, and renal insufficiency. In some alternatives, the processor 126 may diagnose the health condition based on the z-score.

[0112] Treatments may include, but are not limited to, vasodilators, vasoconstrictors, antiangiogenic agents, thrombolytic agents, chemotherapy, surgery, intermittent hypoxia, exercise, diet, hydration, radiation therapy, brain stimulation, and neuromodulation therapy.

[0113] The diagnosis or assessment may be output to the user interface 124 .

[0114] Blocks 204 through 220 may be repeated to obtain repeated measurements of the subject.

[0115] In view of the above, it will now be apparent that variations, combinations, and subsets of the above-described embodiments are contemplated. For example, while a first hypoxic state is described as a baseline state and a second hypoxic state is described as a vasoactive stimulant, it should be understood that gradual reoxygenation may be used solely for measuring perfusion indices, and other vasoactive stimulants may be administered to the subject. In one example, the baseline is normocapnia and the stimulant is hypercapnia. In another example, the vasoactive stimulant is an injection of acetazolamide (ACZ).

[0116] In a further variation, the ΔR2 measured during the first reoxygenation * , and ΔR2 measured during the second reoxygenation * are used as arterial input functions (AIFs), which are deconvolved and used to calculate CBF (cerebral blood flow), CBV (cerebral blood volume), and MTT (mean transit time).

[0117] It will now be apparent to those skilled in the art that the present disclosure offers many advantages over the prior art, and in particular provides clear improvements over Johnson et al. (2024).

[0118] First, Johnson reported that PCO2 could not be controlled independently of PO2 during hypoxia and required mathematical correction for the lack of CO2 control. Therefore, the authors combined hypoxia and hypercapnia as opposed to hypoxia alone. In contrast, the present invention provides a method for controlling PCO2 independently of PO2.

[0119] Second, our target hypoxia is 60 mmHg, corresponding to an SaO2 of 85-90%. This is a very slight desaturation and has little effect on vasodilation. Inaccurate control of arterial PCO2 confounds data on hypoxia-induced changes in cerebral blood flow. Our method, on the other hand, reduces PaO2 below 60 mmHg, specifically below 40 mmHg (SaO2 = 70%), which is adjacent to the steep portion of the oxyhemoglobin dissociation curve, resulting in a large signal change and allowing for more accurate calculation of blood flow.

[0120] Third, Johnson used phase contrast to measure the blood flow response to hypoxia, which is only suitable for the extracranial large arteries, specifically the carotid and vertebral arteries. In contrast, we use magnetic susceptibility imaging to measure blood flow in the brain parenchyma and generate a map of the distribution of increased blood flow.

[0121] Finally, in Johnson, reoxygenation was hyperoxic (PO2 of 110 mmHg). Such hyperoxic reoxygenation significantly prolongs the time to reach repeated measurements of baseline cerebral hemodynamic parameters, reducing the practicality of the approach in clinical settings where repeated measurements are desirable. The method described herein resaturates hemoglobin to near saturation while maintaining PO2 at a level where repeated rapid desaturation readily occurs.

