WO2017029671A1

WO2017029671A1 - Methods and systems for onsetting low-level field mri hyperpolarization of a patient

Info

Publication number: WO2017029671A1
Application number: PCT/IL2016/050903
Authority: WO
Inventors: Uri Rapoport
Original assignee: Aspect Imaging Ltd.
Priority date: 2015-08-18
Filing date: 2016-08-17
Publication date: 2017-02-23
Also published as: DE202015104743U1

Abstract

A system and method of magnetic resonance imaging comprises administering to a subject a hyperpolarizable fluid in a non-hyperpolarized state. The subject is then subjected to a predetermined sequence of magnetic field intensities to cause hyperpolarization of the fluid. Then a magnetic resonance imaging process on the subject may be performed on the subject.

Description

METHODS AND SYSTEMS FOR ONSETTING LOW-LEVEL FIELD MRI

HYPERPOLARIZATION OF A PATIENT

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62/206,293 filed on August 18, 2015, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. TECHNICAL FIELD

[0002] The present invention relates in general to the field of magnetic resonance imaging (MRI). MRI is used in many fields including medical diagnosis.

2. DISCUSSION OF RELATED ART [0003] MRI provides unsurpassed soft tissue contrast, but the inherent low sensitivity of this modality has limited the clinical use to imaging of water protons. With hyperpolarization techniques, the signal from a given number of nuclear spins can be raised more than 100,000 times. The strong signal enhancement enables imaging of nuclei other than water protons, e.g. 13C and 15N, and their molecular distribution in vivo can be visualized in a clinically relevant time window. For example, it was published that hyperpolarized 13C nuclei were injected into rabbits, followed by rapid 13C MRI with high spatial resolution (scan time <1 s and 1.0 mm in- plane resolution).

[0004] A problem with hyperpolarized materials is that once prepared, e.g. after hyperpolarization, the hyperpolarized materials may breakdown or "relax" and may revert to their pre-hyperpolarization state within time frames on the order of a few seconds to a few minutes, for example, depending on the ambient environment, the type of hyperpolarized material and/or other factors that are known in the art. Therefore efforts have been made to slow down this process.

[0005] Mu-metal is a nickel-iron soft magnetic alloy with very high permeability suitable for sensitive electronic equipment shielding. Mu-metal is composed of approximately 80% nickel, 5% molybdenum, balance iron. The high permeability makes mu-metal useful for shielding against static or low-frequency magnetic fields. [0006] Examples of DC magnetic properties of some commercially available mu-metals are as follows: Coercive force from H=1.0 Oe, Oersted 0.008 to 0.02; Hysteresis loss from H=1.0 Oe, erg/cm3 per cycle 18 to 24; form of bar or wire, μ at B = 40 G; μ max of 200,000; Ho from H=l Oersted is 0.02 max; DC hysteresis loss from H = 1 Oe, erg/cm3 per cycle 16, Induction, gauss 7,300; Residual Induction, gauss 3,500 (Split strip or split rod specimens). More specifications of commercially available mu-metals are presented in currently available web site http://www.mumetal.com/ mumetal_specifications .html..

SUMMARY OF THE INVENTION

[0007] Some embodiments of the present invention provide methods and systems for onsetting of the hyperpolarization of a hyperpolarizable substance in which the substance is pre- administrated to a subject and the onsetting may be done in situ and optionally in real time.

[0008] Some embodiments of the invention provide a method of magnetic resonance imaging comprising administering to a subject a hyperpolarizable fluid in a non-hyperpolarized state, also known as equilibrium. The subject may then be subjected to a predetermined sequence of magnetic field intensities to cause hyperpolarization of the fluid. A magnetic resonance imaging process may then be performed on the subject, for example while the fluid is in a hyperpolarized state, for example before it has relaxed.

[0009] Some embodiments of the invention provide a magnetic resonance device (MRD) integrated system in which the onsetting is done under reversible timed conditions of zero-gauss magnetic field. Such a system may comprise a zero-gauss chamber (ZGC) having at least one zero-gauss module (ZGM), wherein the ZGC and/or ZGM is configured for at least temporarily enveloping the subject or otherwise inducing zero-gauss magnetic field over the subject whilst it is accommodated within the MRD.

[0010] The subject may be any of but is not limited to mammals, laboratory animals (mouse, rat, rabbit, pig etc.), human patients, including neonates, portions of any of the foregoing, and organs, biopsies and one or more slices of the foregoing.

[0011] The terms" zero-gauss chamber" and "zero-gauss module" are abbreviated herein to "ZGC" and "ZGM" respectively.

[0012] The ZGC may be provided with one or both of at least one mu-metal layer inner shell for absorbing magnetic field energy and a solenoid coil. [0013] The ZGC may be provided with at least one non-mu metal outer shell, for example a triple-layer mu-metal shell.

[0014] The ZGM may be provided with a magnetic field source, for example a coil, configured to be maneuverable relatively to the subject.

[0015] The ZGM may be configured to be switchable between an "on" state characterized by about 5μΤ to about 80μΤ and an "off state characterized by about 90 nT to about 220 nT.

[0016] A system according to some embodiments of the invention may further be provided with a signal generator configured to reversibly induce a magnetic field by means of the magnetic field source, thereby providing the onsetting of the hyperpolarization.

