WO2014071196A1 - Système et appareil d'imagerie par résonance magnétique combinée à une spectroscopie magnétique de mouvement brownien et/ou à une imagerie de nanoparticules magnétiques - Google Patents

Système et appareil d'imagerie par résonance magnétique combinée à une spectroscopie magnétique de mouvement brownien et/ou à une imagerie de nanoparticules magnétiques Download PDF

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WO2014071196A1
WO2014071196A1 PCT/US2013/068082 US2013068082W WO2014071196A1 WO 2014071196 A1 WO2014071196 A1 WO 2014071196A1 US 2013068082 W US2013068082 W US 2013068082W WO 2014071196 A1 WO2014071196 A1 WO 2014071196A1
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axis
field
magnetic
along
nanoparticles
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John B. Weaver
Alexander Hartov
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The Trustees Of Dartmouth College
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Priority to US14/440,268 priority Critical patent/US10222438B2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves  involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0033—Features or image-related aspects of imaging apparatus classified in A61B5/00, e.g. for MRI, optical tomography or impedance tomography apparatus; arrangements of imaging apparatus in a room
    • A61B5/0035—Features or image-related aspects of imaging apparatus classified in A61B5/00, e.g. for MRI, optical tomography or impedance tomography apparatus; arrangements of imaging apparatus in a room adapted for acquisition of images from more than one imaging mode, e.g. combining MRI and optical tomography
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/0515—Magnetic particle imaging
    • 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
    • G01R33/4808—Multimodal MR, e.g. MR combined with positron emission tomography [PET], MR combined with ultrasound or MR combined with computed tomography [CT]

Definitions

  • the present document describes apparatus for generating medical information and images through magnetic spectroscopy of Brownian motion (MSB) and/or magnetic nanoparticle imaging, nearly simultaneously with nuclear magnetic resonance imaging.
  • MSB Brownian motion
  • Nanoparticles may be tagged with bioactive molecules. Proteins and other molecules, such as nucleic acids, often have active sites that are capable of binding compounds of interest, or analytes, with great specificity. These analytes may be substances, such as nucleic acids or proteins, found in the bloodstream or interstitial fluid of tissues, or that may appear on cell surfaces. Nanoparticles tagged with a bioactive molecule, such as an enzyme, antibody, aptamer or other molecule, capable of selectively binding such analytes are known. [0006] Nanoparticles, whether plain or tagged, may also be present in, or leak from, or be trapped in vasculature. In particular, they may leak from vasculature damaged by, or grown in response to presence of, tumors.
  • Magnetic nanoparticles, nanoparticles formed with either a core, or a layer, of a magnetic material such iron, an iron alloy, or iron oxide, can be located within a subject because of their magnetic properties.
  • Brownian motion can be detected and monitored with a technique called Magnetic Spectroscopy of nanoparticle Brownian Motion (MSB), described in an article published as A.M. Rauwerdink, J.B.
  • MSB Magnetic Spectroscopy of nanoparticle Brownian Motion
  • FIG. 1 A basic, prior, MSB apparatus 100 is illustrated in Fig. 1.
  • Tissue 102 that may contain magnetic nanoparticles is placed near at least one AC magnetic field driving coil 104, and may be placed between two such driving coils.
  • driving coils 104 are driven by AC field driver electronics 106, such that driving coils 104 operate as an electromagnet providing an AC magnetic field to tissue 102.
  • One or more sensing coils 108 are provided between driving coils 104 and tissue 102, changes in the magnetic field at sensing coil 108 induce currents in coil 108, these induced currents are processed by sense amplifier and signal processing electronics 110.
  • Nanoparticles in tissue 102 change magnetic coupling between the driving coils 104 and sensing coils 108, and Brownian motion of the nanoparticles in turn modulates that coupling, causing changes in the induced currents.
  • Balancing coils 112 may also be provided to sense the applied AC magnetic field without influence from the nanoparticles, a signal from the balancing coils 112 may in some systems be used by electronics 110 to help isolate changes in signal from sensing coil 108 due to nanoparticles in the tissue 102. Electronics 110 produces a signal 114 representing a signal component at the sensing coils 108 due to the presence of the nanoparticles.
  • a basic prior or traditional Magnetic Particle Imaging (MPI) system 150 has a pair of bias-field magnets 148 oriented in opposition to each other to create a nonuniform magnetic field within the space to be occupied by tissue and nanoparticles.
  • System 150 also has multiple sets 152, 154, 156 of driving coils and sensing coils, with each set oriented on or parallel to a different coil axis, such as Y axis 158, X axis 160, and Z axis 162.
  • These systems are typically arranged, and magnets powered, such the vector sum of fields from each coil produce a zero field point, or "field free point” (FFP) 165 that is located within the tissue and nanoparticles to be examined.
  • FFP field free point
  • balancing coils, driving electronics, and sensing electronics are omitted for clarity.
  • Prior MPI using the FFP obtained high sensitivity by recording signal at harmonics of the AC driving field, so the signal caused by the magnetization can be isolated from the signals caused by the drive field. High sensitivity allows very low amounts of mNPs to be detected. Further, spatial selectivity was obtained from saturating the signal from mNPs at all other locations than the FFP. The FFP was scanned to produce a sequence of responses at voxels, the image being derived from signal at each voxel.
