EP0148184A1 - Procede d'amelioration de mise en image a resonance magnetique nucleaire et son utilisation a des fins diagnostiques - Google Patents

Procede d'amelioration de mise en image a resonance magnetique nucleaire et son utilisation a des fins diagnostiques

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Publication number
EP0148184A1
EP0148184A1 EP19840900669 EP84900669A EP0148184A1 EP 0148184 A1 EP0148184 A1 EP 0148184A1 EP 19840900669 EP19840900669 EP 19840900669 EP 84900669 A EP84900669 A EP 84900669A EP 0148184 A1 EP0148184 A1 EP 0148184A1
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EP
European Patent Office
Prior art keywords
particles
area
magnetic resonance
nuclear magnetic
magnetic field
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19840900669
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German (de)
English (en)
Inventor
Robert Thomas Gordon
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Individual
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Individual
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Publication date
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Publication of EP0148184A1 publication Critical patent/EP0148184A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent

Definitions

  • This invention relates to medical imaging and more particularly to a method for enhancing nuclear magnetic resonance imaging.
  • Nuclear magnetic resonance imaging is based on the manipulation of an entire population of nuclei by the exposure of the nuclei to an external magnetic field, altering the characteristics of said field and measuring the response of the nuclei thereto.
  • the magnetic behavior of the entire population of nuclei can be defined by the macroscopic or bulk magnetization vector, which represents the net effect of all of the magnetic moments of all of the nuclei of a given species in the sample being analyzed.
  • the magnetic dipoles will be pointing in random directions hence the bulk magnetization will be zero.
  • the dipoles become oriented, pointing in a direction parallel to the applied field.
  • the analogy of a spinning top or gyroscope has been applied to illustrate the effect of this second magnetic field.
  • the spinning nuclei are represented as spinning tops or gyroscopes and because of, the influence of the initial magnetic field all of the axes of the gyroscopes are pointed vertically. If the axis of a spinning gyroscope is tipped away from the vertical, the gyroscope will continue to rotate about the former vertical axis in a motion describing the wall of an inverted cone. This motion is known as precession. Similarly, the bulk magnetization vector can be caused to precess about its original axis under the "tipping" influence of a second magnetic field.
  • NMR nuclear magnetic resonance
  • a simple mathematical relation links the resonance frequency, often called the Larmor frequency, to the value of the externally applied static magnetic field.
  • the frequency is equal to the strength of the field multiplied by the "gyromagnetic ratio,” which is unique for each nuclear species of nonzero spin.
  • the resonance frequency is 42.57 megahertz (MHz), or 42.57 million cycles per second.
  • nuclei of the isotope phosphorus 31 ( 31 P) in the same field the resonance frequency is 17.24 MHz; for nuclei of sodium 23 ( 23 Na) it is 11.26 MKz.
  • a pulse long and strong enough to tip the bulk vector from its original position to one which is parallel to the rotating field is known as a 90° pulse owing to the perpendicular arrangement of the two magnetic fields.
  • Precession pattern of nuclei under these conditions resemble a flattened disc rather than a cone.
  • the nuclei in the excited (high energy) state tend to revert to the more stable (low energy) state.
  • the return to equilibrium of the nuclei is characterized by two principal "relaxation times", T 1 and T 2 .
  • the relaxation times T 1 (spin - lattice or longitudinal relaxation time) and T 2 (spin-spin or transverse relaxation time) are parameters which describe the exponential return to equilibrium of the nuclear magnetism of the sample nuclei in directions parallel or perpendicular, respectively, to the applied (i.e. rotating) magnetic field.
  • the rate at which nuclei assume the ground state depends on how readily they can dispose of their excess energy.
  • T 1 represents a time constant describing one route for the dissipation of said energy, specifically the loss of energy to the local molecular environment ⁇ i.e. the lattice).
  • T 2 is a rate constant which describes a second route of dissipation, namely the loss of energy to other protons. This latter disposition of energy has the effect of dephasing many of the excited nuclei without loss of energy to the surrounding environment.
  • the field center (or "saddle point") is used as the reference to choose an exciting RF frequency to achieve the resonance condition.
  • an image is created by moving the body area to be examined through the saddle point in an ordered fashion so that a recognizable structure will be achieved from the signal determinations at each location of interest.
  • Lauterbur and Lai have described a method of image reconstruction involving the analysis of many planes of NMR signals in a manner similar to x-ray computed tomographic (CT) images.
  • CT computed tomographic