[0017] The ZGM and the subject may be maneuverable with respect to each other in any manner including the ZGM being maneuverable whilst the subject is stationary, the ZGM being stationary whilst the subject is maneuverable, and both the ZGM and the subject being maneuverable relative to one another.

[0018] The maneuverability relative to the subject may be in any fashion including but not limited to linear movement, non-linear movement, twist, fold, rotation and any combination thereof.

[0019] The ZGM may be maneuverable relative to the subject in a continuous movement or a non-continuous movement or both.

[0020] The maneuverability relatively to the subject may be by a rail.

[0021] A system according to some embodiments of the invention may further be provided with a holding subsystem for the subject, e.g. for an animal including a human.

[0022] A system according to some embodiments of the invention may further be provided with at least one life supporting system.

[0023] A system according to some embodiments of the invention may further comprise at least one intravenous (IV) line configured for pre-administering at least one hyperpolarizable material into the subject.

[0024] A system according to some embodiments of the invention may further be provided with a cable configured to serve as a noise-reducing, artificial ground.

[0025] The cable may be any of a coaxial cable, a twisted-pair cable and any combination thereof.

[0026] According to some embodiments of the invention the reversible timed conditions of zero- gauss magnetic field may be varied, for example by operation of the ZGM, according to said predetermined sequence of magnetic field intensities. The predetermined sequence may comprise a first starting state; a drop in field intensity to a second intermediate state; and a rise in the field intensity to a third steady state.

[0027] The starting or "on" state may have a field intensity ranging from about 5 μΤ to about 85 μΤ. The drop in field intensity may be linear, and may be over a period ranging from about 5 ms to about 110 ms. The intermediate or "off state may have a field intensity in a range of about 25 nT to about 175 nT. The intermediate state may be sustained for a period ranging from about 100 ms to 950 ms. The rise in the field intensity may be over a period ranging from about 0.5 seconds to 5.2 seconds, and may be to a range from about 5 μΤ to about 85 μΤ. The steady- state field value may range from about 2.5 μΤ to about 105 μΤ.

[0028] The rise in the field intensity may be any of linear, non-linear, step-wise, exponential and any combination thereof.

[0029] Systems and methods according to embodiments of the invention may include hyperpolarization of the hyperpolarizable substance, followed by application of the predetermined sequence of magnetic field intensities. The zero gauss module may be operable to achieve this.

[0030] A system according to some embodiments of the invention may further be provided with an external magnetic field module configured to switchably induce a magnetic field into the zero- gauss module.

[0031] The external magnetic field module may comprise at least one solenoid coil configured to induce a magnetic field into the zero-gauss module.

[0032] The external magnetic field module may be operable to provide a magnetic field of at least about 50 μΤ.

[0033] A system according to some embodiments of the invention may further comprise an active magnetic field module operable according to a predetermined protocol.

[0034] The predetermined protocol may include a mechanical translocation of the active magnetic field module, an electric modulation of the active magnetic field module, or both.

[0035] The active magnetic field module may comprise at least one solenoid coil and a signal generator.

[0036] According to some embodiments of the invention the subject may be accommodated in a receptacle configured to be maneuverable between the zero-gauss module and the active magnetic field module. [0037] Some embodiments of the invention may provide a method comprising: pre- administering a hyperpolarizable substance to a subject; and onsetting hyperpolarization of the hyperpolarizable substance by at least temporarily enveloping the subject, or a portion thereof in a zero-gauss module.

[0038] A method according to some embodiments of the invention may further comprise switching the zero-gauss module between an "on" state characterized by a magnetic field intensity ranging from about 5 μΤ to about 85 μΤ and an "off state characterized by a magnetic field intensity ranging from about 25 nT to about 175 nT.

[0039] A method according to some embodiments of the invention may further comprise reversibly inducing a magnetic field in the zero-gauss module by means of a signal generator, thereby providing the onsetting of the hyperpolarization.

[0040] A method according to some embodiments of the invention may further comprise positioning an external magnetic source externally to the zero-gauss module and reversibly providing a magnetic field to the subject, or a portion thereof.

[0041] A method according to some embodiments of the invention may further comprise maneuvering the zero-gauss module relative to the subject by the zero-gauss module being maneuverable whilst the subject is stationary, the zero-gauss module being stationary whilst the subject is maneuverable, or both the zero-gauss module and the subject being maneuverable relatively to one another.

[0042] The maneuvering may be any of linear movement, non-linear movement, twist, fold, rotation and any combination thereof, and may comprise continuous movement or non- continuous movement or both.

[0043] A system according to some embodiments of the invention may be provided with a shielded cable serving as a noise -reducing, artificial ground.

[0044] The shielded cable may comprise a coaxial cable, a twisted-pair cable and any combination thereof.

[0045] Some embodiments of the invention may provide a method of in situ real-time onsetting the hyperpolarization of a hyperpolarizable substance pre- administrated to a subject under reversible timed conditions of zero-gauss magnetic field, comprising steps of integrating an MRD integrated system with a ZGC having at least one ZGM, and at least temporarily enveloping the subject by means of the ZGC and/or ZGM. [0046] Some embodiments of the invention may provide a method of in situ real-time onsetting of hyperpolarization of a hyperpolarizable substance pre-administrated to a subject under reversible timed conditions of zero-gauss magnetic field, comprising integrating an MRD integrated system with a ZGC having at least one ZGM, and inducing a zero-gauss magnetic field over the subject whilst it is accommodated within the MRD.