  • a limitation of this current MPI implementation is that high gradients are required to achieve images with reasonable resolution. Gradients of 3T/m to 9T/m are required, this requires intense fields if a volume is to be scanned that is large enough for human subjects to fit in the field.
  • a conventional MRI machine has a large magnet (main magnet) that provides a very strong static bias field in an imaging zone, into which a subject is placed for imaging.
  • the main magnet may be a C-shaped permanent magnet as in some smaller "open- MRI" systems, it may be a superconducting toroidal electromagnet, or may have some other configuration.
  • Also provided in a standard MRI machine are a radio-frequency signal source with transmitter coils, antennae or emitters for applying a radio-frequency electromagnetic field to portions of the subject within the bias field, and receiver antennae or coils and electronics for measuring any response due to resonance of protons in the bias field.
  • Additional, controllable, magnets are provided that create gradients in that field during capture of each MRI image, allowing resonance to be swept along the gradients by sweeping radio-frequency stimulus frequencies, and thereby helping to localize resonances and thereby image tissues.
  • Magnetic nanoparticles have been coated with proteins or other molecules capable of selectively binding to analytes. When such particles are in suspension, a change in Brownian motion as measured by MSB can be detected when the particles are exposed to the analytes.
  • a system for measuring responses of magnetic nanoparticles has a static magnetic bias field along first axis, and AC driving coils providing an AC magnetic field along a second axis perpendicular to the first axis, both fields passing through an imaging zone. Sensing coils are oriented to sense fields parallel to the first axis, but not parallel to the second axis.
  • a processor determines MSB response of nanoparticles in the imaging zone to the AC field.
  • Another system has either or both the AC driving coils and the static field/sensing coils combination rotating either electronically or physically.
  • the signal processor provides a voxel based model of magnetic nanoparticle distribution in imaging zone.
  • the static magnet has strength at least two ten thousandths tesla.
  • the static magnet is a main magnet of a magnetic resonance imaging system.
  • a system for measuring a response of magnetic nanoparticles has a static magnet providing a bias field oriented on first axis, and AC driving coils configured to provide an AC magnetic field along second axis, both fields passing through an imaging zone, and the second axis perpendicular to the first axis.
  • the system also has at least one sensing coil between imaging zone and poles of the static magnet oriented to sense fields parallel to the first axis, while not sensing fields parallel to the second axis.
  • a signal processing subsystem is configured to determine an MSB response of nanoparticles in the imaging zone to the AC magnetic field based upon the signal from the sensing coil.
  • a method of producing magnetic nanoparticle data includes applying a unidirectional DC bias magnetic field along a first axis to nanoparticles in a sensing zone, applying an AC magnetic field along a second axis to the nanoparticles, the second axis perpendicular to the first axis, then, while both the DC and AC magnetic fields are applied, sensing a response from the nanoparticles with a sensing coil oriented to respond primarily to field perturbations along the first axis, while minimizing response to field perturbations along the second axis; and processing the sensed response to provide the nanoparticle data.
  • FIG. 1 is a schematic illustration of a prior Magnetic Spectroscopy of
  • Brownian Motion (MSB) system having paired driving and sense coils.
  • FIG. 2 is a schematic illustration of a prior Magnetic Particle Imaging
  • FIG. 3 is a simplified schematic illustration of an embodiment of the magnetic particle imaging system of present invention.
  • Fig. 4 is a schematic illustration illustrating a combined MRI and MSB system, with MSB sensing coils aligned with static field provided by the MRI system magnets and MSB driving coils at right angles to the static field.
  • FIG. 5 is a schematic illustration of a combined MRI and MSB system utilizing a solenoid main magnet.
  • Fig. 6 is a timing diagram of waveforms of the magnetic particle imaging system of the present invention illustrating how received signals change with position along a magnetic field gradient.
  • Fig. 7 is an illustration of an embodiment that synthetically rotates drive, bias, and/or sensing coils about a subject having tissue containing nanoparticles by controlling ratios of drive energy to multiple coils.
  • Fig. 8 is an illustration of a stand-alone MPI embodiment capable of three- dimensional image construction, the images representing nanoparticle concentrations.
  • FIG. 9 is an illustration of an embodiment with a bipolar gradient in Z axis, and AC drive in an X-axis, where a zero-field plane is swept along the Z axis while taking data.
  • Fig. 10 is a schematic representation of the magnetic fields achieved in the apparatus resembling that of Fig. 7 or Fig. 8, showing one set of driving coils.
  • Fig. 11 is a schematic representation of fields in a combined MPI-MRI system.
  • Fig. 12 is a schematic representation of magnets and magnetic fields in an apparatus resembling that of Fig. 7 or Fig. 8, showing multiple sets of driving coils on axes at multiple angles, for MPI or MSB/MPI.
  • Fig. 13 is a schematic illustration of field gradients in a system for performing MPI.
  • Fig. 14 is a schematic illustration of a field gradient having a zone of sharp field change in a system for performing MPI.
  • Fig. 15 is an illustration of a Z-axis magnet pole showing a field strength gradient in X axis.
  • Fig. 16 is an illustration of a Z-axis magnet pole showing a field strength gradient in X axis.
  • Fig. 17 illustrates relaxation of aligned nanoparticles in an applied field.
