WO2020012487A1

WO2020012487A1 - Method and apparatus for magnetic resonance analysis

Info

Publication number: WO2020012487A1
Application number: PCT/IL2019/050784
Authority: WO
Inventors: Uzi Eliav; Gil Navon; Tamar KUSHNIR
Original assignee: Ramot At Tel-Aviv University Ltd.; Tel Hashomer Medical Research Infrastructure And Services Ltd.
Priority date: 2018-07-13
Filing date: 2019-07-11
Publication date: 2020-01-16

Abstract

A method of magnetic resonance (MR) analysis of a body, comprises applying to the body a pulse sequence, acquiring an MR signal from the body following a period of magnetization exchange and longitudinal relaxation; and analyzing the MR signal to determine presence, absence or level of a molecule which comprises at least one hydrogen atom having an anisotropic motion within the molecule. The pulse sequence can have a magnetic field gradient pulse at least partially co-existing with a radiofrequency pulse selected to selectively suppress magnetization of the water while preserving a generally longitudinal magnetization of the molecule.

Description

METHOD AND APPARATUS FOR MAGNETIC RESONANCE ANALYSIS

RELATED APPLICATION

This application claims the benefit of priority of U.S. Provisional Patent Application No. 62/697,406 filed July 13, 2018, the contents of which are incorporated herein by reference in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to magnetic resonance and, more particularly, to a method and system for magnetic resonance analysis and/or imaging of a body having therein a molecule in which a hydrogen atom has an anisotropic motion.

Magnetic resonance imaging (MRI) is a method to obtain an image representing the chemical and physical microscopic properties of materials, by utilizing a quantum mechanical phenomenon, named Nuclear Magnetic Resonance (NMR), in which a system of spins, placed in a magnetic field resonantly absorb energy, when applied with a certain frequency.

A nucleus can experience NMR only if its nuclear spin 7 does not vanish, i.e., the nucleus has at least one unpaired nucleon. Examples of non-zero spin nuclei frequently used in MRI include 'H (7=1/2), ¾ (7=1), ²³Na (7=3/2), etc. When placed in a magnetic field, a nucleus having a spin 7 is allowed to be in a discrete set of energy levels, the number of which is determined by 7, and the separation of which is determined by the gyromagnetic ratio of the nucleus and by the magnetic field. Under the influence of a small perturbation, manifested as a radiofrequency magnetic field, which rotates about the direction of a primary static magnetic field, the nucleus has a time dependent probability to experience a transition from one energy level to another. With a specific frequency of the rotating magnetic field, the transition probability may reach the value of unity. Hence at certain times, a transition is forced on the nucleus, even though the rotating magnetic field may be of small magnitude relative to the static magnetic field. For an ensemble of spin 7 nuclei the transitions are realized through a change in the overall magnetization.

Once a change in the magnetization occurs, a system of spins tends to restore its magnetization longitudinal equilibrium value, by the thermodynamic principle of minimal energy. The time constant which control the elapsed time for the system to return to the equilibrium value is called "spin-lattice relaxation time" or "longitudinal relaxation time" and is commonly denoted 7i. An additional time constant, T₂ (£Ti), called "spin-spin relaxation time" or "transverse relaxation time", controls the elapsed time in which the transverse magnetization diminishes, by the principle of maximal entropy. However, inter-molecule interactions and local variations in the value of the static magnetic field alter the value of T₂, to an actual value commonly denoted T₂ ^*.

In MRI, a static magnetic field having a predetermined gradient is applied on an object, thereby creating, at each region of the object, a unique magnetic field. By detecting the NMR signal, knowing the magnetic field gradient, the position of each region of the object can be imaged.

In MRI, pulse sequences are applied to the object ( e.g ., a human or animal) to generate NMR signals and obtain information therefrom which is subsequently used to reconstruct images of the object. The produced image is affected by parameters such as spin density, transverse and longitudinal relaxation times, residual dipolar interactions in anisotropic media (such as fibrous biological tissues), chemical exchange between proteins, membranes and water. The aforementioned relaxation times and the density distribution of the nuclear spin are properties which vary from one normal tissue to the other and from one diseased tissue to the other. These quantities are therefore responsible for contrast between tissues in various imaging techniques, hence permitting image segmentation.

A common characteristic for many MRI techniques is that the properties of water molecules are measured, which properties are indirectly dependent on interaction with macromolecules such as proteins.

Over the years, many MRI methods have been developed to meet the requirements of contrast enhancement. Representative examples of such methods include Ti weighted MRI, T₂ weighted MRI, fat suppression MRI and diffusion weighted MRI.

U.S. Patent No. U.S. Patent No. 7,795,867, the contents of which are hereby incorporated by reference, discloses a method suitable for magnetic resonance (MR) analysis of a body having therein a molecular species and water. MR signals induced by a second radiofrequency pulse sequence are subtracted from MR signals induced by a first radiofrequency pulse sequence followed by an evolution period. The first radiofrequency pulse sequence suppresses magnetization for the water but preserves a longitudinal magnetization of the molecular species. The second radiofrequency pulse sequence suppresses transverse and longitudinal magnetization for both the water and the molecular species.

SUMMARY OF THE INVENTION

According to an aspect of some embodiments of the present invention there is provided a method of magnetic resonance (MR) analysis of a body having therein water and a molecule which comprises at least one hydrogen atom having an anisotropic motion within the molecule. The method comprises: applying to the body a pulse sequence; acquiring an MR signal from the body following a period of magnetization exchange and longitudinal relaxation; and analyzing the MR signal to determine presence, absence or level of the molecule. The pulse sequence optionally and preferably has a magnetic field gradient pulse at least partially co-existing with a radiofrequency pulse selected to selectively suppress magnetization of the water while preserving a generally longitudinal magnetization of the molecule.

According to some embodiments of the invention the pulse sequence comprises a preparation radiofrequency pulse preceding any of the radiofrequency pulse and the magnetic field gradient pulse, the preparation radiofrequency pulse being characterized by a pulse length of the order of a characteristic longitudinal relaxation time of the water.

According to some embodiments of the invention the method comprises varying an offset of the preparation radiofrequency pulse, acquiring the MR signal for each of a plurality of different offsets, and analyzing the signals as a function of the offsets.