[0122] The present specification encompasses any one of the following embodiments. 1) A method for measuring cerebrovascular reactivity in a subject, comprising: (a) imposing a first stepwise reoxygenation from a first hypoxic condition using sequential gas supply; (b) using sequential gas delivery to impose a second stepwise reoxygenation from a second hypoxic condition, the second hypoxic condition being selected to cause greater vasodilation than the first hypoxic condition; (c) ΔR2 at the target voxel in response to the first stepwise reoxygenation and the second stepwise reoxygenation. * measuring the passage of time; (d) the ΔR2 measured during the first reoxygenation and the second reoxygenation, respectively. * calculating a first perfusion index and a second perfusion index based on the time course; (e) comparing the first perfusion index to the second perfusion index to determine cerebrovascular reactivity. 2) The method of aspect 1, wherein the steps of imposing the first reoxygenation and the second reoxygenation comprise restoring normoxic conditions in the subject. 3) The method of aspect 1 or 2, wherein the steps of imposing the first reoxygenation and the second reoxygenation comprise restoring the subject's arterial blood oxygen tension (PaO2) to 90-100 mmHg. 4) The method of any one of aspects 1 to 3, wherein the second hypoxic state has a longer duration or a lower arterial oxygen partial pressure (PaO2) than the first hypoxic state. 5) The method of aspect 3, wherein the PaO2 during the first hypoxic state and during the second hypoxic state is less than 60 mmHg. 6) The method of aspect 5, wherein the PaO2 during the first hypoxic state and during the second hypoxic state is less than 40 mmHg. 7) The method of embodiment 2, further comprising maintaining arterial blood carbon dioxide partial pressure (PaCO2) during steps (a) and (b). 8) The step of calculating the first perfusion index and the second perfusion index uses a sigmoid function to calculate the ΔR *Aspect 8. The method of any one of aspects 1-7, comprising fitting a time course, wherein calculating the perfusion index of the target voxel is further based on the sigmoid function. 9) The method of aspect 8, wherein the first perfusion index and the second perfusion index comprise relative cerebral blood volume (rCBV), and wherein calculating the first perfusion index and the second perfusion index comprises calculating the magnitude of the sigmoid function. 10) The method of aspect 8 or 9, wherein the first perfusion index and the second perfusion index comprise relative cerebral blood flow (rCBF), and the step of calculating the first perfusion index and the second perfusion index comprises calculating a maximum rate of decrease of the sigmoid function. 11) The method of any one of aspects 8 to 10, wherein the first perfusion index and the second perfusion index comprise mean transit time (MTT), and the first perfusion index and the second perfusion index are calculated as MTT = rCBV / rCBF. 12) A method for measuring cerebrovascular reactivity in a subject, comprising: (a) using sequential gas delivery to impose a first stepwise reoxygenation from a first hypoxic state selected to minimize vasodilation; (b) administering to the subject a vasoactive stimulator; (c) imposing a second stepwise reoxygenation from a second hypoxic condition using sequential gas delivery, the second hypoxic condition being selected to minimize vasodilation; (d) ΔR2 at the target voxel in response to the first stepwise reoxygenation and the second stepwise reoxygenation. * measuring the passage of time; (e) the ΔR2 measured during the first reoxygenation and the second reoxygenation, respectively. * calculating a first perfusion index and a second perfusion index based on the time course; (d) comparing the first perfusion index to the second perfusion index to determine cerebrovascular reactivity. 13) The method of aspect 12, wherein the vasoactive stimulant is carbon dioxide, step (a) further comprises imposing normocapnic conditions in the subject, and step (b) further comprises imposing hypercapnic conditions in the subject. 14) The method of aspect 13, wherein the steps of imposing the first reoxygenation and the second reoxygenation comprise restoring normoxic conditions in the subject. 15) The step of calculating the first perfusion index and the second perfusion index uses a sigmoid function to calculate the ΔR * 15. The method of any one of aspects 12 to 14, including fitting a time course, wherein calculating the perfusion index of the target voxel is further based on the sigmoid function. 16) The method of aspect 15, wherein the perfusion index comprises relative cerebral blood volume (rCBV) and calculating the perfusion index comprises calculating the magnitude of the sigmoid function. 17) The method of aspect 15 or 16, wherein the perfusion index comprises relative cerebral blood flow (rCBF), and calculating the perfusion index comprises calculating a maximum rate of decrease of the sigmoid function. 