  • Fig. 18 illustrates a stand-alone, three-dimensional, MSB/MPI machine having static-field electromagnets, oriented along each of three mutually-perpendicular axes, and driving coils, and sensing coils oriented along each of three mutually-perpendicular axes.
  • Fig. 19 is a flowchart of the method herein described of obtaining a multimode MRI and MSB/MPI result, or of obtaining an improved MSB/MPI result, from nanoparticles in a subject.
  • Fig. 20 is an illustration of differences in relative signal strength of harmonics in signal detected due to differences in applied DC magnetic field strength.
  • Fig. 21 is an illustration of a bridge circuit useful for sensing magnetic nanoparticles.
  • Fig. 22 is a schematic diagram of a program-controllable autobalancing circuit for use in the bridge circuit of Fig. 21.
  • Fig. 23 is a schematic diagram of a circuit for cancelling stray coupling from AC driving coils into perpendicular sensing coils.
  • NPs nanoparticles
  • complimentary imaging technologies such as nuclear Magnetic Resonance Imaging (MRI). It is particularly desirable that nanoparticle location and imaging be performed without moving or repositioning of the patient between NP imaging or sensing and complimentary imaging, because soft tissues are readily deformed, and knowing relative positions of NPs and the many structures visible in complimentary images can be important for treatment decisions and for locating tumors during later surgical treatment.
  • MRI nuclear Magnetic Resonance Imaging
  • the present invention results from understanding that a static field can be used to decouple the alternating applied drive field from the pickup coil used to detect the magnetization. This allows a more sensitive system because it is no longer necessary to reduce the effects of the drive field in the pickup coils and the associated detection chain. Decoupling the two also allows the base harmonic to be measured which is difficult to do when the drive field is at the same frequency and oriented in the same direction because of strong coupling from driving coils to sensing coils when the driving and sensing coils are oriented along the same axis.
  • FIG. 3 and 10 A basic outline of a new machine for measuring and detecting magnetic nanoparticles is illustrated schematically in Fig. 3 and 10.
  • This basic system can be used as a spectrometer for MSB measurements. Gradient fields can be added to make the system an imaging system.
  • a pair of drive coil electromagnets 190 are oriented on one axis 192 (Fig. 3).
  • a pair of sense coils 194 are oriented on a perpendicular axis 196, along with a pair of static field bias coils 198.
  • the bias coils 198 provide a static magnetic bias field through the imaging volume.
  • Magnetic core material may be provided to focus the fields and guide conduction of fields external to the imaging volume between the coils, this core material is not shown in the figures for simplicity.
  • a small static field provided by the bias coils 198 provides a preferential direction for the mNPs as they pass through the plane perpendicular to the alternating field. So the static field produces a magnetization pulse every time the alternating field goes through zero, pulling the mNPs from one orientation to the other orientation. Henceforth, we will term the magnetization pulse in the direction perpendicular to the alternating field as the "pulse".
  • the frequency of the pulses is twice that of the alternating field. If the strength of the alternating field is much larger than the static field, the pulses are very sharp and have a very short duration while the alternating field is small compared to the static field.
  • the sense coils respond to the pulse by providing a detected alternating current signal at second or higher harmonics of a frequency of the alternating field.
  • the static field produces no signal in the coils measuring the pulses because voltages are only induced by changing magnetic fields. So there are no extraneous signals produced in coils measuring the pulses allowing high gain and high sensitivity to be achieved.
  • the sensitivity should allow the very small magnetizations produced by the relatively small AC fields when the nanoparticles are almost saturated by the static field of an MRI to be measured.
  • spatial localization of nanoparticles is achieved by using the standard MPI moving field free point.
  • spatial localization of nanoparticles is achieved by changing the time that the pulses occur by imposing a static magnetic field gradient 197 oriented in the same direction as the alternating field but changing in magnitude along one of the three axes, such as may be produced by current in gradient coils 199, such that the AC drive field, static bus field, and gradient field superimpose on tissue containing the nanoparticles in an experimental volume 195.
  • the pulses occur when the alternating field passes through zero so adding a small static magnetic field gradient 197 in the same direction as the alternating field changes the time the pulse created by mNPs at each position. As illustrated in Fig.
  • an AC field 240 is shown superimposed on a static field gradient 242 for magnetic nanoparticles having positions with negative gradient field 236, neutral gradient field 238, and positive gradient field 244.
  • the magnetic nanoparticles orient in the AC field as indicated at 246, resulting in a pulses 248 detected by sensing coils 194.
  • the pulses 248A, 248B, 248C occur when the total of the alternating field and the gradient passes through zero. That is also the time that the net magnetic field passes through zeros as well.
  • pulses 248A from nanoparticles in negative gradient field being clearly distinguishable from pulses 248B from nanoparticles in neutral gradient field and pulses 248C from nanoparticles in positive gradient field.
  • localization is also be achieved by using gradients with fields in the direction of the static field.
  • the magnitude and sign of the pulses is changed by changing the sign and amplitude of the static field.
  • a combination of the two gradient systems is also used. Initial data suggests that the gradients with fields in the same direction as the AC field produce the smallest pulses and the most accurate localization information with the highest spatial resolution for a given amplitude gradient.
  • the gradient can be in any direction so a 3D image can be obtained by taking the signal for a range of directions and using a Radon transform reconstruction.