According to some embodiments of the invention the pulse sequence comprises a fat suppressing pulse subsequence, a predetermined time period following each of the radiofrequency pulse and the magnetic field gradient pulse.

According to some embodiments of the invention the pulse sequence comprises a repetition of the magnetic field gradient pulse and the radiofrequency pulse factor.

According to some embodiments of the invention the method comprises: applying to the body an additional pulse sequence selected to non- selectively suppress magnetization of both the water and the molecule, following an additional period of magnetization exchange and longitudinal relaxation, acquiring an additional MR signal from the body; and subtracting the MR signal from the additional MR signal, wherein the determination of the presence, absence or level of the molecule is based on the subtraction.

According to some embodiments of the invention the method comprises producing at least one magnetic resonance image of the body using the signal. According to some embodiments of the invention the method comprises: applying to the body an additional pulse sequence selected to non- selectively suppress magnetization of both the water and the molecule, following an additional period of magnetization exchange and longitudinal relaxation, acquiring an additional MR signal from the body; producing an additional magnetic resonance image of the body using the additional signal; and subtracting the magnetic resonance image from the additional magnetic resonance image, wherein the determination of the presence, absence or level of the molecule is based on the subtraction. According to some embodiments of the invention the analysis comprises spectroscopy analysis without producing a magnetic resonance image of the body.

According to some embodiments of the invention the analysis comprises fitting the signal to a bi-exponential function.

According to some embodiments of the invention the method comprises producing a map of a parameter of the bi-exponential function.

According to some embodiments of the invention the parameter is a coefficient indicative of a fraction of hydrogen atoms residing in the molecule.

According to some embodiments of the invention the method comprises identifying fibrotic tissue based on the coefficient.

According to some embodiments of the invention the radiofrequency pulse is a Hermite shaped pulse.

According to some embodiments of the invention the radiofrequency pulse has a duration of from about 500 pm to about 5 ms. According to some embodiments of the invention the radiofrequency pulse has a duration of from about 1 ms to about 4.5 ms. According to some embodiments of the invention the radiofrequency pulse has a duration of from about 1.5 ms to about 4 ms. According to some embodiments of the invention the radiofrequency pulse has a duration of from about 1.5 ms to about 3.5 ms. According to some embodiments of the invention the radiofrequency pulse has a duration of from about 2 ms to about 3 ms.

According to some embodiments of the invention the molecule comprises collagen. According to some embodiments of the invention the molecule is part of a myelin. According to some embodiments of the invention the molecule is part of an amyloid. According to some embodiments of the invention the molecule is selected from the group consisting of a protein, a glycoprotein, a proteolipid, a carbohydrate and a nucleic acid. According to some embodiments of the invention the molecule is part of a complex of macromolecules which comprises at least two components selected from the group consisting of a protein, a glycoprotein, a proteolipid, a lipid, a carbohydrate, a nucleic acid. According to some embodiments of the invention the molecule is part of a tissue selected from the group consisting of a fiber, a membrane and a cell nucleus.

According to some embodiments of the invention the body is a body of a mammal or a part thereof. According to some embodiments of the invention the body is a liver. According to some embodiments of the invention the body is a heart. According to some embodiments of the invention the body comprises nervous tissues. According to some embodiments of the invention the body is a body of a subject having Alzheimer's disease. According to some embodiments of the invention the body comprises an organ selected from the group consisting of a brain, a kidney, a gland, a testicle, an ovary, an eye, a pancreas and a spleen.

According to some embodiments of the invention the body comprises a tissue selected from the group consisting of a connective tissue, a tendon, a portion of a skin, a bone, a muscle, a cartilage, a blood vessel, a ligament and a lymph node.

According to an aspect of some embodiments of the present invention there is provided a magnetic resonance imaging system for imaging a body, the system comprising a control system configured for executing the method as delineated above and optionally and preferably as exemplified below.

Unless otherwise defined, all technical and/or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and/or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

Implementation of the method and/or system of embodiments of the invention can involve performing or completing selected tasks manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of embodiments of the method and/or system of the invention, several selected tasks could be implemented by hardware, by software or by firmware or by a combination thereof using an operating system.

For example, hardware for performing selected tasks according to embodiments of the invention could be implemented as a chip or a circuit. As software, selected tasks according to embodiments of the invention could be implemented as a plurality of software instructions being executed by a computer using any suitable operating system. In an exemplary embodiment of the invention, one or more tasks according to exemplary embodiments of method and/or system as described herein are performed by a data processor, such as a computing platform for executing a plurality of instructions. Optionally, the data processor includes a volatile memory for storing instructions and/or data and/or a non-volatile storage, for example, a magnetic hard-disk and/or removable media, for storing instructions and/or data. Optionally, a network connection is provided as well. A display and/or a user input device such as a keyboard or mouse are optionally provided as well. BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings and images. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

In the drawings:

FIGs. 1A and 1B are schematic illustrations of a pulse sequence, which includes a pulse that momentarily produces a generally transverse magnetization for the water, but preserve a generally longitudinal magnetization for a molecule such as a macromolecule;

FIGs. 1C and 1D are schematic illustrations of a pulse sequence, which includes a non specific pulse that momentarily produces a generally transverse magnetization for both the water and the macromolecule, according to some embodiments of the present invention;

FIG. 2 is a schematic illustration of a pulse sequence, which comprises a magnetic field gradient pulse at least partially co-existing with a radiofrequency pulse, according to some embodiments of the present invention;

FIG. 3 is a schematic illustration of a pulse sequence, which comprises a preparation radiofrequency pulse preceding the co-existing gradient and radiofrequency pulses, according to some embodiments of the present invention;

FIG. 4 is a flowchart diagram of a method suitable for analyzing and/or imaging a body, according to some embodiments of the present invention;

FIG. 5 is a schematic illustration of a magnetic resonance imaging system for imaging a body, according to some embodiments of the present invention;

FIGs. 6A-C are schematic illustrations of selective and non-selective pulse sequences;

FIG. 7 shows maps of parameters for porcine spinal cord obtained in experiments performed according to some embodiments of the present invention;

FIGs. 8A-D are magnetic resonance images acquired using different frequency offsets during in experiments performed according to some embodiments of the present invention;

FIGs. 9A and 9B are images of fibrotic liver tissue (FIG. 9A) and control (non-fibrotic) tissue (FIG. 9B), obtained in experiments performed according to some embodiments of the present invention;

FIGs. 10A-C show statistical analysis of fibrotic and control rats, obtained in experiments performed according to some embodiments of the present invention; FIGs. 11A and 11B are typical images of human fibrotic liver tissue (FIG. 11A) and human control (non-fibrotic) tissue (FIG. 11B), obtained in experiments performed according to some embodiments of the present invention;

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth in the following description and/or illustrated in the drawings and/or the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways.

