TESTING FOR NEUROVASCULAR UNCOUPLING IN MULTIPLE SCLEROSIS USING SEQUENTIAL GAS DELIVERY VERSUS FIXED INSPIRED CO2

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.

Claims

1. A method comprising: during an inspiration by a subject with multiple sclerosis, delivering a first gas to the subject, the first gas provided in a volume that is less than a tidal volume minus an anatomical dead space, the first gas containing a concentration of oxygen to meet a respiratory need of the subject and to target an end-tidal partial concentration of oxygen, the first gas further containing a concentration of carbon dioxide to target an end-tidal concentration of carbon dioxide and thereby provide a vasoactive stimulus to the subject to assess vascular compliance with regard to multiple sclerosis-related cognition of the subject; and during the same inspiration and after delivering the first gas to the subject, delivering a second gas to the subject, wherein the second gas contains a concentration of carbon dioxide approximately equal to the target end-tidal concentration of carbon dioxide or, if at a resting state, equilibrated with an arterial partial pressure of carbon dioxide of the subject.

2. The method of claim 3, further comprising delivering the first and second gases during repeated inspirations by the subject.

3. The method of claim 3, wherein the second gas includes rebreathed gas exhaled by the subject during an expiration prior to the inspiration.

4. The method of claim 3 further comprising, targeting a first end-tidal concentration of carbon dioxide for a first series of repeated inspirations by the subject; when the first end-tidal concentration of carbon dioxide is reached, measuring blood flow in the subject's brain; targeting a second end-tidal concentration of carbon dioxide for a second series of repeated inspirations by the subject; when the second end-tidal concentration of carbon dioxide is reached, measuring blood flow in the subject's brain; and calculating a cardiovascular response using a difference between the blood flow measured at the first and second end-tidal concentrations of carbon dioxide.

5. The method of claim 6 further comprising: selecting the first end-tidal concentration of carbon dioxide to induce normocapnia in the subject; and selecting the second end-tidal concentration of carbon dioxide to induce hypercapnia in the subject.

6. The method of claim 6 further comprising measuring blood flow using one or both of cerebral blood flow imaging and blood oxygen level dependent signal.

7. The method of claim 6 further comprising measuring blood flow in a plurality of layers of the subject's cerebral cortex.

8. The method of claim 6 further comprising calculating the vascular compliance using the cardiovascular response.

9. An apparatus for providing a vasoactive stimulus to a subject with multiple sclerosis to assess vascular compliance with regard to multiple sclerosis-related cognition of the subject, the apparatus comprising: (a) a gas delivery device; and (b) a processor connected to the gas delivery device, wherein the processor is configured to: during an inspiration by a subject with multiple sclerosis, control the gas delivery device to deliver a first gas to the subject, the first gas provided in a volume that is less than a tidal volume minus an anatomical dead space, the first gas containing a concentration of oxygen to meet a respiratory need of the subject and to target an end-tidal partial concentration of oxygen, the first gas further containing a concentration of carbon dioxide to target an end-tidal concentration of carbon dioxide; and during the same inspiration and after delivering the first gas to the subject, control the gas delivery device to deliver a second gas to the subject, wherein the second gas contains a concentration of carbon dioxide approximately equal to the target end-tidal concentration of carbon dioxide or, if at a resting state, equilibrated with an arterial partial pressure of carbon dioxide of the subject.

10. The apparatus of claim 11, the processor further configured to control the gas delivery device to deliver the first and second gases during repeated inspirations by the subject.

11. The apparatus of claim 11 wherein the second gas includes rebreathed gas exhaled by the subject during an expiration prior to the inspiration.

12. The apparatus of claim 11 further comprising a sensor connected to the processor; the processor further configured to: control the gas delivery device to target first end-tidal concentration of carbon dioxide for a first series of repeated inspirations by the subject; when the first end-tidal concentration of carbon dioxide is reached, control the sensor to measure blood flow in the subject's brain; control the gas delivery device to target a second end-tidal concentration of carbon dioxide for a second series of repeated inspirations by the subject; when the second end-tidal concentration of carbon dioxide is reached, control the sensor measure blood flow in the subject's brain; and calculate a cardiovascular response using the difference between the blood flow measured at the first and second end-tidal concentrations of carbon dioxide.