  • the key is that a relatively small gradient is required.
  • the gradient may be imposed by a single set of coils that rotate about tissue 195, together with sensing 194, bias 198, and drive 190 coils, in an imaging zone or an experimental volume.
  • the tissue is rotated within the coils to achieve an effect similar to that of rotating the coils around tissue.
  • synthetic rotation embodiment the effect of rotating a single set of coils about tissue is achieved synthetically.
  • coils of each of drive, sensing, and bias coils types are provided on two or more axes.
  • a drive field of a particular direction is synthesized by providing appropriate ratios of drive currents to drive coils on two or more axes as illustrated in Fig. 7, for example if drive coil sets, such as set 190 A and set 190Bs, are provided on both X and Y perpendicular axes, a drive field along an axis, such as axis 189 between the X and Y axes, is synthesized by driving the X and Y drive coils with appropriate currents.
  • sensing can be steered or rotated by multiplying currents from two or more sets of sense coils 194A, 194B by angle-dependent constants, and summing the products.
  • gradient fields may be generated along an arbitrary axis by providing appropriate currents in multiple gradient coils.
  • gradient and drive field coils can also be merged into a single set of coils along each axis with appropriate currents; in such an embodiment an appropriate current may be a sum of a gradient current and an AC drive current in each coil.
  • the system applies the static bias field along a Z axis 902, and initially applies drive currents and a magnetic field gradient along an X axis 904; the X, Y (906), and Z axes being mutually perpendicular and passing through an imaging volume including tissue of a subject 908.
  • Sets of drive, sense, and bias coils are provided for each axis, coils 910 on the Z axis, 912 on the X— axis, and 914 on the Y-axis; the coils mounted to an iron frame 916 for controlling magnetic fields outside the imaging volume.
  • Bias and drive coils of coil sets 910, 912, 914 are controlled and powered by a bias and coil drivers 918 controlled by a processor 920.
  • Detected signals from sense coils of coil sets 910, 912, 914 are received through sense coil receivers 922 into processor 920.
  • Processor 920 operates under control of a memory 924 that contains a set of scan and data gathering routines 926, and a set of image construction routines 928.
  • the system applies a bias field along a first axis, such as the Z axis using Z- axis coil set 910, as driven by bias and drive coil drivers 918, and an AC drive field and static in-line gradient as previously described along a second axis using one or more of X and Y coil sets 912, 914.
  • Magnetic nanoparticle responses are sensed and timing of pulses measured by sense coil receivers 922 using sense coils of the first axis, such as in z-axis coil set 910; data from this sensing and time measuring is stored in memory 924.
  • the second axis is then rotated by changing ratios of X and Y coil drive, and additional data obtained by sensing and timing pulses as measured by sense coil receivers 924.
  • Processor 920 constructs a voxel-based model of the subject and fits the model to the acquired data to generate a 3-dimensional image of the nanoparticle distributions in the subject. This image is then transferred to a medical records database over a network 930 and/or displayed on a display 932, where the image may be useful for diagnostic purposes.
  • data is gathered with a gradient in the static field along the Z axis.
  • the gradient may be unipolar, or may be a bipolar magnetic gradient having a null- field zone.
  • pulse heights and directions are a function of the Z-axis magnetic field strength at each nanoparticle, and hence the position of nanoparticles along the Z-axis.
  • the Z-axis field gradient is bipolar, having a zero-field plane 958 that is swept through a series of positions along the Z axis 960 by adjusting currents in the Z axis bias coils, while data is taken on pulse heights, directions, and timing, as recorded by sense coils 956, to provide data useful for detailed image reconstruction in the processor.
  • the sense coils are adjacent to the Z-axis bias field coils, slow changes in gradient will not induce significant artifacts in data recorded from sense coils.
  • the swept Z-axis gradient is combined with an X-axis gradient.
  • the X-axis may be rotated synthetically or electronically to gather yet more data, while sweeping the Z axis gradient at each X-axis position. The roles of X and Z axis may then be swapped to gather yet more data useful in locating nanoparticles.
  • an AC drive along a first axis and a static field along a second axis may be combined with magnetic fields oriented along either the first axis and/or second axis, with gradients along the first or second axes, or along a third axis mutually perpendicular to the first and second axes.
  • these gradients may then be dynamically changed and additional data recorded. Any one of the axes may then be rotated electronically, or swapped with another axis, and yet more data recorded. All recorded data is useful in fitting nanoparticle locations to a 3-dimensional voxel-based model of the tissue.
  • the combinations of magnetic field gradients results in a null-bias-field zone that may be swept or scanned through tissue of a subject; it should be noted, however, that the null-field zone is a zone of minimum nanoparticle response to the AC drive field, not a zone of maximum response as is common in prior MPI technologies.
  • the alternating field for the perpendicular field system might be 80 millitesla with a one tenth millitesla bias field strength.
  • the magnetic particle imaging system herein described may stand alone, or may be combined with an MRI machine as a combined MRI-MPI embodiment.
  • a new dual-mode imaging device 200 (Fig. 4) combines an existing MRI system with additional circuitry for magnetic particle imaging MPI through Magnetic Spectroscopy of NP Brownian Motion (MSB).
  • the system may be used to obtain MRI images as known in the MRI art.
