# US 11,998,351 B2 · Testing for neurovascular uncoupling in multiple sclerosis using sequential gas delivery versus fixed inspired CO2 > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,998,351 B2 - Document ID: US11998351B2 - Status: Granted - Kind: B2 - Application number: 17/000,229 - Filed: 2020-08-21 - Published: 2021-02-25 - Granted: 2024-06-04 - Earliest claimed: 2019-08-23 - Assignees: Thornhill Scientific Inc. - Applicants: Thornhill Scientific Inc. - Inventors: Joseph Arnold Fisher; James Duffin; Olivia Sobczyk; David Mikulis - Web page: https://patentgrep.com/patent/US11998351B2 ## CPC - A61B 5/4884: {inducing physiological or psychological stress, e.g. applications for stress testing} - A61B 5/0263: {using NMR} - A61B 5/0836: {Measuring rate of CO2 production} - A61B 5/4082: {Diagnosing or monitoring movement diseases, e.g. Parkinson, Huntington or Tourette} - A61B 6/037: {Emission tomography} - A61B 6/507: {for determination of haemodynamic parameters, e.g. perfusion CT} - A61M 16/0078: {Breathing bags} - A61M 16/024: {including calculation means, e.g. using a processor} - A61M 16/0883: {Circuit type} - A61M 16/12: by mixing different gases - G01R 33/4806: {Functional imaging of brain activation} - A61B 5/14542: {for measuring blood gases (A61B5/14551 takes precedence)} - A61M 16/0045: {Means for re-breathing exhaled gases, e.g. for hyperventilation treatment} - A61M 16/208: {Non-controlled one-way valves, e.g. exhalation, check, pop-off non-rebreathing valves} - A61M 2016/1025: {the O2 concentration} - A61M 2016/103: {the CO2 concentration} - A61M 2202/0208: Oxygen - A61M 2202/0225: Carbon oxides, e.g. Carbon dioxide - A61M 2202/0266: Nitrogen (N) - A61M 2205/3317: Electromagnetic, inductive or dielectric measuring means - A61M 2230/08: Other bio-electrical signals - A61M 2230/202: partial carbon oxide pressure, e.g. partial dioxide pressure (P-CO2) - G01R 33/56366: {Perfusion imaging} - A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D) - A61M: DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY (introducing media into or onto the bodies of animals A61D7/00; means for inserting tampons A61F13/26; devices for administering food or medicines orally A61J; containers for collecting, storing or administering blood or medical fluids A61J1/05); DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY (surgery A61B; chemical aspects of surgical articles A61L); DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR {(Electrotherapy, e.g. producing anaesthesia by the use of alternating or intermittent currents A61N1/36021)} - G01R: MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES (indicating correct tuning of resonant circuits H03J3/12) ## 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 ### Claim 1 A method of assessing a subject with multiple sclerosis comprising: targeting a first end-tidal concentration of carbon dioxide for a first series of repeated inspirations by the subject, and targeting a second end-tidal concentration of carbon dioxide for a second series of repeated inspirations by the subject, wherein targeting the first and second end-tidal concentrations of carbon dioxide comprises: 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 the first or second 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; when the first end-tidal concentration of carbon dioxide is reached, measuring blood flow in the subject's brain; 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. ### Claim 2 (depends on 1) The method of claim 1, further comprising delivering the first and second gases during repeated inspirations by the subject. ### Claim 3 (depends on 1) The method of claim 1, wherein the second gas includes rebreathed gas exhaled by the subject during an expiration prior to the inspiration. ### Claim 4 (depends on 1) The method of claim 1 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. ### Claim 5 (depends on 1) The method of claim 1 further comprising measuring blood flow using one or both of cerebral blood flow imaging and blood oxygen level dependent signal. ### Claim 6 (depends on 1) The method of claim 1 further comprising measuring blood flow in a plurality of layers of the subject's cerebral cortex. ### Claim 7 (depends on 1) The method of claim 1 further comprising calculating the vascular compliance using the cardiovascular response. ### Claim 8 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: control the gas delivery device to target a first end-tidal concentration of carbon dioxide for a first series of repeated inspirations by the subject, and 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, wherein targeting the first and second end-tidal concentrations of carbon dioxide comprises: during an inspiration by a subject with multiple sclerosis, controlling 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, controlling 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, when the first end-tidal concentration of carbon dioxide is reached, control a sensor to measure blood flow in the subject's brain; when the second end-tidal concentration of carbon dioxide is reached, control the sensor to 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. ### Claim 9 (depends on 8) The apparatus of claim 8, the processor further configured to control the gas delivery device to deliver the first and second gases during repeated inspirations by the subject. ### Claim 10 (depends on 8) The apparatus of claim 8 wherein the second gas includes rebreathed gas exhaled by the subject during an expiration prior to the inspiration. ### Claim 11 (depends on 8) The apparatus of claim 8, 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. ### Claim 12 (depends on 8) The apparatus of claim 8, 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. ### Claim 13 (depends on 8) The apparatus of claim 8, the processor further configured to control the sensor to measure blood flow in a plurality of layers of the subject's cerebral cortex. ### Claim 14 (depends on 8) The apparatus of claim 8, the processor further configured to calculate vascular compliance using the cardiovascular response. ### Claim 15 A method of using sequential gas delivery to test for neurovascular uncoupling in a subject with multiple sclerosis, the method 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. ### Claim 16 A method of using sequential gas delivery to determine vascular compliance in a subject with multiple sclerosis; the method 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.