13. The apparatus of claim 14, the processor further configured to: select the first end-tidal concentration of carbon dioxide to induce normocapnia in the subject; and select the second end-tidal concentration of carbon dioxide to induce hypercapnia in the subject.

14. The apparatus of claim 14, the processor further configured to control the sensor to measure blood flow using one or both of cerebral blood flow imaging and blood oxygen level dependent signal.

15. The apparatus of claim 14, the processor further configured to control the sensor to measure blood flow in a plurality of layers of the subject's cerebral cortex.

16. The apparatus of claim 14, the processor further configured to calculate vascular compliance using the cardiovascular response.

17. Use of sequential gas delivery, including delivery of a gas containing carbon dioxide, to test for neurovascular uncoupling in a subject with multiple sclerosis.

18. Use of sequential gas delivery, including delivery of a gas containing carbon dioxide, to determine vascular compliance in a subject with multiple sclerosis.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1 is a formula for calculating the CVR using CBF.

[0021] FIG. 2 is a formula for calculating the CVR using BOLD.

[0022] FIG. 3 is a formula for calculating the rate of decay of CVR in arterial blood.

[0023] FIG. 4 is a formula for calculating the rate of decay of CVR in venous blood.

[0024] FIG. 5 is a graph describing CBF-based CVR in a first, second, third, and fourth layer of the cerebral cortex for healthy controls, cognitively normal MS, and cognitively slow MS.

[0025] FIG. 6 is a graph describing BOLD-based CVR in a first, second, third, and fourth layer of the cerebral cortex for healthy controls, cognitively normal MS, and cognitively slow MS.

[0026] FIG. 7 is a schematic diagram of a sequential gas delivery device.

[0027] FIG. 8 is a schematic diagram of the sequential gas delivery device in FIG. 7 wherein the reservoirs are remote from the subject.

[0028] FIG. 9A is a schematic diagram of a subject exhaling into the sequential gas delivery device of FIG. 7.

[0029] FIG. 9B is a schematic diagram of a first part inhalation into the sequential gas delivery device of FIG. 7.

[0030] FIG. 9C is a schematic diagram of a second part of inhalation into the sequential gas delivery device of FIG. 7.

[0031] FIG. 10 is a schematic diagram of another sequential gas delivery device.

[0032] FIG. 11 is a flowchart showing a method of assessing vascular compliance in a subject with MS.

DETAILED DESCRIPTION

[0033] The present invention will be described with respect to a method apparatus for providing a vasoactive stimulus to a subject with MS to assess vascular compliance with regard to MS-related cognition. According to the method, the subject sequentially inhales compositions of gas including carbon dioxide and oxygen that are calculated to attain a targeted PETCO.sub.2. Vascular compliance is then assessed in the patient.

[0034] This method and apparatus offer a number of advantages over the prior art method in which the PETCO.sub.2 is highly variable and the true physiologic independent variable (PaCO.sub.2) is unknown. In the method disclosed herein, PETCO.sub.2 is more precisely controlled and is approximately equal to PaCO.sub.2. By targeting a particular value of PETCO.sub.2, it is possible to designate a normal range for vascular compliance and determine a threshold between a normal and abnormal test result. Furthermore, the method allows the PaCO.sub.2 to be changed from one targeted value to a second targeted value within two breaths. In contrast, the timing of PETCO.sub.2 changes in the prior art method was determined by the functional residual capacity (FRC) and respiratory response of the subject, both of which are unknown and outside of the control of the tester.

[0035] The PaCO.sub.2 of the subject may be controlled with a sequential gas delivery (SGD) device. For example, RespirAct (Thornhill Medical Inc., Toronto, Canada) may be used in this method, although the method is not particularly limited to the RespirAct system.