  • Components of the MRI system include a powerful main magnet with poles 202, between which a static bias field exists, and within which a subject and/or tissue 204 may be placed. While a C-shaped magnet is illustrated as used in some open-MRI systems, the main magnet may be a superconducting toroid as used in many traditional MRI machines; for purposes of Fig.
  • the system includes gradient magnets 206 for trimming and applying gradients to the bias field applied to an imaging zone, as well as radio-frequency emitters 208 and receiver antennae 210 as known in the MRI art. Also provided are gradient magnet driving, radio frequency source, and radio frequency receiving electronics 212, and an MRI image reconstruction computer 214, also as known in the MRI art.
  • the dual-mode imaging device 200 also includes AC magnetic driving coils 216 coupled to be driven by an AC signal source 218 operable at a much lower frequency than the radio frequency of emitters 208, in some embodiments the frequency of signal source 218 is an audio frequency.
  • the driving coils 216 are arranged to provide an AC magnetic field along an axis 220 perpendicular to an axis 222 between the poles 202 of the MRI main magnet and passing through the imaging zone.
  • MSB AC sensing coils 224 are configured to sense changes in magnetic fields within the imaging zone along the axis 222 between pole pieces 202, and are provided for sensing an MSB signal, or a nanoparticle polarity-switch pulse signal, produced by interactions of the AC magnetic field along axis 220 with magnetic nanoparticles in subject and/or tissue 204.
  • Coils 224 are coupled to signal receiver and sense amplifier electronics 226; electronics is coupled to processor 228 which is configured to perform spectral analysis and image reconstruction based upon signals from coils 224.
  • Sense amplifier electronics 226 and processor 228 together form a signal processing subsystem for determining an MSB response from signals form coils 224.
  • the AC drive magnetic field strength may be approximately 100 millitesla
  • the AC driving coils 216 might not be driven to avoid interference with the MRI imaging.
  • MRI images are obtained as known in the art of MRI imaging.
  • the main magnet field of a typical MRI machine is somewhat intense.
  • gradients are introduced in that field along the Z axis, an X axis aligned with AC drive coils, and/or along a Y axis perpendicular to the X and Z axes.
  • the X axis may be
  • the alternating uniform drive field is used to induce an alternating magnetization from the nanoparticles and the static field provided by the MRI system' s main magnet is used to guide the magnetization through the axis of the pickup or sensing coils 224.
  • AC signal source 218 is then activated to provide an AC magnetic field.
  • Sensing coils 224 pick up any MSB (or in variants with more magnets and coils sufficient to provide a strong gradient, an MPI) signal, which is amplified by sense electronics, including ac signal receivers 226, as preconditioned by auto adjustment DACs 227, and processed by processor 228 to provide MSB, and in some embodiments MPI, information, which is then annotated onto images provided by the MRI computer 214.
  • MSB or in variants with more magnets and coils sufficient to provide a strong gradient, an MPI
  • sense electronics including ac signal receivers 226, as preconditioned by auto adjustment DACs 227, and processed by processor 228 to provide MSB, and in some embodiments MPI, information, which is then annotated onto images provided by the MRI computer 214.
  • spectra determined by processor 228 depend on properties of the microenvironment in which NPs are located, including the temperature, viscosity, chemical binding and rigidity of the matrix to which the NPs are bound.
  • the system therefore can provide a signal indicative of temperature at those locations within tissue or subject 204 where NPs are located, or, if tagged NPs are present, may provide indication of presence or absence, of particular substances such as tumor antigens.
  • nanoparticle locations are mapped within tissue or subject 204.
  • the pickup or sense coils 235 are oriented to detect any signal superimposed on the axial magnetic field 231.
  • At least one set of AC driving coils 237 are located on an axis 241 perpendicular to the magnetic field 231, in some embodiments additional sets of AC driving coils 239 are located along different axes also perpendicular to the static magnetic field 231.
  • the magnet poles 202, 243, 245, 250, 251 are of opposite polarity, with one pole a "north" pole and the other a "south” pole, in order to produce a unidirectional field.
  • the bias field provided by magnet 202 or 229 has strength of at least two tenths Tesla, and in most embodiments between two tenths and three Tesla.
  • the bias field provided by the bias magnet is of one tenth millitesla (0.0001 Tesla) or more, and in a particular embodiment two tenths millitesla or more.
  • MRI imaging components other than the main magnet 202 may be omitted in a machine for providing MSB / MPI data and images alone without near-simultaneous MRI imaging.
  • the central principle behind this system and method is that the NP magnetization in an alternating magnetic field can be guided through a preferential perpendicular direction allowing the magnetization to be detected in the direction
  • a static magnetic field is used to guide the magnetization as it flips back and forth.
  • That static magnetic field can be the static magnetic field of the MRI system as provided by main magnet 202 for MRI-based multimodality systems (MRI/MSB, MRI/MPI and MRI/MPI/MSB). Or it can be an independently applied static field for a standalone system.
  • FIG. 10 Fields applied by the system are illustrated schematically in Fig. 10, including a static or bias field 254 between pole pieces 250 of the main magnet, an alternating magnetic field 252 between AC driving coils 258, and a weak MPI/MSB signal field 256 that can be detected by sensing coils 260.
  • FIG. 11 Fields applied by a particular embodiment of a combined MPI-MRI system having a conventional superconducting toroidal main magnet, such as is common with 1.5 Tesla imaging machines, are illustrated in Fig. 11.