  • zeugmatography signals from the sample volume are contained in each one-dimensional projection. Imaging may be achieved by superimposing a linear magnetic field gradient on the area of interest (e.g., human anatomic area or organ) that has been placed in a uniform magnetic field. The resonance frequencies of the precessing nuclei will depend on their position along the direction of the magnetic gradient. If one obtains a series of one-dimensional projections at different gradient orientations, two- and three-dimensional images of the structure or organ of interest can be obtained by this technique.
  • NMR imaging is plagued with several problems. Firstly, NMR is much less sensitive than other forms of spectroscopy and secondly, its use is restricted to certain atomic nuclei. Three nuclei have been used almost exclusively in biological NMR imaging studies, the hydrogen atom or proton ( 1 H) , phosphorus ( 31 P), and 13 carbon ( 13 C) . Of the three the proton gives the strongest signal but is so ubiquitous in living tissue that special techniques are necessary to resolve individual signals from a multitude of overlapping peaks. The most abundant isotope of carbon is 12 C, which possesses no nuclear spin. Only 1% of natural carbon is 13 C which yields a much weaker signal than the proton. Most NMR work on intact biological systems has centered on 31 P, the naturally occurring isotope of phosphorus, but this nucleus only gives a signal one-sixth the strength of the proton.
  • NMR spectroscopy One further aspect of NMR spectroscopy must be mentioned: the time taken for the nuclei perturbed by the radiofrequency signal to relax back to their unperturbed state. This obviously limits the rate at which pulses can usefully be administered to the sample. Investigations by Brady, T.J. et al. (Radiology 143:343-347 (1982)) and Ujeno, Y. (Physiol. Chem. & Physics 12:271-275 (1980)) have sought to enhance proton signals by the addition of substances which affect the T 1 and T 2 relaxation times of the NMR-sensitive nuclei.
  • one object of the instant invention is to enhance NMR-imaging, not by affecting T 1 /T 2 per se, but rather to focus and concentrate the magnetic field which is applied to the sample, so that the sharpness of the signal is augmented (i.e., less dispersion in the peaks) whereby the resolution or clarity of the mapped signals, i.e., the image is enhanced.
  • This invention relates to the area of nuclear magnetic resonance imaging enhancement.
  • the subject invention relates to a method of enhancing NMR imaging by the introduction of ferromagnetic, diamagnetic or paramagnetic particles which act to focus and concentrate the magnetic field in the area to be imaged, thereby improving image intensity due to NMR-sensitive nuclei within the sample area. Further, by comparing the images before. and after addition of the particles, the changes therein can be related to the spatial density and distribution of the particles themselves. The increased resolution and sensitivity resulting from the application of the instant invention will permit, not only structural evaluations, but metabolic monitoring as well.
  • the ferromagnetic, diamagnetic, a paramagnetic particles are themselves subject to metabolism by the cells of the sample to be analyzed.
  • the particles then serve as sensitive metabolic "probes" of the extracellular and/or intracellular environment of the cells within the area to be imaged.
  • This invention relates to the area of medical imaging and more specifically to the enhancement of nuclear. magnetic resonance imaging.
  • the subject invention may be employed with any of many imaging systems currently available, a zeugmatography system will be used for ease of discussion.
  • the controlled nonuniformity is achieved by superimposing upon the static magnetic field a linear magnetic field gradient.
  • the first images produced by Lauterbur borrowed image-reconstruction computer algorithms, used in computerized tomography scanning. If a sample of water is placed in a homogeneous magnetic field, the NMR frequency spectrum of the hydrogen nuclei in the water molecules is a single narrow line. If the magnetic field is perfectly uniform, the shape of the line is independent of the geometry of the sample. If a linear magnetic field gradient is now superimposed, resonant nuclei at one side of the sample will feel a weaker total magnetic field than those at the other side. There will thus be a linear distribution of Larmor frequencies across the sample. Then the free induction decay signal can be subjected to Fourier transformation, a mathematical procedure that transforms the data from a curve representing signal strength v. time into one representing signal strength v. frequency.
  • the result is a spectrum that is broadened to a shape corresponding to the one-dimensional projecting of the strength of the NMR signal onto the frequency axis.
  • Accessory materials particular useful in the light of the subject invention are those described by Gordon in U.S. Patent Nos. 4,303,636 and 4,136,683.
  • the particles so described do not contain NMR-sensitive nuclei (i.e. an odd number of protons or neutrons) they do possess unpaired electrons and hence display a magnetic moment.
  • the particles will thus influence the magnetic fields of an NMR system and therefore, the images resulting from the signals generated by nuclei which are NMR-sensitive will be enhanced.
