Abstract: Z maps combined with a standardized stimulus in the form of a targeted arterial partial pressures of carbon dioxide provide surprisingly enhanced images for the assessment of pathological CVR. For example, the z-map assessment of patients with known steno-occlusive diseases of the cervico-cerebral vasculature showed an enhanced resolution of the presence, localization, and severity of the pathological CVR. Z-map have been found to be useful to reduce the confounding effects of test-to-test, subject-to-subject, and platform-to-platform variability for comparison of CVR images showing the importance of combining this analysis with the standardized stimulus.

Abstract: A system (100) and a method (200) for providing intermittent hypoxia using sequential gas delivery to a subject are disclosed. The method (200) comprises the step (204) of inducing a normoxic end tidal partial pressure of oxygen using a sequential gas delivery system within a first specific number of breaths for a first duration and the step (208) of inducing a hypoxic end tidal partial pressure of oxygen using the sequential gas delivery system within a second number of breaths for a second duration and repeating the steps for a target number of cycles until a therapeutically effective dose of intermittent hypoxia is attained. The sequential gas delivery system (100) may control the end tidal partial pressure of carbon dioxide simultaneously and independently of the end tidal partial pressure of oxygen. The method (200) may be applied in the treatment of a pathological condition in a subject or for improving a health condition of a subject.

Abstract: A method for quantitative measurement of cerebral vascular reactivity (CVR) combines sequential gas delivery with ?R2*-based perfusion analysis. Sequential gas delivery imposes a first stepwise reoxygenation after a first hypoxic condition and a second stepwise reoxygenation after a second hypoxic condition. In one mode, the second hypoxic condition produces greater vasodilation than the first; in another mode both hypoxia levels are minimal and an independent vasoactive stimulus, such as hypercapnia or acetazolamide, is applied between reoxygenations. MRI gradient-echo imaging records the ?R2* time course in a target voxel during each reoxygenation. Sigmoid fitting yields perfusion metrics including relative cerebral blood flow, relative cerebral blood volume and mean transit time. Comparison of the metrics derived from the two reoxygenations provides a numerical CVR value that can be reproduced across sessions and subjects.

Abstract: When a periodic deoxyhemoglobin signal is implemented in a subject, the blood flow in a selected voxel can be measured and compared to the input signal. Differences in phase lag reflect the degree of dispersion in the tissue. In conjunction with amplitude, phase lag can be used to distinguish veins from arteries, identify vessel orientation and identify changes in voxel cerebral blood flow or cerebral blood volume.

Abstract: The present specification discloses a method for measuring brain tissue oxygenation in a subject. The method comprises the following steps: measuring a magnetic signal in a reference voxel of the subject's brain while imposing a series of arterial oxygen saturation changes using sequential gas delivery; calculating a relationship between the magnetic signal and the arterial oxygen saturation in the reference voxel; measuring a magnetic signal in a target voxel; and calculating the hemoglobin saturation in the target voxel based on the established relationship between the magnetic signal and the SaO2 in the reference voxel. This calibration of magnetic signal for SaO2 enables the conversion of magnetic signal to SaO2 throughout blood-containing voxels throughout the brain.

Abstract: An improved method and system are provided for determining a perfusion metric in a subject using magnetic resonance imaging and physiologically induced contrast. A respiratory device induces a stepwise increase in arterial partial pressure of oxygen by sequentially delivering hypoxic and oxygenated gas mixtures. Magnetic resonance signal data are acquired from a selected voxel, and a change in effective transverse relaxation rate (?R2*) is computed over time. A perfusion metric is determined based on the ?R2* time course without requiring deconvolution of an arterial input function. In some examples, the ?R2* response is characterized using a sigmoidal model such as a Gompertz function to extract physiologically relevant parameters including relative cerebral blood volume, relative cerebral blood flow, and mean transit time.