[0036] FIG. 7 shows a schematic diagram of a SGD device at 1, as taught by Fisher et al. in U.S. Pat. No. 6,622,725. The SGD device 1 includes a subject port 10 that provides gases to the subject. The flow of gases through the subject port 10 may be controlled by an inspiratory valve 11. The inspiratory valve may be a type of valve that opens in response to a subject inspiring and closes in response to the subject exhaling, for example, a one-way check. The inspired gas may be provided from the inlet 12, the by-pass limb 13, or the inspiratory limb 14. All three sources of gas are in communication with the subject port 10 when the inspiratory valve 11 is open. When the subject expires, the inspiratory valve 11 closes and an expiratory valve 15 opens. The expiratory valve 15 may be a one-way check valve. The expired gas flows through the expiratory limb 16 but cannot flow through the by-pass limb 13 due to a cross-over valve 17, which remains closed as the subject expires. Instead, the expired gas flows into the expiratory reservoir 18. The expiratory reservoir may have a fixed volume such that excess gas is forced out through the outlet 19. An inspiratory reservoir 20 is connected to the inspiratory limb 14. In contrast to the expiratory reservoir 18, the inspiratory reservoir 20 does not have a fixed volume and may expand and contract to hold different volumes of gas.

[0037] Turning now to FIG. 8, a schematic diagram of the sequential gas delivery device from FIG. 7 is shown at 21. In this implementation, the reservoirs 18, 20 are remote from the subject.

[0038] When a subject is being assessed for MS, the subject may be instructed to breathe through subject port 10, which may be connected to a ventilation mask or mouthpiece. The SGD device 1 operates such that a first gas may be inspired during a first part of a subject's inspiration and a second gas may be inspired during a second part of a subject's inspiration.

[0039] FIGS. 9A to 9C show schematic diagrams of a subject 24 exhaling and inhaling through the SGD device 1. In the example shown in FIGS. 9A to 9C, the second gas 28 is a previously exhaled gas.

[0040] First, FIG. 9A shows the subject expiring the second gas 28 into the subject port 10. The second gas 28 passes through the expiratory valve 15 and through the expiratory limb 16 to fill the expiratory reservoir 18. Any excess of the second gas 28 may be expelled through the outlet 19. As the subject 24 exhales, the first gas 26 may be provided through the inlet 12 to fill the inspiratory reservoir 20.

[0041] Next, FIG. 9B shows a schematic diagram 30 of a first part inhalation into the SGD device 1. When the subject inhales through the subject port 10, the inspiratory valve 11 opens and the first gas 26 from the inspiratory reservoir 20 may flow through the inspiratory limb 14 to be delivered to the subject through the subject port 10.

[0042] The first gas 26 contains a concentration of oxygen required to meet the respiratory need of the subject and to target an end-tidal concentration of oxygen. The first gas 26 contains a concentration of carbon dioxide required to target a PETCO.sub.2. The first gas 26 is provided in a volume that is less than the subject's tidal volume, minus the subject's anatomical dead space. Consequently, the subject 24 will continue to inspire after the quantity of the first gas 26 contained in the inspiratory reservoir 20 has been depleted.

[0043] On the second part of the subject's inspiration and after the first gas has been delivered to the subject, a second gas is delivered to the subject. FIG. 9C shows a schematic diagram 32 of a second part of inhalation into the SGD device 1. In the system shown in FIGS. 9A to 9C, the second gas 28 is provided by the expiratory reservoir 18 and passes through the cross-over limb, through the inspiratory limb, and out through the subject port.

[0044] In the example shown in FIGS. 9A to 9C, the second gas 28 is the expired gas, although in other implementations, the second gas 28 may be a gas mixture provided by a gas blender. Regardless of the source of the second gas 28, the second gas 28 contains a concentration of carbon dioxide approximately equal to the target PETCO.sub.2. Alternatively, if the subject 24 is in a resting state, the concentration of carbon dioxide may be equilibrated with a PaCO.sub.2 in the subject 24.

[0045] Precise compositions of the first gas may be provided to the gas delivery device with a gas blender. FIG. 10 shows a schematic diagram of an SGD device 34 that includes a processor 36 and a gas blender 38. The gas blender 38 may be in communication with the inlet 12. One or more gas sources 40, 42, 44, 46 may provide gases to the gas blender 38. The gases may include, but are not limited to, carbon dioxide, oxygen, and nitrogen. One or more of the gases may be selected to induce a vasoactive response in the subject. The gases may be provided in quantities that are controlled by the processor 36.

