Magnetic resonance imaging methods for the study of gastrointestinal transit

Abstract

Methods and apparatus for the study of gastrointestinal transit in a human or animal subject. The method being for the study of a subject which has previously ingested a container containing first and second fluids that are detectable and distinguishable by MRI, which method comprises the steps of forming a first magnetic resonance image of at least a portion of the subject's GI tract in which the container is located, wherein the magnetizations of the first and second fluids are in-phase; forming a second magnetic resonance image, coincident with the first image, wherein the magnetizations of the first and second fluids are out-of-phase; and subtracting the second image from the first image, or vice versa, to form a composite image.

Claims

1. A method of imaging a human or animal subject that has ingested a container containing first and second fluids that are detectable and distinguishable by MRI comprising: forming a first magnetic resonance image of at least a portion of the subject's GI tract in which the container is located, wherein the first and second fluids contain .sup.1H and the magnetizations of the first and second fluids are in-phase; forming a second magnetic resonance image, coincident with the first image, wherein the magnetizations of the first and second fluids are out-of-phase; subtracting the second image from the first image, or the first image from the second image, to form a composite image; and analysing the composite image to determine a location of the container within the subject's GI tract.

2. The method of claim 1, wherein the subject has ingested a plurality of containers.

3. The method of claim 1, wherein containers are ingested by the subject at two or more time points and are distinguishable from each other.

4. The method of claim 3, wherein the containers are distinguishable by virtue of having different shapes that are discernible in the MRI images.

5. The method of claim 3, wherein the containers are distinguishable on the basis of their MRI properties.

6. The method of claim 1, wherein the first and second fluids are water, or a water-containing aqueous medium; and an oil.

7. The method of claim 1, wherein the container has the form of a capsule having a hollow shell within which the first and second fluids are contained, and the wall of the container is such that it retains its integrity in the acid environment of the stomach and the alkaline conditions prevalent in the intestines.

8. The method of claim 7, wherein the container comprises separate compartments for the first and second fluids.

9. The method of claim 7, wherein the first and second fluids constitute distinct phases of a colloidal dispersion such as an emulsion.

10. The method of claim 1, wherein the container has a maximum dimension of from 0.5 mm to 10 mm.

11. The method of claim 1, wherein the container is a hollow particle filled with MRI-detectable fluid.

12. The method of claim 11, wherein the particle is generally spherical or oblong, with diameters or other dimensions of the order of 2 mm or less.

13. The method of claim 12, wherein particles are administered as a suspension or slurry.

14. The method of claim 1, wherein the forming the first magnetic resonance image, forming the second magnetic resonance image, subtracting the second image from the first image, or the first image from the second image, to form a composite image, and analysing the composite image steps are repeated several times in order to track the location of the container through the subject's GI tract over a period of time.

Description

(1) The methods of the present invention may utilise the magnetic resonance properties of any nuclide. However, in the overwhelming majority of cases the nuclide of interest will be .sup.1H. Standard, commercially available MRI equipment is adapted for .sup.1H imaging, and suitable fluids for use in the invention contain high proportions of .sup.1H nuclei (eg water and vegetable oils and the like).

(2) The methods by which the MRI images are generated may involve any suitable MRI techniques. These include, without limitation, selective/suppressed imaging, T1-weighted imaging, T2-weighted imaging, Chemical Exchange Saturation Transfer (CEST) imaging, and diamagnetic CEST (DIACEST) imaging.

(3) The container preferably has the form of a capsule or the like, ie a hollow shell, bead or coated bead/droplet, within which the first and second fluids are contained. The wall of the container should be such that it retains its integrity in the acid environment of the stomach and the alkaline conditions prevalent in the intestines.

(4) The container may comprise separate compartments for the first and second fluids. However, it is particularly preferred that the first and second fluids occupy precisely the same spatial locations. Thus, the first and second fluids may be intimately mixed. Hence, the first and second fluids may constitute distinct phases of a colloidal dispersion such as an emulsion. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion.