The present embodiments are useful for producing magnetic resonance images of a body of a human or an animal. In particular, the present embodiments are useful for improving the contrast of a molecule that comprise one or more hydrogen atom having an anisotropic motion within the molecule. Such a molecule is referred to herein as SRMP, an abbreviation for Species with Restricted Motion of Protons, where "proton" symbolizes the hydrogen nucleus.

Preferably, the SRMP has a molecular mass of more than 50 kDa.

Representative examples of an SRMP for which the contrast can be improved include organic and biological molecules, such as, but not limited to, a protein, a glycoprotein, proteolipid, a carbohydrate, a nucleic acid, and any complex of macromolecules which comprises two or more of these types of molecules.

Representative examples of substances having SRMP include, without limitation, a myelin, a lipid, and a complex of macromolecules which comprises at least two components selected from the group consisting of a protein, a glycoprotein, a proteolipid, a lipid, a carbohydrate, a nucleic acid.

Magnetic resonance images can be obtained according to the present embodiments for the whole body of the mammalian subject or for any part (e.g., organ) thereof, including, without limitation, the brain, the heart, a kidney, a gland, a testicle, an ovary, an eye, the liver, the pancreas and the spleen. Such images and analyses can provide information regarding the type and/or content of various tissues, such as, but not limited to, tendons, cartilage, nerves, fibers, membranes and cells nuclei. The present embodiments are also useful for providing images of other tissues, e.g., skin portions, bones, muscles, blood vessels, ligaments, lymph nodes and the like.

Also contemplated are embodiment in which the method and system are used for analysis purposes, e.g., spectroscopy and the like. In these embodiments, the body can be a sample of a biological material (e.g., a tissue sample, a plant sample) or a non-biological material, provided the analyzed material has a water component and optionally and preferably also SRMP.

Magnetic resonance analysis or imaging of biological materials according to the present embodiments can be performed on live human or animals or ex-vivo.

Any magnetic resonance method for analyzing or imaging a body includes an application of a radiofrequency pulse sequence to the body, so as to create excitations within the atoms making the body. In an acquisition step, following the pulse sequence, excitations signals from the body are further analyzed by computational methods to provide a spectroscopic analysis or a visual image of the body or part thereof.

For purposes of better understanding some embodiments of the present invention, as illustrated in FIGs. 2-11B of the drawings, reference is first made to a pulse sequence that can be used for obtaining magnetization transfer, and a pulse sequence that can be used for obtaining longitudinal relaxation substantially without detection of magnetization transfer, as illustrated in FIGs. 1A-D.

FIGs. 1A and 1B illustrate a pulse sequence 10, comprising a 90° pulse 12 which momentarily produce a generally transverse magnetization for the water, but preserve a generally longitudinal magnetization for a molecule such as a macromolecule. Following a period t_s of the order of from a few microseconds to a few milliseconds, a gradient pulse 14 is applied by the gradient coils of the MRI system so as to suppress the transverse magnetization by dephasing it.

The effect of pulse sequence 10 on the magnetization vector M is illustrated in FIG. 1B. Shown in FIG. 1B are the magnetization vectors the water molecules and the macromolecule projected on an x-z plane. The Cartesian x-y-z coordinate system is such that the z direction is parallel to the direction of the static magnetic field Bo applied by the magnetic resonance system. The z direction is referred to herein as the longitudinal direction. The x-y plane (represented by the x axis in FIG. 1B) is referred to as the transverse plane. The magnetizations are illustrated in FIG. 1B as block arrows and are designated by reference numerals 16 (for the magnetization of water) and 18 (for the magnetization of the macromolecule). Transitions between states are illustrated in FIG. 1B as single arrows.

When the primary static magnetic field Bo is not perturbed by a radiofrequency pulse, both magnetizations 16 and 18 are oriented generally along the longitudinal direction, because the nuclei spins tend to align parallel to the external magnetic field so as to minimize the energy of the system. This state is referred to as equilibrium. The result of pulse 12 is an exclusive tilt of the water magnetization by 90° away from the z direction. The tilt is "exclusive" in the sense that magnetization vector 18 of the macromolecule remains generally along the longitudinal direction. With the application of pulse 14, magnetization 16 is suppressed while magnetization 18 remains generally in the longitudinal direction. Thus, sequence 10 suppresses the magnetization for the water while preserving a generally longitudinal magnetization for the macromolecule. During an evolution period, ί_zr, the (longitudinal) magnetization of the macromolecule is transferred to the water molecules, such that a "pseudo-equilibrium" between the water and the macromolecule is established. In other words, the magnetization is transferred from the macromolecule to the water such that the ratio between the two magnetizations is identical to its value in thermal equilibrium. Since the magnetization of the water prior to the magnetic resonance acquisition is proportional to the magnetization of the macromolecule, the obtained magnetization configuration allows the analysis of the macromolecule based on magnetic resonance signals acquired from the water. The acquisition time and pulse sequence are shown at 13.

FIGs. 1C and 1D schematically illustrate another pulse sequence 20. This sequence comprises a preparation radiofrequency pulse 21 which is characterized by a pulse length of the order of the characteristic longitudinal relaxation time of the water. Thereafter a non-specific 90° radiofrequency pulse 22 is applied to momentarily produce a generally transverse magnetization for both the water and macromolecule. Following the period t_s, a gradient pulse 24 is applied by the gradient coils of the MRI system so as to suppress the transverse magnetizations of the water and macromolecule by dephasing it. The effect of pulse sequence 20 on the magnetization vector M is illustrated in FIG. 1D. Following the application of pulse 22, both magnetization vectors 16 and 18 lie in the transverse plane. Subsequently, pulse 24 is applied and magnetizations 16 and 18 are suppressed. This situation is symbolically illustrated in FIG. 1D as "M oc 0". During the time period /ZQ, the magnetization vectors 16 and 18 experience longitudinal relaxation and recover to their longitudinal direction such that the ratio between the two magnetizations is identical to its value in thermal equilibrium. The suppression of both magnetizations 16 and 18 following pulse 24, results in a recovery which is solely controlled by longitudinal relaxation, substantially without chemical exchange which may affect the measurement. Acquisition of magnetic resonance signals can be performed following the relaxation period. The acquisition time and pulse sequence are shown at 23. The difference between sequence 10 and sequence 20 is that in sequence 10 the pulse 12 is selective and excites only the magnetization 16 of the water, while in sequence 20 the pulse 22 is non-selective and excites both the water and the macromolecule. Such different effects can be achieved by judicious selection of the parameters of pulses 12 and 22. These parameters can be the length and/or intensity of the pulses.