  • the obverse is also true, whereby the intensification of extant NMR sensitive nuclei is used as an indicator of the spatial density and distribution of the particles.
  • This application is particular useful when the enhancing particles are to be used ultimately in a treatment regimen as described by Gordon in U.S.
  • Patent No. 4,106,488. More specifically, these fine particles, responsive to and interactive with the imposed magnetic field (provide more local anomalies) in the field and enhance the mapped signal image in much the manner of the enhancement of a television image by increasing the number of "lines" transmitted and displayed. Less dispersion is seen in individual peaks, i.e., they are sharper whereby the image is better resolved, offering enhanced clarity.
  • the particles serve a "shadowing" function, intensifying and contrasting an image generated by the NMR sensitive nuclei. More specifically the particles affect particularly spin-spin interactions related to the dephasing of nuclei and the transfer of energy between adjacent nuclei, hence T 2 values are influenced by the presence of the particles.
  • the presence of a substance having a certain magnetic susceptibility in a high frequency oscillating field causes a change in frequency as a consequence of a "heterodyning" phenomenon relative to a fixed frequency signal.
  • Each magnetically susceptible nucleus when dephased acts as a high frequency oscillator; and the presence of the ferromagnetic, diamagnetic or paramagnetic particles thus dampens or reinforces the phased precession of the magnetically susceptible muclei, affecting the observed frequencies directly and therefore sharpening the resultant NMR peaks reflected in individual plots of signal vs frequency, or mapped sample regions collecting such peaks.
  • the particles employed are those generically disclosed in Gordon U.S. Patent Nos. 4,303,636 and 4,136,683. These fine particles, unlike macro-particulate materials intended merely to modify T 1 T 2 , by reason of their size (and shape), provide a multiplicity of anomalies to the magnetic field in a localized area. Where the particles are selectively absorbed or collected through bioprocesses, the particle spatial distribution or density itself further enhances resolution of the images in the localized region of interest. Then, the pattern of distribution itself evidences the underlying bioprocess as for example malignancy requiring treatment such as that of Gordon U.S. Patent No. 4,106,488.
  • the particles may be supplied to the system, e.g., tissue, organ or organism in a selective manner to provide intracellular absorption or more generally, are selected to have a fine particle size sufficient to enhance the NMR image.
  • the particles lie in the micron range, and preferably are of no more than 1 micron in dimension. Shape selection may be of importance in a given system, and will be chosen in relation to use and performance.
  • metabolically susceptible ferromagnetic, diamagnetic, or paramagnetic particles may be employed.
  • Particularly useful materials in this regard include iron dextrans, metal-containing hematoporphyrins, such as rare-earth metal-containing porphyrins and the like.
  • a specific location with the sample area may be examined by employing metabolically susceptible image enhancing particles which will specifically localize in the area of interest. This specific targeting may be achieved by judicious selection of the metabolically susceptible particles. For example, selection based upon particle size, charge and' composition can be used to ensure intracellular localization or, if desired, cellular exclusion of the particle. Specific cell types or cellular locations may be monitored by specifically targeting the particles by means of antigens, antibodies, enzymes or specific prosthetic groups.
  • porphyrins containing ferromagnetic, diamagnetic or paramagnetic particles are employed, for example, to ensure localization within specific intracellular compartments such as mitochondria or chloroplasts. If intracellular localization is desired, the particles may be constructed and delivered to the same area as described by Gordon in U.S. Patent Nos. 4,303,636; 4,136,683, or 4,106,488 incorporated herein by reference. In accordance with preferred embodiments, a metabolizable form of particle is employed. Particularly useful material for such a formulation is an iron dextran as described by Cox et al. (J. Pharmacy and Pharacol. 24(7):513-17 (1971)).
  • the image-enhancing particles thus become sensitive probes of the metabolic environment and are therefore useful for the diagnosis of various metabolic diseases as well as malignancies. All that is necessary for such a determination to be made is to image a sample area containing the metabolically susceptible image enhancing particles, wait for a sufficient period of metabolic time, e.g. that amount of time required for a significant, measurable change to occur in the magnetic properties of the susceptible particles due to the action of cellular metabolism, then reimage the area of interest. A comparison of the images resolvable at the beginning and the end of said time span is then correlated with various metabolic disease or malignant states.
  • a sufficient period of metabolic time e.g. that amount of time required for a significant, measurable change to occur in the magnetic properties of the susceptible particles due to the action of cellular metabolism