(5) The container preferably has sufficiently small dimensions that it may easily be ingested by the subject, even if the subject is an elderly person or a child. Preferably, the dimensions of the container do not exceed 10 mm. More preferably, the dimensions of the container do not exceed 5 mm. The dimensions of the container may be of the order of 1 mm or 2 mm or 3 mm. Thus, the container may have a maximum dimension of from 0.5 mm to 10 mm, or from 0.5 mm to 5 mm, or from 0.5 mm to 3 mm.

(6) The container may be spherical or non-spherical, eg oval or oblong. Spherical containers may be preferred for reasons of manufacturing simplicity, particularly in the case of very small containers. However, non-spherical containers may be more readily discernible in MRI images and oblong containers may be easier to swallow than disk or spherical shapes

(7) In other embodiments, the containers are smaller, and have the form of hollow particles filled with MRI-detectable fluid. Such particles are typically, though not necessarily, generally spherical or oblong, with diameters or other dimensions of the order of 2 mm or less, eg between 0.01 mm and 1 mm. The particles may be administered as a suspension or slurry that may be relatively easy for the subject to ingest. For instance, the particles may be suspended in a liquid or viscous medium to form a drink.

(8) Suitable microparticulate containers may resemble commercially available microcapsules such as those available from Ashland (www.ashland.com) under the trade name ISP MicroCapsules, but formed from, or coated with, a material that maintains its integrity during passage through the GI tract.

(9) Such small particulates may comprise both the first and second fluids, especially where the first and second fluids are intimately mixed, as in an emulsion. Alternatively, the particulates may contain just one of the fluids, but may be administered as a mixture of particulates containing the first fluid and particulates containing the second fluid.

(10) Small fluid-filled particulates of this kind will generally not be individually discernible in MRI images, but will collectively be apparent as a diffuse cloud of material, the progress of which through the GI tract can be followed by the method of the invention.

(11) Whatever the nature of the containers, they preferably have a density that is comparable with that of the stomach contents, ie ingested food material and chyme, so that the containers do not sink to the base of the stomach or float within the stomach, which could delay the passage of the container from the stomach. Thus, the container preferably has a density of 1.0-1.5 g/cm.sup.3, more preferably 1.0-1.2 g/cm.sup.3.

(12) The use of capsules containing oil in the monitoring of GI transit by MRI is believed to be novel, and represents a further aspect of the invention. According to that aspect of the invention, there is provided a method of imaging a human or animal subject, which subject has previously ingested a container containing an oil that is detectable by MRI, which method comprises forming a magnetic resonance image of at least a portion of the subject's GI tract in which the container is located.

(13) Whereas endogenous water present within the GI tract and the surrounding tissues may make it difficult to discern water-based markers in the methods of the invention, it has been found that this is not such a problem for oil-based markers. It is believed that this because the lumen of the GI tract would in general not be expected to contain pockets of substantial quantities of material having similar MRI properties to the oils that are useful in the present invention (eg fat and the like).

(14) A related aspect of the invention is a method of assessing GI transit in a human or animal subject, which subject has previously ingested a container containing an oil that is detectable by MRI, which method comprises the steps of a) at a known time after ingestion by the subject of the container, forming a magnetic resonance image of at least a portion of the subject's GI tract in which the container is located; and b) identifying the location of the container within the subject's GI tract at said time.

(15) Another aspect of the invention that is believed to be novel is the use of a plurality of markers that are detectable and distinguishable by MRI, and which are ingested at different times, in a method of assessing GI transit. Thus, according to another aspect of the invention, there is provided a method of assessing GI transit in a human or animal subject, which method comprises the steps of a) at a time point after the subject has ingested a first form of MRI-detectable and MRI-distinguishable marker, forming a magnetic resonance image of at least a portion of the subject's GI tract in which the first form of marker is located; and b) at a time point after the subject has ingested a second form of MRI-detectable and MRI-distinguishable marker, forming a magnetic resonance image of at least a portion of the subject's GI tract in which the second form of marker is located.