Abstract: Conventionally, the arterial input function is determined by administering a contrast agent and measuring the responsive magnetic signal in a reference voxel located in a large artery such as the middle cerebral artery. By instead measuring the signal in a voxel of the choroid plexus, a more accurate profile for the arterial input function may be obtained. The metabolic activity in the choroid plexus is negligible, which provides greater certainty for signal sampling.

Abstract: A method of implementing changes in deoxyhemoglobin concentration, the method comprising: targeting a sequence of partial pressures of oxygen in arterial blood (PaCh) values in a subject using a sequential gas delivery device in a periodic input pattern; measuring a blood-oxygen level dependent (BOLD) signal in a voxel of the subject's brain using a magnetic resonance imaging device while targeting the sequence of values; comparing the pattern to the signal; and determining a vascular tissue characteristic (vessel type, vessel orientation, or pathological condition) for the voxel based on the comparison.

Abstract: Deoxyhemoglobin contrast has been used to locate arteries based on the earlier blood oxygen-level dependent (BOLD) signal arrival time, higher BOLD signal strength, and shorter mean transit time. However, additional strategies of identifying arteries with oxygen modulation are required to improve the sensitivity and specificity of results. The present disclosure provides a method of distinguishing extravascular voxels from intravascular voxels based on the magnetic signal obtained from two hypoxic boluses having two different baselines. Intravascular voxels are responsive to changes in the baseline due to their high blood volume, while extravascular voxels are not affected by changes to the baseline. Amongst intravascular voxels, arteries can be distinguished from veins because the extraction fraction of the arterial blood is reduced during hypoxia, and therefore veins are less sensitive to changes in the baseline.

Abstract: Hypoxia-induced deoxyhemoglobin concentration ([dOHb]) may be used as a susceptibility contrast agent in subjects. With sequential gas delivery methods, reoxygenation can be implemented abruptly, inducing an arterial input function with a square shape. Since the concentration of deoxyhemoglobin is known, the arterial input function can be pre-determined and perfusion metrics can be completed without error-prone measurements. Pre-determined arterial input functions provide a faster, more reliable method of analyzing BOLD-MRI images, and the resolution is not limited by the breath rate.

Abstract: The present specification discloses a method for measuring brain tissue oxygenation in a subject. The method comprises the following steps: measuring a magnetic signal in a reference voxel of the subject's brain while imposing a series of arterial oxygen saturation changes using sequential gas delivery; calculating a relationship between the magnetic signal and the arterial oxygen saturation in the reference voxel; measuring a magnetic signal in a target voxel; and calculating the hemoglobin saturation in the target voxel based on the established relationship between the magnetic signal and the SaO2 in the reference voxel. This calibration of magnetic signal for SaO2 enables the conversion of magnetic signal to SaO2 throughout blood-containing voxels throughout the brain.

Abstract: Deoxyhemoglobin contrast has been used to locate arteries based on the earlier blood oxygen-level dependent (BOLD) signal arrival time, higher BOLD signal strength, and shorter mean transit time. However, additional strategies of identifying arteries with oxygen modulation are required to improve the sensitivity and specificity of results. The present disclosure provides a method of distinguishing extravascular voxels from intravascular voxels based on the magnetic signal obtained from two hypoxic boluses having two different baselines. Intravascular voxels are responsive to changes in the baseline due to their high blood volume, while extravascular voxels are not affected by changes to the baseline. Amongst intravascular voxels, arteries can be distinguished from veins because the extraction fraction of the arterial blood is reduced during hypoxia, and therefore veins are less sensitive to changes in the baseline.

Abstract: The speed and range of the transition to low lung PO2 can be optimized such that it approaches the PO2 and timing profile of reoxygenation from a hypoxic profile. However, such hypoxic “spikes” are much more difficult to implement than re-oxygenation. A solution is to control the independent variables which contribute to hypoxia in the lung. These variables may be controlled in alone or in aggregate to minimize the time required to generate a target profile of transient lung hypoxia. In particular, a rapid decrease in [dOHb] can be implemented by breathing deeply, exhaling at least a portion of the functional residual capacity, lowering the PO2 at baseline, increasing the breathing rate, and increasing the PCO2 to shift the oxygen-hemoglobin dissociation curve to the right.