[0046] The processor 36 may include a central processing unit (CPU), a microcontroller, a microprocessor, a processing core, a field-programmable gate array (FPGA), an application-specific integrated circuit (ASIC), or a similar device capable of executing instructions. The processor may be connected to and cooperate with a non-transitory machine-readable medium (not shown) that stores instructions and data.

[0047] The non-transitory machine-readable medium may include an electronic, magnetic, optical, or other physical storage device that encodes the instructions. The medium may include, for example, random access memory (RAM), read-only memory (ROM), electrically-erasable programmable read-only memory (EEPROM), flash memory, a storage drive, an optical device, or similar.

[0048] Instructions may be provided to carry out the functionality and methods described herein. Instructions may be directly executed, such as a binary file, and/or may include interpretable code, bytecode, source code, or similar instructions that may undergo additional processing to be executed. The instructions may dictate the quantities of gas provided to the subject 24 by the gas blender 38 in order to achieve a target PETCO.sub.2.

[0049] In this system, PETCO.sub.2 is approximately equal to PaCO.sub.2. Therefore, PETCO.sub.2 may be measured as an approximation of the value of PaCO.sub.2 in the subject 24. In some implementations, the subject's actual PaCO.sub.2 may be within 2 mmHg of the targeted PaCO.sub.2. In other implementations, the subject's actual PaCO.sub.2 may be within 1 mmHg of the targeted PaCO.sub.2.

[0050] The gas blender 38 may include a carbon dioxide analyzer and/or an oxygen analyzer, which are in communication 48 with the subject port 10. The carbon dioxide analyzer may measure the subject's PETCO.sub.2 at the end of each breath by the subject 24. The measured PETCO.sub.2 may be transmitted from the gas blender 38 to the processor 36. The measured PETCO.sub.2 may be stored on the non-transitory machine-readable medium.

[0051] The processor 36 may transmit instructions for the gas blender 38 to target one PETCO.sub.2 for a first series of inspirations. In some examples, the number of inspirations in the first series of inspirations is two or three. When the processor 36 receives a transmission from the gas blender 38 indicating that the first targeted PETCO.sub.2 has been reached, the processor 36 may instruct the gas blender to provide a composition of the first gas appropriate to targeting a different PETCO.sub.2 for a further series of inspirations by the subject 24. The targeted PETCO.sub.2 may be reached within two or three inspirations by the subject 24.

[0052] The first and second targeted PETCO.sub.2 values may be input into the processor 36 by a user. In some implementations, the processor 36 may be programmed to implement two pre-determined targeted PETCO.sub.2 values that are stored on the non-transitory machine-readable medium. In further implementations, the processor 36 may be programmed to calculate a first and second targeted PETCO.sub.2 value based on physiologic attributes of the subject 24.

[0053] A number of different values are possible for the two PETCO.sub.2 targets. For example, a PETCO.sub.2 associated with normocapnia may be targeted for a number of inspirations and then a PETCO.sub.2 associated with hypercapnia may be targeted for a further number of inspirations. However, the steps do not need to be performed in that order. In some implementations, a PETCO.sub.2 associated with hypercapnia may be targeted for a number of inspirations and then a PETCO.sub.2 associated with normocapnia may be targeted for a further number of inspirations. The two targeted PETCO.sub.2 values do not necessarily need to be associated with normocapnia and hypercapnia, as long as the two targeted PETCO.sub.2 are sufficiently different to elicit a vasoactive response in the subject 24. For instance, one of targeted values may be associated with hypocapnia. In another example, both of the targeted values may be within a range of values associated with one of normocapnia, hypercapnia, or hypocapnia.

[0054] The carbon dioxide acts as a vasoactive stimulus for studying the vascular compliance of the subject 24. A sensor 50 may measure blood flow in the subject's brain when the first targeted PETCO.sub.2 is reached and re-measure blood flow in the subject's brain when the second targeted PETCO.sub.2 is reached. The sensor 50 may transmit the first and second measured blood flow to the processor 36.