The present inventors found that while to pulse sequences 10 and 20 shown in FIGs. 1A- D, are adequate for some situations, they possess some operative limitations that would best be avoided. In particular, the present inventors found that in many cases the Tl can be fairly short. This is the case, for example, in clinical scanners with low static magnetic field, or when analyzing fatty tissues such as the liver. The present inventors found that while the application the sequence in FIG. la may last 12 ms, in many cases the clinical scanners can employ radiofrequency and gradient pulses that cannot exceed 3 ms.

In a search for the solution of the above operative problems, the inventors found an improvement to pulse sequences shown in FIGs. 1A-D. The improvement is particularly suitable for clinical setups since it provides selective suppression of the water magnetization at time scales that are sufficiently short and compatible with the exchange times.

FIG. 2 is a schematic illustration of a pulse sequence 30 according to some embodiments of the present invention. Pulse sequence 30 is particularly useful for providing analysis and/or images of SRMP.

Sequence 30 preferably comprises a magnetic field gradient pulse 34 at least partially co existing with a water-suppressing radiofrequency pulse 32. In some embodiments of the duration of pulse 34 encapsulates the duration of pulse 32, so that pulse 32 co-exists in its entirety with pulse 34. Preferably, radiofrequency pulse 32 momentarily produces a generally transverse magnetization for the water, but preserve a generally longitudinal magnetization for the SRMP, and pulse 34 suppresses the magnetization of the water but not the magnetization of the SRMP. However, since pulses 32 and 34 co-exist, the combination of pulses 32 and 34 ensures selective suppression of the magnetization of the water while preserving a generally longitudinal magnetization of the molecule. The suppression of magnetization is preferably by at least 90 %, more preferably 95 %. In various exemplary embodiments of the invention pulse 34 substantially nulls the magnetization of the water.

In some embodiments of the present invention the suppression is slice selective. In these embodiments, the suppression occurs only within one or more selected slices of the body under analysis. This can be achieved by exciting a bandwidth for a specific slice without applying a refocusing gradient, thus effecting suppression of the magnetization within the selected slice(s). The technique of the present embodiments can therefore be used for studying magnetization transfer in many slices regardless of the MR imaging method.

Pulse 32 is optionally and preferably a 90° pulse. The length of pulse 32 can be at least 100 ps, more preferably at least 200 ps, more preferably at least 250 ps, more preferably at least 300 ps, more preferably at least 350 ps, even more preferably from about 400 ps to about 1 ms, say between 400 ps and 1 ms, inclusive.

As used herein the term“about” refers to ± 10 %.

It is appreciated that the magnetization vector of the materials in question (either water or molecular species) is an averaged quantity over all nuclei spins, and, as such may slightly deviate from precise orientation along the z axis in the lower energy state. Such small deviations (by say, 2° or less) is known to those skilled in the art of magnetic resonance and the use of term "generally longitudinal magnetization" is intended to include all such deviations.

Further, in various exemplary embodiments of the invention the excited energy state of the material in question is characterized by a magnetization vector which lies in the transverse plane. However, this need not necessarily be the case, since, for some applications, there may be a non-zero component of the magnetization vector along the longitudinal direction. The term "generally transverse magnetization" refers to any situation in which the magnetization vector is tilted by a sufficiently large angle ( e.g ., 80° or more) with respect to the longitudinal direction. In any event, for any material, the transition from the lower energy state to the excited energy state is realized by an inclement of the transverse component of the magnetization vector.

A difference between sequence 30 and sequences 10 and 20, is that while in sequences 10 and 20 there is a time period t_s of a few microseconds to a few milliseconds between the 90° pulse and the gradient pulse, In sequence 30 pulses 32 and 34 co-exist with each other thereby shortening the overall duration of sequence 30 compared to sequences 10 and 20.

In some embodiments of the present invention radiofrequency pulse 32 is a Hermite shaped pulse. Also contemplated are rectangular pulses, sine shaped pulses, and sinus hyperbolic shaped pulses.

In some embodiments of the present invention pulse 32 has a duration of from about 500 pm to about 5 ms, more preferably from about 1 ms to about 4.5 ms, more preferably from about 1.5 ms to about 4 ms, more preferably from about 1.5 ms to about 3.5 ms, more preferably from about 2 ms to about 3 ms.

In some embodiments of the invention sequence 30 comprises n repetition of pulses 12 and 14, where n is a positive integer, referred to as a repetition factor. For example, when n = 2, sequence 30 comprises four pulses: [32, 34] x2 = (32, 34), (32, 34), where (32, 34) represent at least partial co-existence of pulses 32 and 34. The value of n is preferably selected so as to minimize the magnetization of the water subsequently to the application of sequence 30. Optimization of the repetition factor n can be achieved in more than one way. For example, in one embodiment a series of magnetic resonance images are provided, each image with a different value of n. The images of the series can then be examined to select the image with best contrast. Alternatively, the remnant magnetization of water as a function of n can be constructed by spectroscopic means, and the value of n which minimizes the water signal can be selected.

In some embodiments of the present invention pulse sequence 30 comprises a fat suppressing pulse subsequence 36, applied a predetermined time period t following pulses 32 and 34. It was found by the Inventors that subsequence 36 reduces interference between contrast originating from the fat Ti and contrast formed by the exchange between the SRMP and the water. The subsequence 36 is particularly useful when pulse sequence 30 is applied to human subjects.