18) The method of any one of aspects 15 to 17, wherein the perfusion index comprises a mean transit time (MTT), and the perfusion index is calculated as MTT = rCBV / rCBF. 19) A system for measuring cerebrovascular reactivity in a subject, comprising: A sequential gas supply device, comprising: Imposing a first stepwise reoxygenation from a first hypoxic state, configured to impose a second stepwise reoxygenation from the second hypoxic condition; a sequential gas delivery system, wherein the second hypoxic condition is selected to cause greater vasodilation than the first hypoxic condition; ΔR2 at the target voxel in response to the first stepwise reoxygenation and the second stepwise reoxygenation * a magnetic resonance imaging system configured to measure a time course; 1. A processor, comprising: The ΔR2 measured during the first reoxygenation and the second reoxygenation, respectively * calculating a first perfusion index and a second perfusion index based on the time course; a processor configured to compare the first perfusion index to the second perfusion index to determine cerebrovascular reactivity. 20) The system of aspect 19, wherein imposing the first reoxygenation and the second reoxygenation comprises restoring normoxic conditions in the subject. 21) The system of aspect 19 or 20, wherein imposing the first reoxygenation and the second reoxygenation comprises restoring the subject's arterial blood oxygen partial pressure (PaO2) to 90 to 100 mmHg. 22) The system of any one of aspects 19 to 21, wherein the second hypoxic state has a longer duration or a lower arterial blood oxygen partial pressure (PaO2) than the first hypoxic state. 23) The system of aspect 21, wherein the PaO2 during the first hypoxic state and during the second hypoxic state is less than 60 mmHg. 24) The system of aspect 23, wherein the PaO2 during the first hypoxic state and during the second hypoxic state is less than 40 mmHg. 25) The system of aspect 20, wherein the sequential gas supply device is further configured to maintain arterial blood carbon dioxide partial pressure (PaCO2) during the imposition of the first stepwise oxygenation and the second stepwise oxygenation. 26) Calculating the first perfusion index and the second perfusion index involves using a sigmoid function to calculate the ΔR * 26. The system of any one of aspects 19 to 25, including fitting to a time course, wherein calculating the perfusion index of the target voxel is further based on the sigmoid function. 27) The system of aspect 26, wherein the first perfusion index and the second perfusion index comprise relative cerebral blood volume (rCBV), and calculating the first perfusion index and the second perfusion index comprises calculating the magnitude of the sigmoid function. 28) The system of aspect 26 or 27, wherein the first perfusion index and the second perfusion index comprise relative cerebral blood flow (rCBF), and calculating the first perfusion index and the second perfusion index comprises calculating a maximum rate of decrease of the sigmoid function. 29) The system of any one of aspects 26 to 28, wherein the first perfusion index and the second perfusion index comprise mean transit time (MTT), and the first perfusion index and the second perfusion index are calculated as MTT = rCBV / rCBF. 30) A system for measuring cerebrovascular reactivity in a subject, comprising: A sequential gas supply device, comprising: Imposing a first stepwise reoxygenation from a first hypoxic condition selected to minimize vasodilation; administering to the subject a vasoactive stimulator; a sequential gas delivery device configured to impose a second graded reoxygenation from a second hypoxic condition selected to minimize vasodilation; 1. A magnetic resonance imaging system comprising: ΔR2 at the target voxel in response to the first stepwise reoxygenation and the second stepwise reoxygenation * a magnetic resonance imaging system configured to measure a time course; 1. A processor, comprising: The ΔR2 measured during the first reoxygenation and the second reoxygenation, respectively * calculating a first perfusion index and a second perfusion index based on the time course; a processor configured to compare the first perfusion index to the second perfusion index to determine cerebrovascular reactivity. 31) The system of aspect 30, wherein the vasoactive stimulator is carbon dioxide, administering the vasoactive stimulator comprises imposing a hypercapnic state in the subject, and imposing the second stepwise reoxygenation comprises restoring normocapnia in the subject. 32) The system of aspect 31, wherein imposing the first reoxygenation and the second reoxygenation comprises restoring normoxic conditions in the subject. 33) Calculating the first perfusion index and the second perfusion index comprises using a sigmoid function to calculate the ΔR * 33. The system of any one of aspects 30 to 32, including fitting to a time course, wherein calculating the perfusion index of the target voxel is further based on the sigmoid function. 34) The system of aspect 33, wherein the perfusion index comprises relative cerebral blood volume (rCBV) and calculating the perfusion index comprises calculating the magnitude of the sigmoid function. 35) The method of aspect 33 or 34, wherein the perfusion index comprises relative cerebral blood flow (rCBF) and calculating the perfusion index comprises calculating the maximum rate of decrease of the sigmoid function. 36) The method of any one of aspects 33 to 35, wherein the perfusion index comprises mean transit time (MTT), and the perfusion index is calculated as MTT = rCBV / rCBF.