(16) This aspect of the invention may of course involve further forms of marker, eg third and fourth forms of marker. As described above in relation to the first aspect of the invention, the different forms of marker may be distinguishable by various means. For instance, the containers may have different shapes that are discernible in the MRI images. Alternatively, the markers may be distinguishable on the basis of their MRI properties. For instance, the markers may be containers filled with materials having differing MRI properties, eg water doped with differing concentrations of a contrast agent such as gadolinium, the effect of which is that the aqueous fluids in different containers have differing relaxation times, so that they can be distinguished from each other by appropriate choice of imaging parameters.

(17) The methods of the invention are particularly useful in the assessment of GI transit in paediatric patients, young patients (eg up to 21 years of age) and women of child-bearing age. In such patients, conventional use of X-Rays is discouraged. MRI markers that are small are relatively easy to ingest and behave within the GI tract in a manner that is representative of GI transit in the subject. Thus, the invention further provides a method of assessing GI transit in a human or animal subject, which subject has previously ingested a plurality of MRI-detectable markers having maximum dimensions of less than 5 mm, which method comprises forming a magnetic resonance image of at least a portion of the subject's GI tract in which the markers are located.

(18) The MRI markers employed in this aspect of the invention may be any of those described above, ie containers holding first and second fluids (eg oil and water or an emulsion), containers of oil, or containers of water, or containers of a solution of an MRI contrast agent. The number and nature of the containers, the number of times that images are generated and the timescale over which images are generated may be as described above.

(19) The methods of the invention involve the use of novel MRI-detectable markers. According to a further aspect of the invention, there is therefore provided a kit comprising a plurality of MRI-detectable markers suitable for use in any of the foregoing methods, together with instructions for their use in any one of those methods.

(20) As described above, the markers may take the form of containers holding first and second fluids (eg oil and water or an emulsion), containers of oil, or containers of water, or containers of a solution of an MRI contrast agent.

(21) Markers useful in the methods of the invention are also believed to be novel, and represent a further aspect of the invention, which thus provides a marker for use in MRI of a human or animal subject, the marker comprising a container containing first and second fluids that are detectable and distinguishable by MRI.

(22) As described above, the first and second fluids may be water (or a water-containing aqueous medium) and an oil, and in certain embodiments, the first and second fluids together form an emulsion.

(23) In another aspect of the invention, there is provided a marker for use in MRI of a human or animal subject, the marker comprising a slurry or suspension of hollow particles containing an MRI-detectable fluid. In some embodiments, the fluid may comprise an oil. In some embodiments, the fluid may comprise an oil-in-water emulsion or a water-in-oil emulsion.

(24) The instructions may comprise instructions to calculate a geometric centre score (as described below) and may comprise information regarding example geometric centre scores. The instructions may comprise an indication of one or more normal geometric centre scores and/or one or more abnormal geometric centre scores.

(25) The instructions may comprise a chart illustrating the notional sections of the body structure.

(26) The methods of the invention are all useful in the assessment of GI transit. The methods may be used to study whole gut transit or transit through a region of the GI tract, eg small bowel transit, colonic transit or regional colonic transit.

(27) The assessment of GI transit may comprise noting an administration time at which the or each marker is administered to the subject, determining the location for the or each marker within the GI tract of the subject by a method described above, and using the location(s), together with the time that has elapsed between administration and imaging, to produce a score indicative of the transit of the marker(s).

(28) The assessment of GI transit may comprise determining an average transit time. Assessing the transit may comprise simply summing how many capsules are present in any given segment of the GI tract at a given time point and using simple calculations to assign a transit time, or determining a geometric centre score indicative of the transit time. Determining the geometric centre score may comprise the step of notionally dividing the GI tract into a plurality of notional sections. The method may comprise noting how many markers are found in each of the notional sections at the (or each) imaging time.