[0047] The term "about" is used herein to refer to a value being greater or smaller than 20% of the defined measure.

BRIEF DESCRIPTION OF THE DRAWINGS

[0048] For a better understanding of embodiments of the invention and to show how the same may be carried into effect, reference will now be made, purely by way of example, to the accompanying drawings in which like numerals designate corresponding elements or sections throughout.

[0049] In the accompanying drawings:

[0050] Fig. 1 is a (non-proportional) time graph showing a sequence of magnetic field intensity values to which a subject may be subjected according to some embodiments of the invention;

[0051] Fig. 2a is a cross section diagram of a ZGC according to some embodiments of the invention, illustrating an inner, mu-metal layer and an outer, non-mu metal layer;

[0052] Fig. 2b is a cross section diagram of a ZGC according to some embodiments of the invention;

[0053] Fig. 3 is a diagram of a ZGC according to some embodiments of the invention configured with a solenoid coil that produces a magnetic field when supplied with a current by the electrical signal generator;

[0054] Fig. 4a is a schematic illustration of a pre-clinical MRD-based imaging system according to some embodiments of the invention;

[0055] Fig. 4b is a schematic illustration of a pre-clinical animal handling subsystem according to some embodiments of the invention;

[0056] Fig. 4c is a schematic illustration of a system according to some embodiments of the invention with an animal handling system; [0057] Fig. 5 is a diagram that matches time-indexed, changing magnetic field values with a spatial system depiction in which a subject is maneuverable relatively to the ZGC according to some embodiments of the invention;

[0058] Fig. 6. is a (non-proportional) time graph showing a sequence of magnetic field intensity values to which a subject may be subjected according to some embodiments of the invention, having a step- wise rise in magnetic intensity;

[0059] Fig. 7 is a schematic illustration of a system according to some embodiments of the present invention providing a static, stable component and an active, switchable or maneuverable component; and

[0060] Fig. 8 is a schematic illustration of another system according to some embodiments of the present invention providing an external magnetic field module, encompassing the zero-gauss module of the system shown in Fig. 3.

DETAILED DESCRIPTION OF THE INVENTION

[0061] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those of ordinary skill in the art that the invention may be practiced without these specific details. In other instances, well-known methods, procedures, components, modules, units and/or circuits have not been described in detail so as not to obscure the invention.

[0062] Although embodiments of the invention are not limited in this regard, discussions utilizing terms such as, for example, "processing," "computing," "calculating," "determining," "establishing", "analyzing", "checking", or the like, may refer to operation(s) and/or process(es) of a computer, a computing platform, a computing system, or other electronic computing device, that manipulates and/or transforms data represented as physical (e.g., electronic) quantities within the computer's registers and/or memories into other data similarly represented as physical quantities within the computer's registers and/or memories or other information non-transitory storage medium (e.g., a memory) that may store instructions to perform operations and/or processes. Although embodiments of the invention are not limited in this regard, the terms "plurality" and "a plurality" as used herein may include, for example, "multiple" or "two or more". The terms "plurality" or "a plurality" may be used throughout the specification to describe two or more components, devices, elements, units, parameters, or the like. Unless explicitly stated, the method embodiments described herein are not constrained to a particular order or sequence. Additionally, some of the described method embodiments or elements thereof can occur or be performed simultaneously, at the same point in time, or concurrently. Unless otherwise indicated, us of the conjunction "or" as used herein is to be understood as inclusive (any or all of the stated options).

[0063] Some embodiments of the present invention may provide systems and methods for low- field hyperpolarization of a hyperpolarizable substance pre- administered to a subject. The hyperpolarizable substance, which could be in a non-limiting example, a metabolic compound provided with 13C or 15N derivatives, may be provided to the subject in an equilibrium state. In some embodiments, only after subjecting the subject to a zero-gauss, low-field MRI will the substance go through hyperpolarization and the subject may thus be ready for imaging. Therefore, some embodiments of the present invention may provide real-time, in-situ onsetting of the hyperpolarization process, and may allow for greater flexibility and accuracy in using MRI imaging of hyperpolarized substances for diagnostics, research or any other purpose.

[0064] The hyperpolarizable substance may comprise any fluid including but not limited to any substance that continually deforms or flows under an applied shear stress. According to some embodiments of the invention the hyperpolarizable substance may comprise a liquid. Fluids include liquids such as but not limited to water, emulsions, water immiscible fluids, water immiscible fluids, etc.. Fluids include gases, plasmas and plastic solids. Fluids are also any subject(s) that have about zero shear modulus or in simpler terms a fluid is a subject which cannot resist any shear force applied to it. Fluids include water, drugs suspensions, body fluid (blood, urine, fecal, intercellular and extracellular fluids, saliva, etc.), oil, gas, industrial raw materials, by products and products thereof, food and beverages, etc. The term further relates to fluids utilized in infusion of liquids into a patient, e.g., to intravenous therapy-related liquids and to infusion of liquid substances directly into a vein.