[0055] The sensor 50 that measures blood flow in the subject's brain may be selected from a number of suitable devices. For example, the sensor 50 may be a magnetic resonance imaging (MRI) scanner or a positron emission tomography (PET) scanner. If an MRI scanner is used, blood flow may be quantified according to blood oxygen level dependent (BOLD) imaging techniques. If a PET scanner is used, blood flow may be quantified according to cerebral blood flow (CBF) imaging techniques. The blood flow measured at the first and second targeted PETCO.sub.2 may be transmitted to the processor 36.

[0056] The change in blood flow measured at each PETCO.sub.2 may be indicative of multiple-sclerosis related cognition. The processor 36 may calculate the cardiovascular reactivity (CVR) of the subject 24 according to the formulas in FIGS. 1 and 2:

[0057] In some implementations, the sensor 50 may be adapted to measure blood flow in a single layer of the subject's cerebral cortex. In other implementations, the sensor 50 may be adapted to measure blood flow in a plurality of layers of the subject's cerebral cortex.

[0058] The processor 36 may be further configured to calculate a rate of decay for each layer of the subject's cerebral cortex. The rate of decay may be described by a rate constant for the ACI and VCI according to the formulas in FIGS. 3 and 4.

[0059] FIG. 11 shows a flowchart at 55 illustrating a method of assessing vascular compliance in a subject with MS. The blocks in the flowchart may be encoded as instructions and stored in a non-transitory computer-readable memory for execution by a processor.

[0060] The method may begin at block 60 with targeting a first PETCO.sub.2 in a subject with MS. The first PETCO.sub.2 may be a pre-determined value or it may be calculated by a processor. Block 60 may be implemented with instructions to control a gas delivery device to target the first PETCO.sub.2.

[0061] Next, a first gas is delivered to the subject at block 62. The first gas is provided to the subject in a volume that is less than the subject's tidal volume minus the subject's anatomical dead space. The first gas contains both oxygen and carbon dioxide, each provided in sufficient concentrations to meet the respiratory needs of the subject and target the first PETCO.sub.2. Block 62 may be implemented with instructions to control a gas delivery device.

[0062] After delivering a first gas to the subject, a second gas is delivered to the subject at block 64 during the same inspiration. The second gas may contain a concentration of carbon dioxide approximately equal to the first PETCO.sub.2. Alternatively, if the subject is at resting state, the second gas may contain a concentration of carbon dioxide equilibrated with the subject's PaCO.sub.2. Block 64 may be implemented with instructions to control a gas delivery device.

[0063] The next step at block 66 is to determine whether the first PETCO.sub.2 has been reached. Block 66 occurs as the subject expires and the subject's PETCO.sub.2 is measured. The processor may be instructed to compare the subject's PETCO.sub.2 to the value of the first PETCO.sub.2. If the subject's PETCO.sub.2 is not equal or approximately equal to the first PETCO.sub.2, the determination is NO and the method returns to block 62. Blocks 62, 64, and 66 may be repeated a number of times over a series of inspirations by the patient. When the subject's PETCO.sub.2 is equal or approximately equal to the first PETCO.sub.2, the determination is YES and the method proceeds to block 68.

[0064] At block 68, the blood flow in the subject's brain may be measured. Block 68 may be implemented with instructions to a sensor and the measured blood flow may be stored in a memory. The blood flow may be measured in a plurality of layers of the subject's brain. In order to ensure that the measured blood flow corresponds with the targeted first PETCO.sub.2, block 68 may be implemented almost immediately after block 66. In some implementations, block 68 may be implemented simultaneously with block 66. For methods that implement blocks 66 and 68 simultaneously, the blood flow measurement(s) may not be stored in memory, or the blood flow measurement(s) may be erased from a memory, if the determination at block 66 is NO.

[0065] At block 70, a second PETCO.sub.2 may be targeted in a subject with MS. The second PETCO.sub.2 may be a pre-determined value or it may be calculated by a processor. The second PETCO.sub.2 is different from the first PETCO.sub.2. For instance, one of the targeted PETCO.sub.2 values may be correlated with hypercapnia in the subject and the other targeted PETCO.sub.2 value may be correlated with normocapnia. Block 60 may be implemented with instructions to control a gas delivery device to target the first PETCO.sub.2.