(29) Each notional section may be assigned a number. The method may comprise multiplying the number of markers found in a respective section (if any) by the number assigned to that section to produce a weighted number of markers for that section. The method may comprise summing the weighted numbers for each section (or each non-zero weighted number) and dividing by the total number of markers ingested to produce a geometric centre score.

(30) Specific embodiments of the invention include the following.

(31) a) A method of assessing GI transit in a human or animal subject, which method involves ingestion by the subject of a container (or more usually a plurality of containers) containing two different fluids that can be detected and distinguished by MRI. The two fluids may be water (or more commonly an aqueous solution) and an oil, and may be in the form of an emulsion. The containers may be capsules or the like, beads, or coated drops/beads, with sizes of the order of a few millimetres, or they may be microcapsules of much smaller size. In the latter case, the containers may be ingested in the form of a suspension or slurry. At a series of time points subsequent to ingestion of the container(s), images are generated of the subject's GI tract, so that the progess of the container(s) can be monitored. The identification of the location of the container(s) at each measured time point is facilitated by the generation of a composite image, as described above. A defined assessment scheme may be used to evaluate the results, enabling the required clinical assessment of GI function to be made.
b) A method of assessing GI transit in a human or animal subject, which method involves ingestion by the subject of a container (or more usually a plurality of containers) containing an oil that is detectable by MRI. The containers may be capsules or the like, with sizes of the order of a few millimetres, or they may be microcapsules of much smaller size. In the latter case, the containers may be ingested in the form of a suspension or slurry. At a series of time points subsequent to ingestion of the container(s), images are generated of the subject's GI tract, so that the progress of the container(s) can be monitored. A defined assessment scheme may be used to evaluate the results, enabling the required clinical assessment of GI function to be made.
c) A method of assessing GI transit in a child, which method involves ingestion by the child of a plurality of small MRI-detectable markers (with dimensions of less than 5 mm). The containers may be capsules or the like, or they may be microcapsules of much smaller size. In the latter case, the containers may be ingested in the form of a suspension or slurry. The containers may contain an oil that is detectable by MRI. The containers may contain two different fluids that can be detected and distinguished by MRI. The two fluids may be water (or more commonly an aqueous solution) and an oil, and may be in the form of an emulsion. At a series of time points subsequent to ingestion of the container(s), images are generated of the subject's GI tract, so that the progess of the container(s) can be monitored. A defined assessment scheme may be used to evaluate the results, enabling the required clinical assessment of GI function to be made.

(32) The principle underpinning the methods of the invention will now be illustrated with reference to the accompanying FIG. 1, which shows .sup.1H MRI images of a test rig comprising a pair of vials containing agar gel within which sunflower seeds are dispersed. Sunflower seeds are suitable models for illustration of the present invention since they contain moisture and oil, the oil being present in micropockets within the seeds. In addition, the test rig contains a water phantom (i.e. a water-filled feature)—the circular feature at the right of each image—and an oil phantom—the generally semicircular feature to the left of each image.

(33) The images are the following: a) This image is generated under MRI conditions that reveal only the water-containing component of the test rig. The vials are visible, as are the sunflower seeds (as regions of reduced intensity) within the vials. The water phantom is clearly visible, but not the oil phantom. b) This image was generated under MRI conditions that reveal only the oil-containing component of the test rig. Thus only the oil phantom and the sunflower seeds are clearly visible, the latter as bright spots. This illustrates the feasibility of the use of oil-containing capsules or particles in the methods of the invention. c) This image was calculated to show the magnetizations of the oil and water in-phase. This image thus corresponds to the “first image” of the first aspect of the invention. The water and oil phantoms are clearly visible, as are the vials, but the contrast between the sunflower seeds and the surrounding agar gel is rather low. d) In this image, the magnetizations of the oil and water are shown out-of-phase. The image thus constitutes the “second image”. Again, both oil and water phantoms are visible, and the sunflower seeds are readily visible (as areas of reduced intensity compared with that of the surrounding agar gel). e) Finally, this composite image was obtained by subtraction of image c) from image b). The sunflower seeds are readily visible as bright spots against a uniform grey background.