[0065] Reference is now made to Fig. 1, schematically illustrating a scheme of low-field MRI hyperpolarization comprising a sequence of magnetic field intensity values to which a subject may be subjected according to some embodiments of the invention. The scheme begins with a low-field hyperpolarization starting field value A in a range of about 50 μΤ; e.g., a simulated "earth" magnetic field which may be produced when an electrical signal generator 110 shown in Fig. 3 is "on". This may be followed by a drop C in field intensity shown in this example as linear, starting at time B, over a period in a range of about 50 ms from B to D, where B denotes the commencement of the onsetting time (To), to a range of no more than about 100 nT, which may be produced when the electrical signal generator 110 is "off ; a ZGC magnetic field in a range of no more than about lOOnT, (the "off" state,) sustained for a period in a range of about 500 ms from D to E; a linear rise F in the ZGC magnetic field intensity, over a period of 2 seconds from E to -G, back to a range of about 50 μΤ; and then starting at G a steady-state H field value in a range of about 50 μΤ.

[0066] According to some embodiments of the invention, the starting "on" state indicated by A in Fig. 1 may have a field intensity ranging from about 5 μΤ to about 85 μΤ. The linear drop in field intensity may be over a period ranging from about 5 ms to about 110 ms. The subsequent "off state may have no more than a range of about 25 nT to about 175 nT and may be sustained for a period ranging from about 100 ms to 950 ms. The subsequent rise in said field intensity, may be over a period ranging from about 0.5 seconds to 5.2 seconds, and may be to a range from about 5 μΤ to about 85 μΤ. The subsequent steady-state field value may range from about 2.5 μΤ to about 105 μΤ.

[0067] Reference is now made to Fig. 2a, which depicts a cross section of a ZGC, and Fig. 2b which shows a cross section of the chamber of Fig. 2a along the axis A-A in Fig. 2a. In this example the chamber is cylindrical. The ZGC in this and other embodiments of the invention may comprise a predefined volume, in which the environmental magnetic field (Earth field) within said volume may be reduced to near zero.

[0068] These figures show, as a no n- limiting example, three layers of mu-metal 130 and a non- mu metal outer shell 140. It is noted that ZGCs may be embodied in various shapes and the description of the invention should not be interpreted as limiting in the shape of the ZGC.

[0069] Fig. 3 shows a system including a ZGC as shown in Figs 2a and 2b.

[0070] Hence, the present invention provides novel systems [100] and methods for in situ real time hyperpolarization of a substance; e.g., raw materials, by-products and products, industrial lines, laboratory animals or humans [200] ; under conditions of low magnetic field.

[0071] In an embodiment of the present invention, shown in Figs 2a, 2b and 3, a system includes, inter alia, a ZGC or the like 120 encased by an inner and usable to at least partially and/or reversibly accommodate a subject at least one layer mu-metal shell 130 configured for absorbing magnetic field energy; and an outer shell fabricated from a non-mu metal 140; a coil 150, arranged inside the ZGC 120 for producing low-intensity magnetic field from an applied current; a signal generator 110 configured for providing a controlled variable electric current to the coil 150 thereby producing a controlled, variable, low-intensity magnetic field. tThe magnetic field may be defined as "ON" when the coil 15 produces the ZGC magnetic field of about 50 μΤ (micro-Teslas) and "OFF" when about no current is provided to the coil 150 and the magnetic field intensity in the ZGC is about 100 nT (nano-Teslas). The system may further comprise a shielded, noise-reducing cable 170, configured for conducting the electric current from the electrical signal generator to the solenoid coil 150; connecting the mu-metal shell 130 thereby serving as a noise -reducing artificial ground; and a receptacle 501 for holding the subject 500, in this example a human, within the ZTC bore 160.

[0072] In an embodiment of the invention, provided here in a non- limiting manner, said ZGC 160 may be maneuverable relative to an imaged subject 500. The ZGC may be dynamically maneuverable whilst subject is stationary; or the ZGC may be stationary whilst subject is dynamically maneuverable; or both ZGC and subject may be dynamically maneuverable.

[0073] The term "dynamically maneuverable" refers here, for example, to a reciprocal movement, linear or nonlinear movement, twist, fold, or to any motion along the X, Y and/or Z axes and combination thereof, and to any rotation thereof, and to a continuous or non-continuous movement(s).

[0074] Reference is now made to Fig. 3, which depicts a schematic illustration of a clinical MRD-based imaging system 100a according to some embodiments of the invention having a zero gauss module comprising a zero-gauss chamber combined with a solenoid coil. This system comprises an open bore MRD 180, a zero-gauss chamber 120 which contains, inter alia, a subject receptacle 501, here, at least one portion, location, defined volume, segment or mechanically maneuverable sleeve-like apparatus within or in connection with said MRD 180, a solenoid coil 150 or similar coil; and possibly, a wire pair providing current to the solenoid coil 150 and grounding to the mu-metal. Also depicted in the figure are the inner, mu-metal shell 130, the outer, non-mu metal shell, 140 the noise -reducing cable 170, and the electrical signal generator 110. A patient to be imaged, organ or portion to imaged (hand, leg, wrist, head etc.) thereof 500, is shown laying or immobilized on an MRI bed 501.

[0075] Hyperpolarization onset may be carried out by subjecting the patient to a zero-gauss environment. According to some embodiments of the invention the patient may be movable as indicated by arrow 503 and the ZGC may be stationary. Here, the rate of patient movement, e.g., linear reciprocal movement along bed 501, for example by means of a rail in connection with the same or by other means, may determine the onset rate. According to some embodiments of the invention the patient may be stationary, and the ZGC 120 may be movable as indicated by arrow 503. Here, the rate of ZGC movement, e.g., linear reciprocal movement along bed 501 and over patient 500 laying on the bed, for example by means of a rail in connection with the same or by other means, may determine the onset rate. According to some embodiments of the invention the patient may be movable, and the ZGC 120 may also be movable 503. Here, the rate of both patient movement by movement of the bed 501 and ZGC movement, e.g., linear reciprocal movement along bed 501 and over patient 500 laying on the bed, for example by means of a rail in connection with the same or by other means, may determine the onset rate.