[0066] Then at block 72, a first gas is delivered to the subject. The first gas is provided to the subject in a volume that is less than the subject's tidal volume minus the subject's anatomical dead space. The first gas contains both oxygen and carbon dioxide, each provided in sufficient concentrations to meet the respiratory needs of the subject and target the second PETCO.sub.2. Block 72 may be implemented with instructions to control a gas delivery device.

[0067] After delivering a first gas to the subject, a second gas is delivered to the subject at block 74 during the same inspiration. The second gas may contain a concentration of carbon dioxide approximately equal to the second PETCO.sub.2. Alternatively, if the subject is at resting state, the second gas may contain a concentration of carbon dioxide equilibrated with the subject's PaCO.sub.2. Block 74 may be implemented with instructions to control a gas delivery device.

[0068] The next step at block 76 is to determine whether the second PETCO.sub.2 has been reached. Block 76 occurs as the subject expires and the subject's PETCO.sub.2 is measured. The processor may be instructed to compare the subject's PETCO.sub.2 to the value of the second PETCO.sub.2. If the subject's PETCO.sub.2 is not equal or approximately equal to the second PETCO.sub.2, the determination is NO and the method returns to block 72. Blocks 72, 74, and 76 may be repeated a number of times over a series of inspirations by the patient. When the subject's PETCO.sub.2 is equal or approximately equal to the second PETCO.sub.2, the determination is YES and the method proceeds to block 78.

[0069] At block 78, the blood flow in the subject's brain may be measured. Block 78 may be implemented with instructions to a sensor and the measured blood flow may be stored in a memory. The blood flow may be measured in a plurality of layers of the subject's brain. In order to ensure that the measured blood flow corresponds with the second PETCO.sub.2, block 78 may be implemented almost immediately after block 66. In some implementations, block 78 may be implemented simultaneously with block 66. For methods that implement blocks 76 and 78 simultaneously, the blood flow measurements(s) may not be stored in memory, or the blood flow measurements(s) may be erased from a memory, if the determination at block 76 is NO.

[0070] Finally, at block 80, a cardiovascular response is calculated. Block 80 may be implemented with instructions to a processor to calculate the cardiovascular response based on the first PETCO.sub.2, the blood flow in the subject's at the first PETCO.sub.2, the second PETCO.sub.2, and the blood flow in the subject's brain at the second PETCO.sub.2. If blood flow was measured in a plurality of layers of the subject's brain, a cardiovascular response may be calculated for each of those layers. Further, block 80 may be implemented with instructions to a processor to calculate the rate of decay of the cardiovascular response with respect to the plurality of layers of the subject's brain. The calculations implemented at block 80 may be indicative of neurovascular uncoupling associated with MS.

[0071] The methods and apparatus described above may be used to assess the MS-related cognition of a subject with MS. The methods and apparatus may also be used to assess neurovascular uncoupling a subject with MS. The methods and apparatus may further be used to assess vascular compliance in a subject with MS.

[0072] MS testing using sequential gas delivery may be highly repeatable. By collecting data from subjects with and without MS, it may be possible to designate a threshold between a normal test and an abnormal test. Data may be collected from healthy subjects, subjects with cognitively normal MS, and subjects with cognitively slow MS, and standard values or ranges of values may be determined for each category of subjects.

[0073] The repeatability of this test arises from the capability of an SGD device to implement any pre-determined PETCO.sub.2 value. Using an SGD system, a targeted PETCO.sub.2 may be achieved, independent of the rate or pattern of breathing of the subject. Additionally, the process is rapid. A targeted PETCO.sub.2 may be reached within two breaths and a second targeted PETCO.sub.2 value may be reached within another two breaths.

[0074] The repeatability also arises from the precision of targeting a PaCO.sub.2 value. Using the SGD system described above, the subject's PaCO.sub.2 is approximately equal to the PETCO.sub.2 value measured by the device. Therefore, the test results accurately reflect the physiologic conditions in the subject's vascular system.

[0075] The many features and advantages of the invention are apparent from the detailed specification and, thus, it is intended by the appended claims to cover all such features and advantages of the invention that fall within the true spirit and scope of the invention. Further, since 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 accordingly all suitable modifications and equivalents may be resorted to, falling within the scope of the invention.