Fat-suppressing pulse subsequence 36 can include any subsequence known in the art that cause the NMR signals from hydrogen-containing lipids to be reduced as compared to the NMR signals emanating from water containing tissues. Some known fat suppression subsequences suitable for the present embodiments including, without limitation: Chemical Shift Selective (CHESS), Short TI (inversion time) Recovery (STIR), Spectral- selective Inversion Recovery (SPIR), Polarity Alternated Spectral and Spatial Acquisition (PASTA), Spectral- selective Adiabatic Inversion Recovery (SPAIR), Double Fat Suppression (DFS), and water-fat-opposed phase (WFOP).

In some embodiments of the present invention pulse sequence 30 comprises a preparation radiofrequency pulse 31 preceding pulses 32 and 34. This embodiment is illustrated in FIG. 3. Typically, preparation radiofrequency pulse 31 is characterized by a pulse length of the order of a characteristic longitudinal relaxation time Tl of the water. The intensity of pulse 31 is preferably lower than the intensities of pulses 32 and 34 individually. In some embodiments of the present invention the frequency of pulse 31 is an off-resonance frequency relative to the water resonance. The difference between the frequencies of pulse 31 and the water resonance is referred to as the "frequency offset" of pulse 31. The frequency offset can be selected in advance, or, more preferably, sequence 30 can be applied several times with different values for the frequency offset. The inventors found that preparation pulse 31 allows obtaining information pertaining to both the content and the line shape of the SRMP. When radiofrequency pulse 31 is employed, it can be selected such that sequence 30 non-selectively suppresses the magnetization of both the water and the SRMP. Alternatively, pulse sequence 20 can be used for suppresses the magnetization of both the water and the SRMP, e.g., using the time period tm instead of tzQ.

Whether or not there are repetitions of pulses 32 and 34, whether or not sequence 30 includes fat-suppressing pulse subsequence 36, and whether or not sequence 30 includes radiofrequency preparation pulse 31, an acquisition pulse sequence 33 is applied, following a period of magnetization exchange and longitudinal relaxation. This time period is at least tm. Since the magnetization of the water prior to the acquisition 33 is proportional to the magnetization of the SRMP, the obtained magnetization configuration allows determine presence, absence or level of the SRMP based on magnetic resonance signals acquired from the water.

The size of the magnetization vector of the water and SRMP, relative to its equilibrium size, depends on the value of AM. According to a preferred embodiment of the present invention /LM is selected such that the magnetizations of the water and SREMP are lower than their magnetizations before the application of pulse sequence 30. The magnetization buildup can be from about 3 % from the equilibrium value for short values of A_M (about 25 ms) to about 25 % from the equilibrium value for long values of (from about 500 ms to about 5 s). Thus, the typical range for tm in pulse sequence 30 (and sequence 20 if employed in combination with sequence 30) is from about 25 ms to about 5 s, more preferably from about 25 ms to about 500 ms.

FIG. 4 is a flowchart diagram of a method suitable for analyzing and/or imaging a body, according to some embodiments of the present invention. It is appreciated that the analysis performed by the method can include producing a magnetic resonance image of the body, and/or spectroscopy analysis. In some embodiments of the present invention the analysis performed by the method is spectroscopy analysis without producing a magnetic resonance image of the body.

It is to be understood that, unless otherwise defined, the method steps described hereinbelow can be executed either contemporaneously or sequentially in many combinations or orders of execution. Specifically, the ordering of the flowchart diagrams is not to be considered as limiting. For example, two or more method steps, appearing in the following description or in the flowchart diagrams in a particular order, can be executed in a different order (e.g., a reverse order) or substantially contemporaneously. Additionally, several method steps described below are optional and may not be executed.

The method begins at 40 and continuous to 41 in which a radiofrequency pulse sequence, such as sequence 30 without pulse 31 (FIG. 2) is applied to the body, so as to selectively suppress magnetization for the water while preserving a generally longitudinal magnetization to the SRMP. The method continues to 42 in which magnetization transfer and longitudinal relaxation are allowed to take place during a predetermined evolution period /LM, such that at least a part of the magnetization of the SRMP is transferred to the water.

According to some embodiment of the present invention the method continues to 43 in which magnetic resonance signals are acquired from the body, using acquisition pulse sequence 33. The acquisition can be according to any magnetic resonance acquisition protocol known in the art, and it can be performed either to analyze the body and/or to obtain a magnetic resonance image thereof. The acquisition can thus be selected to produce magnetic resonance images weighted, e.g., by magnetization transfer and by longitudinal relaxation time Ti. The parameters of the pulse sequence can also be selected in accordance with the desired type of image. For example, when 74 weighted image is desired, the value of the evolution period I M is preferably shorter than the characteristic 74 of the water.

In some exemplary embodiments of the invention the method continues to 44 in which a second radiofrequency pulse sequence is applied to the body, so as to non-selectively suppress longitudinal and transverse magnetization for both the water and the SRMP. The second radiofrequency pulse sequence can be sequence 30 in the sequence configuration that includes pulse 31 (FIG. 3), or pulse sequence 20.

Following the application 44, the method allows for longitudinal relaxation to take place over a predetermined relaxation period /LM.

The method can then continue to 45 in which magnetic resonance signals are acquired from the body, preferably according to the same magnetic resonance acquisition protocol as in 43. Since the pulse sequence applied in 44 is non- selective, there is typically no magnetization transfer, and the signals acquired at 45 are 74 weighted.

The method optionally and preferably continues to 46 in which the signals acquired during the second acquisition 45 are subtracted from the signals acquired during the first acquisition 43. Since the signals acquired at 45 are induced by a sequence that facilitates solely longitudinal relaxation, and the signals acquired at 43 are induced by a sequence that facilitates longitudinal relaxation as well as magnetization transfer, the subtraction 46 between the MR signals substantially eliminates contributions originating from components which do not exchange magnetization with water. Thus, in accordance with the present embodiments, regions in which there is magnetization transfer between the SRMP and the water are emphasized.

The subtraction between signals can be executed either at the level of raw data, or at the level of images. When the subtraction is at raw data level, an image can be constructed following the subtraction. When the subtraction is at the level of images, the subtraction is preferably performed pixel-by-pixel using digital pixel data of individual pixels of the image. Such operations are known to those ordinarily skilled in the art of signal processing and image processing.