[0076] According to some embodiments of the invention, the patient, or portion thereof, to be imaged may be immobilized on an MRI bed, while possibly interconnected to life support system(s) and lines thereof located at the distal portion of the device, for example including an IV line of a hyperpolarizable agent in a fluid. The patient is thus subjected to a predefined measure of said fluid, which could be administered at any time period before imaging. Then, for a very short predefined time period, the ZGC may envelope the patient or portion thereof thereby zeroing the magnetic field of the patient and the loaded hyperpolarized agent therein, i.e., exposing the hyperpolarizable agent in patient's blood and body to zero ("OFF") gauss and onsetting hyperpolarization of the administered substance. After a predefined time period, the coffin-like or a sleeve-like ZGC may be removed from enveloping the patient, for example at a predefined rate, thereby exposing the patient and hyperpolarized agent therein to its high ("ON") magnetic field. During any of these the hyperpolarization properties of the patient and/or organ thereof may be monitored, e.g. continuously, for example by means of MRD 180.

[0077] According to some embodiments of the invention the solenoid coil may provide a magnetic field, and only by reducing the magnetic field produced by the solenoid coil will the patient be subjected to a zero-gauss environment. Reduction of the magnetic field induced by the solenoid coil over the patient may be done either in a mechanical removal, or movement, of the solenoid coil from an imaging area, e.g. within MRD bore, or by reducing the electrical current provided to the solenoid coil. That means that the solenoid coil may also be maneuverable with respect to the patient, or with respect to the zero-gauss chamber, or both. The coil could also be maneuverable using a rail, a hinge or any standard mechanical feature. [0078] A hyperpolarizable substance may be pre- administered to the patient and the patient may then be accommodated in the zero-gauss chamber having the solenoid coil operating therein. Once onsetting the hyperpolarization is desired, the solenoid coil's induced magnetic field is removed, mechanically or electronically, and therefore the patient, being inside the ZGC is subjected to a zero-gauss field which induces hyperpolarization. After a short predefined time period, the solenoid coil is configured to reintroduce the magnetic field and imaging of the relaxation of the hyperpolarized substance may take place.

[0079] According to some embodiments of the invention, instead of providing a maneuverable ZGC, the ZGC may be alternatively provided with a solenoid coil and a predetermined protocol for inducing a magnetic field by means of the solenoid coil. For example, by controlling the strength of the magnetic field through an electric current provider, zero-gauss may be induced for onsetting, followed by increasing the electric current, and thus increasing the magnetic field, without having to remove the ZGC away from the imaged subject.

[0080] Reference is now made to Fig. 4a, which depicts a schematic illustration of a pre-clinical MRD-based imaging system 1100, provided with a ZGC having a built-in solenoid coil 150 and electric supplier 110. This system comprises an open bore MRD 100b, such as the M2, M3 or M10 series of MRI devices commercially available from Aspect Imaging Ltd. in the USA. An animal handling system (AMS) 1000 such as the animal bed commercially available by Aspect Imaging Ltd. in the USA is provided useful for positioning an immobilized animal in a predefined configuration. The AMS 1000 comprises a portion to be accommodated within the MRD 100b and an external portion 1003.

[0081] Reference is now made to Figs. 4b and 4c, which depict a schematic illustration of a preclinical AMS subsystem according to some embodiments of the invention. AMS 1000 comprises, inter alia, a portion indicated in Fig 4c by reference 1050 configured to be reversibly accommodated within the open bore of an MRD and an external portion 1060 into which external life supporting systems and lines thereof may be interconnected. As this system may be utilizable in pre-clinical purposes, laboratory animals 1100a, including mouse, rat, rabbit etc., may be immobilized under anaesthesia and support (e.g., temperature control, oxygen, medicaments, and hyperpohzable fluids) may be provided via IV lines. The life supporting systems and lines thereof may be communicated to the external environment via an interface interface 1002 of the MRD. [0082] According to some embodiments of the invention, the AMS may comprise a proximal portion, held outside a medical device, comprising at least one inner shaft, and at least one outer shaft, the at least one outer shaft being telescopically maneuverable along the at least one inner shaft to provide a telescopic mechanism of variable (proximal-) length; and a distal portion comprising a configurable encapsulatable life support system (ELSS). The ELSS may be rotatable and/or linearly reciprocatable along the main longitudinal axis of the shafts by means of the maneuverable telescopic mechanism of the proximal portion. The proximal portion may further comprise indicia indicating the linear displacement and rotation of the ELSS of the distal portion, such that the ELSS is accurately and reversibly configured within the medical device to optimized animal analyses.