  • the Z axis 1000 is oriented along the toroidal main magnet.
  • AC driving coils 1002 are located along the Z axis, with Z-axis gradient coils 1002, and with X axis 1006 and Y axis 1008 gradients applied by X 1010 and Y 1012 gradient coils to a subject (not shown) located axially in the toroid.
  • Three- dimensional images can be produced by using three gradient systems (all with fields in the same direction as the drive field but varying in magnitude in the three directions).
  • the signal is still produced by using a static field in a perpendicular direction (or directions) and a pickup coil (or combination of pickup coils in the same direction as the perpendicular static field.
  • the gradient system would essentially be that of an MRI system, permitting rapid retrofitting of MRI machines.
  • the techniques work by oscillating the NPs in an applied magnetic field, such as that from driving coils 216, and then measuring the signal that is produced in a pickup or sensing coil 224, due to the changing flux produced by the NPs' magnetization.
  • this driving field is a pure sine wave, and the signal from the NPs will not be in general, then we can look at their contribution to the signal through the higher harmonics (i.e. distortion in the magnetization).
  • the detected signal in traditional MSB is a combination of the current produced by the applied field including distortions produced by the amplifier and the current produced by the NP magnetization.
  • the detected signal in the systems proposed herein, as for example in Fig. 3 and 10, 17 and 18, have sensing coils oriented at right angles to the AC driving coils so the current produced in sensing coils by the applied AC field is almost eliminated, leaving current produced by the NP magnetization.
  • a static field produces no current in the coil because the voltage is proportional to the time derivative of the magnetic flux. So orienting a static field perpendicular to the alternating field isolates the messy sources of current associated with the applied field from the detected signal allowing much higher sensitivity.
  • MPI uses the same signals MSB used so the same technique can be used to isolate the applied field from the signal detection can be used in that technology as well.
  • the system may have additional sets of AC driving coils 270 on an axis 272 that is perpendicular to the bias field between main magnet poles 250, but at an angle A relative to the axis between the axis 274 defined by the first set of AC driving coils 258.
  • Additional electromagnets 280 may be present to provide magnetic field gradients as may become necessary.
  • magnetic field gradients such as may be produced by additional gradient electromagnets, will prove useful in localizing nanoparticles and providing MPI or MSB-MPI images, going beyond MSB alone. It is desirable that the effective concentration of magnetic lines of force 249 (Fig. 13) increase in the direction 261 of the gradient, but remain as aligned as possible with an axis between poles 251 of the magnet system, as are an axis of pickup or sensing coils 257. This gradient permits resolution along on an axis 255 perpendicular to the axis between poles 251 and along an axis of the gradient.
  • AC driving coils 253 are aligned on an axis (not shown as directly into the page) that is perpendicular to the axis between poles 251 of the magnet system.
  • a first pair of static-field electromagnets 302, 304 are oriented along a first axis 306 (Z axis), together with a pair of sensing coils 308, 310, and a pair of AC driving coils 312, 314.
  • a pair of pickup or sensing coils 308, 310, and a pair of AC driving coils 312, 314 are provided centered on a second, perpendicular, axis 306, the Z-axis.
  • a third pair of static-field electromagnets 330, 332, third pair of sensing coils 338, 340, and AC driving coils 334, 336 oriented along a third axis 342 (X axis) are provided. Additional trimming coils for fine adjustment of the static fields or for shifting fields to more precisely localize NPs in tissue may be provided, but are not shown for simplicity.
  • one set of static field electromagnets such as the Z axis electromagnets 302, 304, is first activated.
  • AC driving coils such as the AC driving coils 324, 326 oriented along an axis, such as the Y axis 328 perpendicular to the Z axis, are then driven with an AC signal.
  • Additional AC driving coils such as driving coils 334, 336, also oriented along an axis (X axis) perpendicular to the Z axis may also be activated; activation of X and Y axis driving coils may be done in a sequence of X, both X and Y, and Y coils to alter the axis of drive to help localize NPs.
  • X axis axis perpendicular to the Z axis
  • Y axis driving coils may be done in a sequence of X, both X and Y, and Y coils to alter the axis of drive to help localize NPs.
  • MSB and MPI signals are received with Z axis sensing coils 320, 322.
  • the first set of static field electromagnets is then turned off, and a second set of static field electromagnets, such as the X axis electromagnets 330, 332 is activated.
  • AC driving coils such as AC driving coils 324, 326 oriented along an axis, such as the Y axis 328 perpendicular to the X axis, are then driven with an AC signal.
  • Additional AC driving coils such as driving coils 312, 314, also oriented along an axis (Z axis) perpendicular to the X axis may also be activated; activation of Y and Z axis driving coils may be done in a sequence of Y, both Y and Z, and Z coils to alter the axis of drive to help localize NPs.
  • electromagnets, MSB and MPI signals are received with X axis sensing coils 338, 340.
  • the second set of static field electromagnets is then turned off, and a third set of static field electromagnets, such as the Y axis electromagnets 316, 318 is activated.
  • AC driving coils such as AC driving coils 334, 336 oriented along an axis, such as the X axis 328 perpendicular to the Y axis, are then driven with an AC signal.