[0123] The present specification will now be illustrated by examples. (Example)

[0124] Example 1 We recognized that the onset of hypoxia during inhalation of hypoxic gases is delayed due to the time required to dilute and eliminate the remaining oxygen in the lungs, known as functional residual capacity (FRC). Therefore, cerebral vasodilation does not occur faster than the dilution of FRC by inhalation of hypoxic gases. We hypothesized that faster elimination of FRC would result in faster hypoxia and faster cerebral vasodilation. Therefore, we used the principle of sequential gas delivery (described herein in connection with Figure 3) and a predicted target gas mixing device (RespirAct™, Toronto, Canada) to administer 4% oxygen in 96% nitrogen in a controlled manner, minimizing the time to reach an arterial P O of 40 mmHg within approximately 4–5 breaths. We studied blood flow velocity (a proxy for blood flow) in the middle and posterior cerebral arteries, as measured by transcranial Doppler, during an acute decline in pulmonary oxygenation in 24 healthy volunteers. The inventors succeeded in lowering pulmonary PO2 in a shorter time than the vasodilatory response, leaving the vasodilatory response as the time-limiting factor. The inventors then studied the time course of the vasodilatory response to hypoxia as described below. These unique findings form the basis of the present application.

[0125] (A study of the time course of cerebral arterial responses to hypoxia) Fourteen healthy, non-smoking subjects (6 females), with a mean age of 28.2 years (standard deviation 8 years), were recruited for this study after providing written informed consent. Subjects wore a face mask and were connected to a sequential gas delivery device (RespirAct™, Thornhill Medical, Toronto, Canada) that targets end-tidal PO2 and PCO2. This device has been shown to operate so that end-tidal values ​​of PO2 and PCO2 are equal to their corresponding arterial values. Flow velocities in the middle and posterior cerebral arteries were measured at 2 MHz and sampled at 125 Hz using a transcranial Doppler (Delica EMS-9D Pro, Shenzhen, 518107, PRChina). An example of a typical response is shown in Figure 5. We found that vasodilation decreased exponentially, with maximum vasodilation occurring at approximately 60 seconds and a time constant of approximately 20 seconds.

[0126] Figure 5 is a graph showing an example of a transcranial Doppler (TCD) velocity response to hypoxia. Dashed lines indicate the onset and end of hypoxia, and breath-by-breath values ​​of end-tidal O2 and CO2 partial pressures are shown. Note that PO2 declines rapidly over approximately 10 seconds, with most of the decline occurring within 5 seconds. The time constant of the middle cerebral artery (MCA) response is approximately 20 seconds. Other values ​​are listed in the figure legend.

[0127] In individuals who tend to have a low FRC, such as short, slender adults, children, and women, it is possible to reach a PO2 of 40 with approximately three large breaths over approximately six seconds. The brief onset of hypoxia in the lungs can result in minimal vasodilation within the cerebral arteries. Therefore, hemodynamic measurements taken during the reoxygenation phase reflect baseline cerebral blood flow. If hypoxia at a PO2 of approximately 40 mmHg persists for approximately 60 seconds or longer, hemodynamic measurements from the acute reoxygenation phase reflect stimulated flow. Therefore, the difference in flow reflects CVR.

[0128] Figures 6 and 7 show the ΔR2 between revascularization in two voxels with different noise levels. *6 and 7 are graphs showing the signal. Figure 6 is a representative example of a noisy signal, and Figure 7 is a representative example of a quiet signal. The solid line shows the ΔR2 response to stepwise reoxygenation. * Fit of a Gompertz function to the signal response. Dashed lines are superimposed on the linear portion of the function, extending from the baseline (top) and the asymptotes (bottom). The vertical dash-dotted line is the reference time cursor used to calculate blood arrival time (BAT) for every voxel.

[0129] 8A-8D are perfusion maps obtained by an exemplary implementation of method 200. FIG. A) CBF obtained by imposing a first hypoxic condition for 30 seconds. ベースライン Shows. B) CBF obtained by imposing a second hypoxic condition of 2 min. stim Shows. C) is CBF stim -CBF ベースライン Figure 1 shows the CVR calculated as the voxel-wise subtraction of In contrast, D) shows CVR calculated as ΔBOLD / ΔPCO2 using a hypercapnic stimulus, using a color scale for relative change.

[0130] Figures 9A to 9D are perfusion maps showing the results of Figures 8A to 8D using color gradation.

[0131] The many features and advantages of the present invention are apparent from the detailed specification, and thus, the appended claims are intended to cover all such features and advantages of the present invention that fall within the true spirit and scope of the invention. Further, because numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation illustrated and described, and therefore, all suitable modifications and equivalents may be employed that are within the scope of the invention.