[0083] Reference is now made to Fig. 4c, which depicts a schematic illustration of a pre-clinical AMS subsystem, for example as shown in Figs. 4a and 4b. According to an embodiment of the invention, AMS may further comprise in its inner portion 1050, or provided in connection with, a zero-gauss chamber 120 which may contain, inter alia, a a receptacle for a subject, e.g. a mouse immobilization bed. A coffin-like or a sleeve-like ZGC having an outer shell 140 may be located with the proximal portion, within the open bore 190 of the MRD. A solenoid coil 150 may be provided with a wire pair providing current to the solenoid coil 150 and grounding to a mu-metal. Also depicted in the figure are inner, mu-metal shell 130, outer, non-mu metal shell, 140 noise- reducing cable 170, and electrical signal generator 110. A subject, e.g. mouse 1000a, to be imaged is immobilized on an MRI bed, and interconnected to life support system located at the distal portion 1060 of the device which may include IV line of hyperpolarizable agent in a fluid. The mouse may be subjected to a predefined measure of said fluid, for example in a respectively high magnetic field, "ON" for a predefined time period. Then, for a very short predefined time, the current provided to the solenoid coil may be eliminated, while the ZGC is enveloping the mouse, thereby zeroing the magnetic field of the mouse and causing the hyperpolarization of the agent therein, for example providing onsetting of the hyperpolarizable agent in mouse blood and body by zero ("OFF") gauss. After a predefined time period, the electric current may be provided in a variable and gradual manner, thereby providing the mouse and hyperpolarized agent therein to its high ("ON") magnetic field whilst continuously or non-continuously measuring the hyperpolarization properties of the mouse and organ thereof by means of said MRD 180.

[0084] According to some embodiments of the invention hyperpolarization of a subject, e.g., patient 500 under conditions of low magnetic field may be useful. Apparatus may comprise a ZGC, for example encased by an inner, triple-layer mu-metal shell 130 for absorbing magnetic field energy; and an outer shell fabricated from a non-mu metal 140. A solenoid coil 150 e.g. made from copper, may arranged inside the zero-gauss chamber 120 for producing low-intensity magnetic field from an applied current. The triple layer shell 130 may comprise three concentric sheets of mu-metal which serve as a barrier for shielding against or otherwise reducing the intensity of a magnetic field.

[0085] An electrical signal generator 110 may provide a controlled variable electric current to the solenoid coil 150 in order to produce a controlled, variable, low-intensity magnetic field. The magnetic field may be defined as "on" when the solenoid coil 150 produces a zero-gauss chamber magnetic field of about 50 μΤ (micro-Teslas) and "off when no current is provided to the solenoid coil 150 and the magnetic field intensity in the zero-gauss chamber 120 is about 100 nT (nano-Teslas). A shielded, two-wire, noise reducing cable 170] may be provided, the first wire of which is configured for conducting the electric current from the electrical signal generator 110 to the solenoid coil 170. The second wire in the shielded, two-wire cable 170, i.e., that wire not connected to the solenoid coil 150, may be connected to the mu-metal shell 130 to serve as a noise-reducing, artificial ground. A receptacle for holding a subject 200 within the zero-gauss chamber 120 may be provided.

[0086] Apparatus according to some embodiments of the invention may be provided with means to reduce electronic noise, which may produce environmental magnetic energy and distort what would otherwise be a carefully controlled magnetic field. Twisted pair cable presents the benefit of further reducing electromagnetic "cross-talk," induction between wires. Coaxial cable presents the benefit of electromagnetic shielding.

[0087] Utilizing a connection with the mu-metal shell is likewise a beneficial magnetic noise reducing strategy, as ambient induction typically creates "earth" fields in excess of the low fields desired or required for specific measurement and diagnostic needs.

[0088] The cable 170 may be either of shielded, coaxial cable and shielded, twisted-pair cable.

[0089] According to some embodiments of the invention, the electrical signal generator 110 may be configured to vary the current to the solenoid coil 150, thereby producing a sequence of magnetic field states in the zero-gauss chamber 120. The sequence may be as follows: a starting field value of about 50 μΤ (a simulated "earth" magnetic field produced when the electrical signal generator 110 is "on"); a linear drop in field intensity, over a period of about 50 ms, to no more than 100 nT (produced when the electrical signal generator 110 is "off); a zero-gauss chamber magnetic field of no more than about lOOnT, (the "off" state,) sustained for a period of around 500 ms; a linear rise in the zero-gauss chamber magnetic field intensity, over a period of about 2 seconds, back to about 50 μΤ; and then a steady-state field value of about 50 μΤ.

[0090] Another potentially beneficial diagnostic or measurement option in the hyperpolarization process might be found in pulsing the increase of the magnetic field when reaching the "earth" or "on" magnetic field state in the zero-gauss chamber 120. No n- linear field- increasing curves at low levels in the zero-gauss chamber might produce useful variations in molecular manipulation.

[0091] Reference is now made to Fig. 5, a diagram that matches time-indexed, changing magnetic field values with a schematic illustration of the pathway a subject 1100 is going through in an MRD such as MRD 100b of Fig. 4a or MRD 180 if Fig. 3, having a zero-gauss chamber 120. The subject, which in Fig. 5 is shown as a non-limiting example as a mouse, is placed on a bed, or receptacle 300. This receptacle 300 may be maneuverable along at least a section of the MRD bore 190. In various embodiments, the ZGC 120 may maneuverable with respect to the receptacle 300, or vice versa they both may be maneuverable relative to one another. Subject 1100 may have a substance administered to it which may be hyperpolarized after being induced by ZGC 120 at time 0. Then, the subject may be subjected to a predetermined sequence of magnetic field intensities configured to take advantage of the hyperpolarized substance and to gain magnetic imaging with increased signal and contrast and reduced noise. The variation in magnetic field intensity may be achieved wholly or partially by movement of the subject with respect to components in a system according to the invention, such as the zero gauss chamber. The graph of field strengths in Fig. 5 may correspond to positions along the bore 190 of an MRD.