  • Additional AC driving coils such as driving coils 312, 314, also oriented along an axis (Z axis) perpendicular to the Y axis may also be activated; activation of X and Z axis driving coils may be done in a sequence of X, both X and Z, and Z coils to alter the axis of drive to help localize NPs.
  • Nanoparticles in a high- intensity field produce a stronger harmonic distribution with fewer high-order harmonics than low-order harmonics of the AC applied field frequency.
  • Line 602 represents a simulated harmonic response in a 10.1 millitesla bias field
  • line 604 represents the harmonic response in a 1.1 millitesla field. Nanoparticles located at each position along the gradient therefore produce a different, linearly independent, combination of harmonics so the number of nanoparticles at each position along the gradient can be found uniquely and with good stability.
  • the direction of the static field and the direction of the gradient can be changed independently; there are six possible gradient fields: fields in the Z direction varying in the X, Y or Z directions, fields in the Y direction varying in the X, Y or Z directions.
  • two uniform static fields in the X and Y directions) are useful to "sweep" the gradient across the subject.
  • Combinations of the eight fields can be used to acquire enough localization information to reconstruct the image.
  • the fields can be applied in discrete combinations or swept slowly across the subject.
  • the gradient can be configured, using additional coils, as having a zone 265 (Fig. 14) of steep gradient between two zones 267, 269 of mild gradient, and the zone of steep gradient can then be swept along the X axis while repeating steps of taking data with a sense coil oriented to pick up signals along the perpendicular (Z) axis to record the combination of harmonics produced by nanoparticles, and analyzing the recorded harmonics. Location of multiple nanoparticle concentrations along that X axis can therefore be resolved.
  • the nanoparticle concentration can be located along the Y axis.
  • locations and shapes of multiple nanoparticle concentrations can be resolved.
  • the locations of multiple nanoparticle concentrations in each axis can be processed to construct a three-dimensional model of nanoparticle concentrations in the subject, and this data is displayed as a tomographic image. Further, this three-dimensional model of nanoparticle concentrations is annotated into data obtained through a second imaging modality, such as MRI or CT scan, and this data is also displayed as tomographic images.
  • a second imaging modality such as MRI or CT scan
  • the apparatus herein described is configured to perform a method as heretofore described and as illustrated with reference to Fig. 19.
  • magnetic NPs which may be tagged NPs
  • the subject, with NPs is then positioned 502 in a static bias magnetic field, such as that provided by magnets 202, 229, 250, 251, or 302-304, the field is oriented along a first axis.
  • a static bias magnetic field such as that provided by magnets 202, 229, 250, 251, or 302-304, the field is oriented along a first axis.
  • the static bias magnetic field is a bias field of an MRI system and MRI imaging is performed 504 as known in the art of MRI imaging.
  • MRI imaging 504 Once MRI imaging 504 is complete, the MRI gradient magnets, and radio frequency source are shut down. Within milliseconds or at most a few minutes, and without repositioning the subject, an AC magnetic field is applied 506 along an axis perpendicular to the first axis. A response of the NPs to the AC magnetic field is sensed or received 508 by a pickup or sense coil, such as sense coil 224, 225, 260, 257, 308, or 310, oriented to respond to field fluctuations along the first axis while ignoring field fluctuations along the second axis.
  • a pickup or sense coil such as sense coil 224, 225, 260, 257, 308, or 310, oriented to respond to field fluctuations along the first axis while ignoring field fluctuations along the second axis.
  • an additional AC magnetic field may be applied 510 along a third axis perpendicular to the first axis, and a response is sensed by the sense coil oriented to respond to field fluctuations along the first axis.
  • a gradient may also be applied 514 to the bias magnetic field, as may be done by energizing gradient
  • Magnetic signals as sensed by the sense coils are processed 522 by a signal processing subsystem, such as AC signal receivers 226 and processor 228, to determine magnetic nanoparticle data including the MSB response and/or MPI map of NP location.
  • a signal processing subsystem such as AC signal receivers 226 and processor 228, to determine magnetic nanoparticle data including the MSB response and/or MPI map of NP location.
  • Neel relaxation may also exist, and can be particularly prominent with small nanoparticles. Brownian signals tend to be more prominent among larger nanoparticles. Both mechanisms will be measured using the previously described methods. But a second type of detection is possible: this second type of signal can be measured in the perpendicular direction because the magnetizations of nanoparticles that are relaxing with the Neel relaxation mechanism precess, and may radiate, with a frequency proportional to the field applied. Neel relaxation signals have been reported from small nanoparticles in the literature.
  • This Neel precession can be detected at the magnetization-dependent resonant frequency for each nanoparticle, and is due to a shift in magnetization due to a shift in electron structure of the nanoparticle rather than a mechanical flipping of the nanoparticle as with MSB.
  • This NMR-like precessional signal may be useful for sensing and imaging in vitro or in vivo.
  • an AC magnetic field is applied 506 along an axis, such as axis 220, perpendicular to the first axis, and a DC magnetic bias field is provided along the first axis, such as axis 222.
  • a Neel-relaxation response of the nanoparticles to the AC magnetic field is sensed or received by a pickup or sense coil, such as sense coil 224, oriented to respond to field fluctuations along the first axis while ignoring field fluctuations along the second axis.
  • a sensing coil 702 (Fig. 21) is coupled in series with a balancing coil 704 in a coil assembly 706 that may also contain a magnetic bias field coil 708.