In some embodiments of the present invention the method proceeds to 47 at which the offset frequency of pulse 31 is varied. In these embodiments, the method optionally and preferably loops back to 41 and is repeated for each value of the frequency offset. The advantage of these embodiments is that they provide the signals or images, or the subtraction of signals or image, at a plurality of different values of the frequency offset, and allows analyzing the signals or images as a function of the frequency offset. As demonstrated in the examples section that follows, such analysis can increase the amount of information received from the body.

In some embodiments of the present invention the method proceeds to 48 at which the time-period tm between the application of the pulse sequence 31 and the acquisition sequences 33 is varied. In these embodiments, the method optionally and preferably loops back to 41 and is repeated for each value of tm. The advantage of these embodiments is that they provide the signals or images, or the subtraction of signals or image, at a plurality of different values of tm, and allows analyzing the signals or images as a function of tm. For example, the signals can be fitted to a function and various parameters that are characteristics to the body region under analysis ( e.g ., the characteristic magnetization transfer time or rate, the longitudinal relaxation time of the SRMP, the fraction of protons residing in the SRMP) can be extracted from the fit. In some embodiments of the present invention the signals are fitted to an exponential function (see, e.g., EQ. 2 in the Examples section that follows), and in some embodiments of the present invention the signals are fitted to a bi-exponential function (see, e.g., EQs. 1 or 3 in the Examples section that follows). The Examples section that follows demonstrates that the fraction of protons residing in the SRMP can be used for distinguishing between fibrotic and non-fibrotic tissues.

The method ends at 49.

Reference is now made to FIG. 5 which is a schematic illustration of a magnetic resonance imaging system 540 for imaging a body 542, according to some embodiments of the present invention. System 540 comprises a static magnet system 544 which generating a substantially homogeneous and stationary magnetic field Bo in the longitudinal direction, a gradient assembly 546 which generates instantaneous magnetic field gradient pulses to form a non-uniform superimposed magnetic field, and a radiofrequency transmitter system 548 which generates and transmits radiofrequency pulses to body 542.

System 540 further comprises an acquisition system 550 which acquires magnetic resonance signal from the body, and a control system 552 which is configured for implementing the various pulse sequences ( e.g ., sequences 30, 33) of the present embodiments. Control system 552 is also configured to control acquisition system 550 such that magnetic resonance signals are sequentially acquired after the magnetization transfer and after the longitudinal relaxation as further detailed above. Once the signals are acquired, control system 552 subtracts the signals of the two acquisitions as described above.

In various exemplary embodiments of the invention system 540 further comprises an image producing system 554 which produces magnetic resonance images from the signals of each acquisition and/or from the signal obtained after the subtraction. Image producing system 554 typically implements a Fourier transform so as to transform the data into an array of image data.

The operation of system 540 is preferably controlled from an operator console 560 which can include a keyboard, control panel a display, and the like. Console 560 can include or it can communicate with a data processor 562.

The gradient pulses and/or whole body pulses can be generated by a generator module 564 which is typically a part of control system 552. Generator module 564 produces data which indicates the timing, strength and shape of the radiofrequency pulses which are to be produced, and the timing of and length of the data acquisition window.

Gradient assembly 546 typically comprises G_x, G_y and G_z coils each producing the magnetic field gradients used for position encoding acquired signals. Radiofrequency transmitter system 548 is typically a resonator which is used both for transmitting the radiofrequency signals and for sensing the resulting signals radiated by the excited nuclei in body 542. The sensed magnetic resonance signals can be demodulated, filtered, digitized etc. in acquisition system 550 or control system 552.

The word "exemplary" is used herein to mean "serving as an example, instance or illustration." Any embodiment described as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments and/or to exclude the incorporation of features from other embodiments.

The word "optionally" is used herein to mean "is provided in some embodiments and not provided in other embodiments." Any particular embodiment of the invention may include a plurality of "optional" features unless such features conflict.

The terms "comprises", "comprising", "includes", "including", “having” and their conjugates mean "including but not limited to".

The term“consisting of’ means“including and limited to”. The term "consisting essentially of" means that the composition, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

As used herein, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" may include a plurality of compounds, including mixtures thereof.

Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases“ranging/ranges between” a first indicate number and a second indicate number and“ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non limiting fashion. The MRI technique of the present embodiments is particularly useful for physical systems that contain collagen ( e.g ., connective tissues and fibrosis in livers and hearts), myelin sheaths ( e.g ., nervous tissues), and amyloid plaques (e.g., in Alzheimer's patients).

The inventors of the present invention found that non-selective suppression of all the exchanging species may be difficult to implement in clinical scanners, since it requires pulses that are too short for implementation in these scanners.

Schematic presentation of pulse sequences are shown in FIGs. 6A-C. In FIGs. 6A-C, the symbols s and ns represent are selective and non-selective radiofrequency pulses respectively, which are used either to selectively suppress the water magnetization or to suppress all species that can exchange magnetization with the water (referred to below as non-selective suppression). The symbol g stands for pulsed magnetic field gradient n denotes the number of repetitions and is typically, but not necessarily, from 2 to 4.

In some optional embodiments, the MR images can be normalized by dividing each MR image by an MR image that is obtained for t_LM»Ti. The advantage of these embodiments is that it reduces the number of parameters in the analysis.

The selective suppression causes the water magnetization of each pixel to recover during period tm (see EQ. 1, below) by magnetization transfer from SRMP and Ti process. Under the condition t_exc«Ti (Ti of both water and SRMP, fast exchange condition), where t_exc and Ti are the exchange time and longitudinal relaxation, the magnetization recovery to equilibrium is described by Eq. 1:

where F is the fraction of protons residing in the SRMP and l/t_{exc º} k is the sum of the forward and reverse magnetization exchange reaction rates between the SRMP and the water. Under fast exchange condition the longitudinal relaxation rate, l/Ti, is given by the statistical average of the corresponding rates of the water and the SRMP in absence of magnetization transfer (MT). The first term on the right hand of EQ. 1 describes MT while the second term describes the longitudinal relaxation.

In many tissues the fast exchange condition is fulfilled, t_exc«Ti, and as a result for l/k«t_LM«Ti the observed water signal is proportional mostly to the first terms in EQ. 1, e.g., the magnetization of the SRMP. This means that the method of the present embodiments can efficiently detect the, heretofore unseen, SRMP and their magnetization exchange rate with water in a way that the two parameters, k and Ti, are separable.