[0092] Using the apparatus and method shown in Fig. 5, the components may be configured according to some embodiments of the invention to vary the sequenced magnetic field intensity, to which the object is subjected, as follows: a starting field value of about 50 μΤ (a) (a simulated "earth" magnetic field; the "on" state); a linear drop, over a period of 50 ms, to no more than about 100 nT (b) (the "off and onsetting state); a zero-gauss chamber magnetic field of no more than about lOOnT, (the "off state) sustained for a period of about 500 ms (c); a linear, or stepwise, rise in the zero-gauss chamber magnetic field intensity, over a period of about 2 seconds (d), back to about 50 μΤ; and then a steady-state field value of about 50 μΤ (e). [0093] Reference is now made to Fig. 6, a (non-proportional) time graph showing a sequence of magnetic field intensity values to which a subject 500 may be subjected. The figure includes sequence states (a) - (e) which may generally correspond to states (a) to (e) in Fig. 5.. In Fig. 6, state (d) is shown as a non-linear, pulsed rise from the "off or "zero-gauss" state (c) to the "on" or "earth" state (e). The shape of the pulse, as well as the overall curvature of the rise, may be changed in the interests of exploring different effects of low-intensity magnetic variation on subjects.

[0094] Some embodiments of the invention provide a system, e.g. 100a 100 and a method for circulating a hyperpolarizable fluid through a mammal, such as a human being 500. The system may comprise a ZGC 120, encased by an inner, triple-layer mu-metal shell 130 for absorbing magnetic field energy and an outer shell fabricated from a non-mu metal 140 in which the subject may be subjected to a "zero-gauss" magnetic field having an intensity no greater than about 100 nT. The system components may be arranged such that the subject 500, when moving relative to the system 100 is subjected to a controlled sequence of varying, low-level magnetic field intensity.

[0095] Some embodiments of the invention provide a system and a method for hyperpolarizing a substance administered into a subject 500 and measuring low field magnetic resonance from a fluid circulating through the subject 500. The system may comprise a fluid zero-gauss chamber 120; a low field magnetic resonance imaging device (MRD) configured to accommodate at least a mouse, and up to a human being, or organ thereof. The ZGC 120 may be operable to hyperpolarize the substance after being administered to the subject; the hyperpolarized fluid may circulate through the subject 500; the MRD may apply a sequence of zero-level to low-level magnetic field states; the MRD may measure resonance properties of the hyperpolarized substance.

[0096] As a key operational variable in the described system and method is the low intensity of the magnetic field affecting the fluid, any agency or object that might come into contact with the fluid may be non-magnetic. Commercially available non-magnetic IV infusion pumps, designed specifically for MRI and characterized by magnetic field lines of about 10,000 Gauss, are commercially available from various sources including IRadimed (US). [0097] Some embodiments of the invention provide a system and a method wherein a hyperpolarizable fluid is passed through a zero-gauss chamber after flowing out of the subject, e.g. human being 500, and only then is subjected to onsetting and imaging.

[0098] Reference is now made to Fig. 7, illustrating another embodiment of the present invention, having at least one stable, constant component and at least one maneuverable component. Either the static, stable component or the maneuverable could be represented by either the ZGC 120 or the solenoid coil 150. In various embodiments, the system is provided with predetermined protocols for establishing the relative positions between the ZGC 120, solenoid coil 150 and patient 500. The position of these components, should determine the net magnetic field induced over patient 500, and will provide the entire sequence of operation, from onsetting the hyperpolarizable substance pre- administered to the patient, through subjecting the hyperpolarized substance to various magnetic field to examine its relaxation properties.

[0099] Reference is now made to Fig. 8, illustrating yet another embodiment of the present invention, having a passive, static ZGC 120 and an active external solenoid coil 250. The solenoid coil is configured to switchably induce a magnetic field, while the ZGC passively imposes a shielding from such field. Thereby, by switching coil 250 to an "on" state, the ZGC will essentially lower the true magnetic field inside its bore 160, by a calibrated magnetic amount. Thus, the system may be configured to induce by means of said solenoid coil 250 an external magnetic field, and by means of said ZGC to reduce this magnetic field to a lower value, such as in a non-limiting manner to the earth magnetic field of about 50μΤ. By switching external coil 250 to an "off state, the subject inside bore 160 is immediately subjected to zero-gauss environment, giving rise to the onset of any hyperpolarizable substance pre- administered to him. The external solenoid coil 250 may then be switched "on" again and may provide any predetermined protocol designed for measuring the hyperpolarized substance.

EXAMPLES

Oncological Scanning

[00100] By polarizing molecular spin, hyperpolarization effectively increases the contrast of NMR scans as the NMR sensitivity is increased. The use of hyperpolarized subjects as contrast agents may thus drastically reduce the acquisition times and accuracy of readings and modeling thanks to the strong signal enhancement. [00101] Nowhere is this more important than in oncological diagnosis, when the identification of cancer cells and an accurate measurement of their concentration are critical.

[00102] In an example embodiment, a system for cancer cell detection and mapping in a human patient may utilize a passive system of hyperpolarization of a flowing fluid under conditions of low magnetic field. The system may comprise a "zero-gauss chamber" e.g. chamber 120, encased by an inner, triple-layer mu-metal shell 130 for absorbing magnetic field energy; and an outer shell fabricated from a non-mu metal 140; through which a pipe may conveys the fluid, and in which the fluid may be subjected to a "zero-gauss" magnetic field with an intensity no greater than 100 nT.