Claims

1. 1. A method for measuring cerebrovascular reactivity in a subject, comprising: (a) imposing a first stepwise reoxygenation from a first hypoxic condition using sequential gas supply; (b) imposing a second stepwise reoxygenation from a second hypoxic condition using sequential gas delivery, the second hypoxic condition being selected to cause greater vasodilation than the first hypoxic condition; (c) ΔR at the target voxel in response to the first graded reoxygenation and the second graded reoxygenation. ２ ＊ measuring the passage of time; (d) the ΔR measured during the first reoxygenation and the second reoxygenation, respectively. ２ ＊ calculating a first perfusion index and a second perfusion index based on the time course; (e) comparing the first perfusion index to the second perfusion index to determine cerebrovascular reactivity; A method comprising:

2. 10. The method of claim 1, wherein the first reoxygenation and the second reoxygenation imposing steps comprise restoring normoxic conditions in the subject.

3. The steps of imposing the first reoxygenation and the second reoxygenation may include adjusting the arterial oxygen partial pressure (PaO ２ 3. The method of claim 1, further comprising restoring the blood pressure to 90-100 mmHg.

4. The second hypoxic state may be of longer duration or lower arterial oxygen partial pressure (PaO) than the first hypoxic state. ２ 4. The method according to claim 1, wherein

5. the PaO during the first hypoxic state and during the second hypoxic state. ２ The method of claim 3, wherein the blood pressure is less than 60 mmHg.

6. 6. The method of claim 5, wherein the PaO2 during the first hypoxic state and during the second hypoxic state is less than 40 mmHg.

7. During steps (a) and (b), arterial blood carbon dioxide partial pressure (PaCO ２ 3. The method of claim 2, further comprising maintaining a

8. The step of calculating the first perfusion index and the second perfusion index may further include using a sigmoid function to calculate the ΔR ２ ＊ The method of any one of claims 1 to 7, comprising fitting a time course, wherein calculating the perfusion index of the target voxel is further based on the sigmoid function.

9. 9. The method of claim 8, wherein the first perfusion index and the second perfusion index comprise relative cerebral blood volume (rCBV), and wherein calculating the first perfusion index and the second perfusion index comprises calculating a magnitude of the sigmoid function.

10. 10. The method of claim 8 or 9, wherein the first perfusion index and the second perfusion index comprise relative cerebral blood flow (rCBF), and calculating the first perfusion index and the second perfusion index comprises calculating a maximum rate of decrease of the sigmoid function.

11. 11. The method of claim 8, wherein the first perfusion index and the second perfusion index comprise mean transit time (MTT), and the first perfusion index and the second perfusion index are calculated as MTT=rCBV / rCBF.

12. 1. A method for measuring cerebrovascular reactivity in a subject, comprising: (a) using sequential gas delivery to impose a first stepwise reoxygenation from a first hypoxic state selected to minimize vasodilation; (b) administering to the subject a vasoactive stimulator; (c) imposing a second stepwise reoxygenation from a second hypoxic condition using sequential gas delivery, the second hypoxic condition being selected to minimize vasodilation; (d) ΔR at the target voxel in response to the first graded reoxygenation and the second graded reoxygenation. ２ ＊ measuring the passage of time; (e) the ΔR measured during the first reoxygenation and the second reoxygenation, respectively. ２ ＊ calculating a first perfusion index and a second perfusion index based on the time course; (d) comparing the first perfusion index to the second perfusion index to determine cerebrovascular reactivity; A method comprising:

13. 13. The method of claim 12, wherein the vasoactive stimulant is carbon dioxide, step (a) further comprises imposing normocapnic conditions in the subject, and step (b) further comprises imposing hypercapnic conditions in the subject.

14. 14. The method of claim 13, wherein the first reoxygenation and the second reoxygenation imposing steps comprise restoring normoxic conditions in the subject.

15. The step of calculating the first perfusion index and the second perfusion index may further include using a sigmoid function to calculate the ΔR ２ ＊ The method according to any one of claims 12 to 14, comprising fitting a time course, and wherein calculating the perfusion index of the target voxel is further based on the sigmoid function.

16. 16. The method of claim 15, wherein the perfusion index comprises relative cerebral blood volume (rCBV), and calculating the perfusion index comprises calculating the magnitude of the sigmoid function.

17. 17. The method of claim 15 or 16, wherein the perfusion index comprises relative cerebral blood flow (rCBF), and calculating the perfusion index comprises calculating a maximum rate of decrease of the sigmoid function.

18. 18. The method of any one of claims 15 to 17, wherein the perfusion index comprises mean transit time (MTT), and the perfusion index is calculated as MTT = rCBV / rCBF.

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