When suppressing the magnetization of all species either by non-selective pulses (FIG. 6B) or by the application of pulse sequence 30 with preparation pulse 31 (FIG. 3) in which the frequency offset is close to the water peak, the dependence on tm is given by the expression in EQ. 2:

In this equation the effect of MT is suppressed and the dominant process is the longitudinal relaxation.

Subtraction of the expression in EQ. 2 from the expression in EQ. 1 gives EQ. 3:

It was found by the Inventors that in cases that the SNR obtained after subtraction is higher than 20, EQ. 3 is making the separation of t_exc and Ti more reliable than the one obtained from the analysis of EQ. 1 since it is a difference of two exponentials. Furthermore the terms that describe MT and longitudinal relaxation in EQ. 3 have similar weight and the extracted value of F is more reliable than the value obtained from the analysis based on Eq. 1.

A particular advantage of the technique of the present embodiments is that it is independent of the longitudinal relaxation time of the water, for significant part of measurement time (tLM<0.05T so that the second term on the right hand side of EQ. 1 is smaller than the first term.

The implementation of the sequence shown in FIG. 6A, along with an analysis based on EQ. 1 according to some embodiments of the present invention is shown in FIG. 7 for a porcine spinal cord. Shown are maps of F, Ti and t_exc of porcine spinal cord obtained by a fit to EQ. 1. A gradient echo (GE) image was acquired at TR/TE=4400/l.6 ms. FOV 10x10 mm, matrix size 64x64 mm. The map of r² is presented as a reference for the quality of the fit of the maps to EQ. 1. The interval t was in range of values 0.01 to 3.2 s. Number of averages was 4. The measurements were carried out at two temperatures, 4 °C and 38 °C. Two selective pulses about 2 ms in duration and selective flip angle of 90°, and two gradients about 1.2 and about 1.8 ms in durations, were used. Thus, the total suppressing time was about 7 ms.

The gradient-echo image reflects mostly spin density with larger amount of water found in the grey matter. On the other hand, the F map that reflects the amount of SRMP (see EQ. 1) shows much larger amount of these species in the white and about a factor of two-three smaller in the grey matter. The Ti map shows values in the following declining order: CSF, GM, and WM. The t_exc map shows that the fastest process is occurring in the gray matter.

In order to get spectral information of the SRMP the pulse sequence in FIG. 6C was applied. The dependence of the images acquired at various values for the frequency offset is shown in FIGs. 8A-D. The images in FIGs. 8A-D were acquired with the low power pulse (7.8mT) applied at the following frequency offsets: 5 kHz (FIG. 8A), 10 kHz (FIG. 8B), 15 kHz (FIG. 8C), and 20 kHz (FIG. 8D). The ratio of the averaged intensities of WM and GM is shown above each of the images. The intensity dependence of each pixel of the image on the offset at which the low power pulse was applied yields an SRMP spectrum.

The present inventors found that the pulse sequence 30 (FIGs. 2 and 3) allows suppression on a time scale shorter or at least not longer than the one achieved by the pulse sequences shown in FIGs. 6A-C. Such modification is advantageous for the following reasons (a) for physical systems such as in low field clinical scanners, or fatty tissues such as liver the Tl can be fairly short; (b) in clinical scanners the radiofrequency and gradient pulses can be as long as 3ms and application the sequence in FIG. 6A may last l2ms.

Experimental Study

In some exemplary embodiments of the invention the suppression of the water magnetization occurs on a time scale shorter than the exchange time, t_exC=l/k. This can be ensured by selecting the durations of the selective RF pulses, and of the gradient pulses, shorter than l/k. Also, the RF pulses duration, t_p, optionally and preferably fulfils the condition "^mnoh,lc « t_p « 7V"""^'' . The actual duration depends also on selective pulse shape that ensures the selective suppression of the water in the desired slice.

In this experimental study, the Inventors examined duration pulses in the range of 1-4 ms and the following pulse shapes: rectangle, sine, hermite and sinus hyperbolic. It was found that for nerve systems and liver the best performance considering acceptable Specific Absorption Rate (SAR) were Hermite pulses with duration of from about 2 to about 3 ms. For human liver sine pulse of 3 ms and 30ms classical FSpulse were used.

Rat model of hepatic fibrosis

A rat model of hepatic fibrosis was induced by Carbon tetrachloride (CCU), using the following procedure: 0.3 ml/lOOgr mixture of CCU and olive oil (1: 1) was injected intraperitoneal to Sprague-Dawley male rats, twice a week for 6 weeks. This duration allows the induction of fibrosis before the stage of cirrhosis. Histology analysis demonstrated an increase in the amount of collagen.

FIGs. 9A and 9B are typical images of fibrotic liver tissue (FIG. 9A) and control (non- fibrotic) tissue (FIG. 9B). Shown are colored F maps (see EQ. 1) overplayed with T₂ weighted images obtained by spin-echo imaging. Color scales of the F values are provided on the right hand side. The enhancement of the amount of SRMP in the fibrotic liver is vivid. Similar measurements were repeated for six fibrotic rats and three controls. A statistical analysis of fibrotic and control rats is shown in FIGs. 10A-C and Table 1-3, respectively for the parameters F, t_exc, and Ti. The statistical analysis included averaging over all the pixels in the region-of- interest (with R²>0.9) and over all the Slices, and performing a two-tailed upaired t-test, significantly different for p<0.5.

Table 1

Statistical analysis for the parameter F

Table 2

Statistical analysis for the parameter t_exc[ms]

Table 3

Statistical analysis for the parameter Ti [ms]

FIGs. 10A-C and Tables 1-3 demonstrate that the p-test for F is 0.026, meaning that there is significant difference in the content of SRMP material between fibrotic and non-fibrotic animals. For t_exc and Ti the p value is larger than 0.6 making these two parameters less good for identification of fibrosis.