[00103] The system 100 components may be arranged such that the fluid 200, a metabolic marker, when flowing through the system 100 may be subjected to a controlled, field cycling sequence of varying, low-level magnetic field intensity for hyperpolarizing fluid. The field cycling sequence for hyperpolarization is described as follows: a starting field value of about 50 μΤ (a simulated "earth" magnetic field produced when the electrical signal generator 110 is "on"); a linear drop in field intensity, over a period of about 50 ms, to no more than about 100 nT (produced when the electrical signal generator 110 is "off"); a zero-gauss chamber magnetic field of no more than about ΙΟΟηΤ, (the "off" state,) sustained for a period of about 500 ms; a pulsed rise in the zero-gauss chamber magnetic field intensity, over a period of 2 seconds, back to about 50 μΤ; and then a steady-state field value of about 50 μΤ.

[00104] A hyperpolarizable substance may be administered to a subject, such as a human, after which the system may hyperpolarize the substance at a desired timing. The hyperpolarized substance may then circulate through the subject, e.g. human, body 500. An MRD 180 may apply a sequence of low-level magnetic field states; the MRD 180 may measure resonance properties of the substance. A scan of organs and bodily regions may be performed as the fluid circulates, continuously field cycled according to the hyperpolarizing sequence. Hyperpolarization of the marker fluid may increase the contrast readings of the resonance signal.

[00105] Some embodiments of the invention may be used in MRI. MRI includes Nuclear

Magnetic Resonance (NMR) spectroscopy, any Electron Spin Resonance (ESR) spectroscopy, any Nuclear Quadruple Resonance (NQR) imaging or any combination thereof. Some embodiments of the invention may be used in other imaging techniques including but not limited to such as computerized tomography (CT) and ultrasound (US). [00106] While the invention is susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the drawings and the above detailed description. It should be understood, however, that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.

Claims

1. A method of magnetic resonance imaging comprising:

administering to a subject a hyperpolarizable fluid in a non-hyperpolarized state;

subjecting the subject to a predetermined sequence of magnetic field intensities to cause hyperpolarization of the fluid; and

performing a magnetic resonance imaging process on the subject.

2. The method of claim 1 wherein a variation in magnetic field intensity to achieve said predetermined sequence is wholly or partially by movement of the subject with respect to the zero gauss chamber.

3. The method of claim 1 wherein the predetermined sequence of magnetic field intensities is provided by variation of applied current to a coil.

4. The method of any preceding claim wherein the predetermined sequence comprises a first starting state; a drop in field intensity to a second intermediate state; and a rise in the field intensity to a third steady state.

5. The method of claim 4 in which the starting state has a field intensity in a range of about 5 μΤ to about 85 μΤ.

6. The method of any of claims 4 or 5 in which the drop in field intensity is linear.

7. The method of claim 4, 5 or 6 wherein the drop in field intensity is over a period ranging from about 5 ms to about 110 ms.

8. The method of any of claims 4 to 7 wherein the intermediate state has a field intensity in a range of about 25 nT to about 175 nT.

9. The method of any of claims 4 to 8 wherein the intermediate state is sustained for a period ranging from about 100 ms to 950 ms;

10. The method of any of claims 4 to 9 wherein the rise in field intensity is over a period ranging from about 0.5 seconds to 5.2 seconds.

11. The method of any of claims 4 to 10 wherein the steady state has a field intensity field in a range of about 5 μΤ to about 85 μΤ.

12. An MRD system for in situ real-time onsetting the hyperpolarization of a hyperpolarizable substance pre- administrated to a subject, the system comprising an open bore MRD and a zero- gauss chamber "ZGC" to at least temporarily envelope said subject whilst it is accommodated within the bore of said MRD.

13. The system according to claim 12, comprising a zero gauss module "ZGM" including a magnetic field source configured to generate a predetermined sequence of magnetic fields to cause said hyperpolarization.

14. The system according to claim 12, wherein said magnetic field source is configured to be switchable between an "on" state characterized by about 5μΤ to about 80μΤ and an "off state characterized by about 90 nT to about 220 nT.

15. The system according to claim 12 or 13, further comprising a receptacle for a subject, wherein said ZGM is maneuverable with respect to said receptacle.

16. The system according to claim 12, 13 or 14, wherein said ZGM is maneuverable relative to said receptacle in a continuous movement or a non-continuous movement or both to at least partially cause a variation in magnetic field to which the subject is subjected.

17. The system according to claim 15 or 16, comprising a rail, wherein said ZGM is maneuverable relatively to said receptacle by a rail.

18. The system according to any of claims 12 to 17, further comprising at least one IV line configured for pre-administering at least one hyperpolarizable material into said subject.

19. The system according to any of claims 12 to 18, further comprising a cable configured to serve as a noise-reducing, artificial ground.

20. A method of in situ real-time onsetting the hyperpolarization of a hyperpolarizable substance pre- administrated to a subject under reversible timed conditions of zero-gauss magnetic field, comprising:

a. pre-administering a hyperpolarizable substance to a subject; and

b. onsetting hyperpolarization of said hyperpolarizable substance by at least temporarily enveloping said subject, or a portion thereof, in a zero gauss module.