Abstract: A method of implementing changes in deoxyhemoglobin concentration, the method comprising: targeting a sequence of partial pressures of oxygen in arterial blood (PaCh) values in a subject using a sequential gas delivery device in a periodic input pattern; measuring a blood-oxygen level dependent (BOLD) signal in a voxel of the subject's brain using a magnetic resonance imaging device while targeting the sequence of values; comparing the pattern to the signal; and determining a vascular tissue characteristic (vessel type, vessel orientation, or pathological condition) for the voxel based on the comparison.

Abstract: Hypoxia-induced deoxy hemoglobin concentration ([dOHb]) may be used as a susceptibility contrast agent in subjects. While the maximal rate of generating blood [dOHb] are limited by constraints in pulmonary gas mixing, decreasing dOHb with reoxygenation of the lungs can be accomplished in one breath, resulting in a step reduction in arterial [dOHb] and thereby a step increase in cerebral BOLD signal recorded with MRI. The BOLD signal changes accompanying a step decrease in [dOHb] can be analyzed to calculate cerebral perfusion measures and compare their maps to those obtained using a bolus of a conventional contrast agent, gadolinium, and a conventional analysis requiring the identification of an arterial input function. The two methods provided comparable anatomically-distributed hemodynamic information.

Abstract: An apparatus and method for assessing vascular compliance in subjects with multiple sclerosis using sequential gas delivery is provided. The apparatus includes a gas delivery device and a processor. The processor controls the gas delivery device to deliver a first and second gas during a single inspiration. The first gas contains a mixture of oxygen and carbon dioxide necessary to target an end-tidal concentration of the two gases. The second gas includes a concentration of carbon dioxide equal to the target end-tidal concentration of carbon dioxide.

Abstract: Z maps combined with a standardized stimulus in the form of a targeted arterial partial pressures of carbon dioxide provide suprisingly enhanced images for the assessment of pathological CVR. For example, the z-map assessment of patients with known steno-occlusive diseases of the cervico-cerebral vasculature showed an enhanced resolution of the presence, localization, and severity of the pathological CVR. Z-map have been found to be useful to reduce the confounding effects of test-to-test, subject-to-subject, and platform-to-platform variability for comparison of CVR images showing the importance of combining this analysis with the standardized stimulus.

Abstract: Z maps combined with a standardized stimulus in the form of a targeted arterial partial pressures of carbon dioxide provide surprisingly enhanced images for the assessment of pathological CVR. For example, the z-map assessment of patients with known steno-occlusive diseases of the cervico-cerebral vasculature showed an enhanced resolution of the presence, localization, and severity of the pathological CVR. Z-map have been found to be useful to reduce the confounding effects of test-to-test, subject-to-subject, and platform-to-platform variability for comparison of CVR images showing the importance of combining this analysis with the standardized stimulus.

Abstract: Conventionally, the arterial input function is determined by administering a contrast agent and measuring the responsive magnetic signal in a reference voxel located in a large artery such as the middle cerebral artery. By instead measuring the signal in a voxel of the choroid plexus, a more accurate profile for the arterial input function may be obtained. The metabolic activity in the choroid plexus is negligible, which provides greater certainty for signal sampling.

Abstract: Deoxyhemoglobin in a subject may be modulated to act as a contrast agent for use in magnetic resonance imaging. Sequential gas delivery may be applied to adjust the level of deoxyhemoglobin in the subject. A suitable magnetic resonance imaging (MRI) pulse sequence that is sensitive to magnetic field inhomogeneities, such as a blood-oxygen-level dependent (BOLD) sequence, may be used to detect deoxyhemoglobin as a contrast agent.