Human studies of hepatic fibrosis

FIGs. 11A and 11B are typical images of human fibrotic liver tissue (FIG. 11A) and human control (non-fibrotic) tissue (FIG. 11B). Shown are colored F maps (see EQ. 1), overlaid on T2 weighted images obtained by fast spin-echo imaging method. Color scale of the F values is provided on the right hand side. The enhancement of the amount of SRMP in the fibrotic liver is vivid. The fat suppression pulse sequence was a commercial medical "classical FS" pulse with 30ms duration (OPTIMA MR450W, VER DV24.0 R01, GE, Milwaukee, WI).

As shown in FIGs. 11A and 11B, the fraction of solid material shows significant difference between fibrotic and non-fibrotic animals (p<0.00l). For Ti the p value is p<0.75 making this parameter less good for identification of fibrosis. However, in the human case, there is also a statistically significant difference (p< 0.014) between the exchange time of the healthy and fibrotic tissue (with reasonable shorter value, 49 ms, for the fibrotic tissues compared to 97 ms for the control) and the healthy tissue.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting.

In addition, any priority document(s) of this application is/are hereby incorporated herein by reference in its/their entirety.

Claims

WHAT IS CLAIMED IS:

1. A method of magnetic resonance (MR) analysis of a body having therein water and a molecule which comprises at least one hydrogen atom having an anisotropic motion within the molecule, the method comprising:

applying to the body a pulse sequence having a magnetic field gradient pulse at least partially co-existing with a water- suppressing radiofrequency pulse selected to selectively suppress magnetization of the water while preserving a generally longitudinal magnetization of the molecule;

following a period of magnetization exchange and longitudinal relaxation, acquiring an MR signal from the body; and

analyzing said MR signal to determine presence, absence or level of the molecule.

2. The method according to claim 1, wherein said pulse sequence comprises a preparation radiofrequency pulse preceding any of said suppressing radiofrequency pulse and said magnetic field gradient pulse, said preparation radiofrequency pulse being characterized by a pulse length of the order of a characteristic longitudinal relaxation time of the water.

3. The method according to claim 2, further comprising varying an offset of said preparation radiofrequency pulse, acquiring said MR signal for each of a plurality of different offsets, and analyzing said signals as a function of said offsets.

4. The method according to any of claims 1 and 2, wherein said pulse sequence comprises a fat-suppressing pulse subsequence, a predetermined time period following each of said suppressing radiofrequency pulse and said magnetic field gradient pulse.

5. The method according to any of claims 1-4, wherein said pulse sequence comprises a repetition of said magnetic field gradient pulse and said water-suppressing radiofrequency pulse factor.

6. The method according to any of claims 1-5, further comprising:

applying to the body an additional pulse sequence selected to non-selectively suppress magnetization of both the water and the molecule, following an additional period of magnetization exchange and longitudinal relaxation, acquiring an additional MR signal from the body; and

subtracting said MR signal from said additional MR signal, wherein said determination of said presence, absence or level of the molecule is based on said subtraction.

7. The method according to any of claims 1-5, further comprising producing at least one magnetic resonance image of the body using said signal.

8. The method according to any of claims 1-5, further comprising:

applying to the body an additional pulse sequence selected to non-selectively suppress magnetization of both the water and the molecule,

following an additional period of magnetization exchange and longitudinal relaxation, acquiring an additional MR signal from the body;

producing an additional magnetic resonance image of the body using said additional signal; and

subtracting said magnetic resonance image from said additional magnetic resonance image, wherein said determination of said presence, absence or level of the molecule is based on said subtraction.

9. The method according to any of claims 1-6, wherein said analysis comprises spectroscopy analysis without producing a magnetic resonance image of the body.

10. The method according to any of claims 1-9, wherein said analysis comprises fitting said signal to a bi-exponential function.

11. The method according to claim 10, further comprising producing a map of a parameter of said bi-exponential function.

12. The method according to claim 11, wherein said parameter is a coefficient indicative of a fraction of hydrogen atoms residing in the molecule.

13. The method according to claim 11, further comprising identifying fibrotic tissue based on said coefficient.

14. The method according to any of claims 1-13, wherein said suppressing radiofrequency pulse is a Hermite shaped pulse.

15. The method according to any of claims 1-14, wherein said suppressing radiofrequency pulse has a duration of from about 500 qm to about 5 ms.

16. The method according to any of claims 1-14, wherein said suppressing radiofrequency pulse has a duration of from about 1 ms to about 4.5 ms.

17. The method according to any of claims 1-14, wherein said suppressing radiofrequency pulse has a duration of from about 1.5 ms to about 4 ms.

18. The method according to any of claims 1-14, wherein said suppressing radiofrequency pulse has a duration of from about 1.5 ms to about 3.5 ms.

19. The method according to any of claims 1-14, wherein said suppressing radiofrequency pulse has a duration of from about 2 ms to about 3 ms.

20. The method according to any of claims 1-19, wherein the molecule comprises collagen.

21. The method according to any of claims 1-19, wherein the molecule is part of a myelin.

22. The method according to any of claims 1-19, wherein the molecule is part of an amyloid.

23. The method according to any of claims 1-19, wherein the molecule is selected from the group consisting of a protein, a glycoprotein, a proteolipid, a carbohydrate and a nucleic acid.

24. The method according to any of claims 1-19, wherein the molecule is part of a complex of macromolecules which comprises at least two components selected from the group consisting of a protein, a glycoprotein, a proteolipid, a lipid, a carbohydrate, a nucleic acid.

25. The method according to any of claims 1-19, wherein the molecule is part of a tissue selected from the group consisting of a fiber, a membrane and a cell nucleus.

26. The method according to any of claims 1-23, wherein the body is a body of a mammal or a part thereof.

27. The method according to any of claims 1-23, wherein the body is a liver.

28. The method according to any of claims 1-23, wherein the body is a heart.

29. The method according to any of claims 1-23, wherein the body comprises nervous tissues.

30. The method according to any of claims 1-23, wherein the body is a body of a subject having Alzheimer's disease.

31. The method according to any of claims 1-23, wherein the body comprises an organ selected from the group consisting of a brain, a kidney, a gland, a testicle, an ovary, an eye, a pancreas and a spleen.

32. The method according to any of claims 1-23, wherein the body comprises a tissue selected from the group consisting of a connective tissue, a tendon, a portion of a skin, a bone, a muscle, a cartilage, a blood vessel, a ligament and a lymph node.

33. A magnetic resonance imaging system for imaging a body, the system comprising a control system configured for executing the method according to any of claims 1-32.