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  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Signal Processing (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • General Physics & Mathematics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Magnetic Resonance Imaging Apparatus (AREA)

Abstract

Amélioration dans les techniques de mise à l'image à résonance magnétique nucléaire (NMR), où l'image est "ombrée" pour intensifier et contraster l'image produite par le noyau sensible NMR, à la suite de l'introduction dans l'endroit examiné, par exemple un tissu humain, de particules ferromagnétiques, diamagnétiques ou paramagnétiques. L'image intensifiée et clarifiée est précieuse à des fins diagnostiques selon les procédés reconnus dans la pratique, mais fournit également une base améliorée d'informations pour l'établissement et le contrôle de modes de traitement, notamment pour la détermination de la densité et de la distribution spatiale des particules en comparant les images standard et améliorées. Selon un mode préférentiel de réalisation, on utilise des particules métabolisables, ce qui permet aux variations et aux taux de variations pendant un temps de métabolisation d'être mises en images, comparées et mises en corrélation avec nombre d'affections métaboliques ou d'états de malignité.
EP19840900669 1983-01-10 1984-01-10 Procede d'amelioration de mise en image a resonance magnetique nucleaire et son utilisation a des fins diagnostiques Withdrawn EP0148184A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US45655583A 1983-01-10 1983-01-10
US456555 1983-01-10
US46088983A 1983-01-25 1983-01-25
US460889 1983-01-25

Publications (1)

Publication Number Publication Date
EP0148184A1 true EP0148184A1 (fr) 1985-07-17

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Application Number Title Priority Date Filing Date
EP19840900669 Withdrawn EP0148184A1 (fr) 1983-01-10 1984-01-10 Procede d'amelioration de mise en image a resonance magnetique nucleaire et son utilisation a des fins diagnostiques

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EP (1) EP0148184A1 (fr)
CA (1) CA1244082A (fr)
WO (1) WO1984002643A1 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4731239A (en) * 1983-01-10 1988-03-15 Gordon Robert T Method for enhancing NMR imaging; and diagnostic use
US5720939A (en) * 1985-08-15 1998-02-24 Nycomed Imaging As Method of contrast enhanced magnetic resonance imaging using magnetically responsive-particles
US5618514A (en) * 1983-12-21 1997-04-08 Nycomed Imaging As Diagnostic and contrast agent
GB8408127D0 (en) * 1984-03-29 1984-05-10 Nyegaard & Co As Contrast agents
EP0184899B1 (fr) * 1984-11-01 1990-04-18 Nycomed As Agents de contraste paramagnétiques pour utilisation dans les méthodes de diagnostic par RMN "in vivo" et leur préparation
SE465907B (sv) * 1984-11-01 1991-11-18 Nyegaard & Co As Diagnosticeringsmedel innehaallande en paramagnetisk metall
US5223242A (en) * 1985-11-05 1993-06-29 The General Hospital Corporation Negatively charged specific affinity reagents
US4770183A (en) * 1986-07-03 1988-09-13 Advanced Magnetics Incorporated Biologically degradable superparamagnetic particles for use as nuclear magnetic resonance imaging agents
US4951675A (en) * 1986-07-03 1990-08-28 Advanced Magnetics, Incorporated Biodegradable superparamagnetic metal oxides as contrast agents for MR imaging
GB8718515D0 (en) * 1987-08-05 1987-09-09 Nat Res Dev Obtaining images
DE4309333A1 (de) * 1993-03-17 1994-09-22 Silica Gel Gmbh Superparamagnetische Teilchen, Verfahren zu ihrer Herstellung und Verwendung derselben

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3489522A (en) * 1965-10-15 1970-01-13 Synvar Ass Electron spin resonance labeling of biomolecules
US4303636A (en) * 1974-08-20 1981-12-01 Gordon Robert T Cancer treatment
US4335427A (en) * 1980-04-21 1982-06-15 Technicare Corporation Method of selecting a preferred difference image

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8402643A1 *

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WO1984002643A1 (fr) 1984-07-19
CA1244082A (fr) 1988-11-01

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