  • the coil assembly is configured such that sensing coil 702 is located closer to, or surrounds, a sample 710 or tissue that may contain magnetic nanoparticles, while balancing coil 704 is located further from the sample or tissue, such that magnetic properties of the nanoparticles affect properties, such as inductance, of the sensing coil more than they affect properties of the balancing coil.
  • the sample 710 is tissue of a subject, the tissue containing magnetic nanoparticles, with some portions of the tissue containing higher concentrations of magnetic nanoparticles than other portions of the tissue.
  • a center-tap connection 712 between the sensing coil 702 and balancing coil 704 is coupled to a sense input to a differential amplifier 714.
  • a reference input to the differential instrumentation amplifier 714 is coupled to a tap node 716 that is connected to two resistors 718, 720.
  • One resistor 718 is connected, along with a terminal of one of the sensing or balancing coils, to an AC signal source 722, the other resistor 720 is coupled, along with a remaining terminal of the sensing or balancing coils, to a second terminal of the AC signal source 722.
  • the second terminal of the AC signal source 722 is a circuit ground 724.
  • At least one of the resistors 718, 720 is an adjustable resistor.
  • the combination of resistors 720, 718, sensing coil 702, and balance coil 704, are referenced herein as a magnetic sensing bridge.
  • the adjustable resistor of the sensing circuit of Fig. 21 is carefully adjusted, or balanced, such that, when the AC signal source is active, a difference between AC signals at the tap node 716 and the center tap 712 is a predetermined difference level that corresponds to no magnetic nanoparticles near sensing coil 702; in a particular embodiment the predetermined difference level is near or at a zero signal level.
  • the magnetic properties of the particles unbalance the magnetic sensing bridge, causing the difference between difference between AC signals at the tap node 716 and the center tap 712 to change, hence changing an output signal of the instrumentation amplifier to a "magnetic nanoparticles present" level.
  • adjustable resistor 720 incorporates a "ten-turn" potentiometer that permits precise adjustment, or balancing, of the circuit.
  • the excitation signal from signal source 722 can be eliminated from the output by adjusting the resistive portion of the bridge and therefore compensate for differences between sensing 702 and balance 704 coils. This, we expect, will increase our sensitivity to nanoparticle concentration measurements by a very large factor.
  • variable resistor such as resistor 720
  • a manual range-setting resistor 750 is in series with a resistive digital-to-analog converter 752 (RDAC), which in an embodiment may be a resistive DAC of the conventional R-2R ladder type. While only three bits are shown, RDAC 752 may have any cost-effective number of bits; RDACs are commonly available with twelve or more bits of resolution. RDAC 752 may be in parallel with a fixed range-determining resistor 754.
  • RDAC resistive digital-to-analog converter
  • each AC signal receiver 226 of a system for detecting and localizing magnetic nanoparticles in a subject incorporates a bridge circuit of Fig. 21, where sensing coils 224 are sensing coils 702.
  • the bridge circuits of Fig. 21 incorporate the electronically-variable resistance assembly of Fig. 22, where the RDAC 752 of each sensing circuit is coupled to processor 228 (Fig. 3), as auto-adjustment DACs 227 (Fig. 3), such that processor 228 can adjust the circuit null for any magnetic effects of subject or tissue 204 prior to injection of the magnetic nanoparticles.
  • AC signal and amplifiers 226 also has filtering circuits to permit any signal detectable at harmonics, such as a third harmonic, of the fundamental frequency provided by AC signal source 722.
  • a reference signal 778 is tapped by three resistors 780, 782, 784 coupled in series across the AC drive 786 to driving coils 258 (Fig. 23).
  • Digital compensation control signals from processor are converted to an analog control level 788 by a digital to analog converter 790.
  • the analog control level 788 is multiplied by the reference signal 778 in an analog multiplier 792 to produce a compensation signal 793.
  • a sense signal from perpendicular sensing coil 224 is buffered by an amplifier 794 and then passed through an analog subtractor or differential amplifier 796, where the compensation signal 793 is subtracted, to provide a compensated signal 797.
  • Compensated signal 797 is further processed by amplifiers, band-pass filters, and analog-to-digital converters 798 (ADCs) that are also part of AC signal receivers and amplifiers 226, digital outputs of the ADCs are provided to processor 228 so that the processor can extract MSB signal information.
  • ADCs analog-to-digital converters
  • a Neel Relaxation signal may be found in the same axis as the applied AC magnetic field; this signal is weak, however, when compared to the applied field strength.
  • the actively- nulled bridge circuit of Figs. 21 and 22 may, however, sufficiently reduce the fundamental signal that this relaxation signal can be detected.
  • an AC magnetic field is applied along an axis, such as axis 220, perpendicular to the first axis, and a DC magnetic bias field is provided along the first axis, such as axis 222.
  • a Neel-relaxation response of the nanoparticles to the AC magnetic field is sensed or received by a pickup or sense coil, such as sense coil 208, 210, oriented to respond to field fluctuations along the first axis - the axis of the AC field.
  • Components of the system for Magnetic Particle Imaging with and without MSB and/or MRI may be combined in many ways. Among these are combinations as follows:
  • a system designated A for measuring a response of magnetic nanoparticles in an imaging zone has a static magnet configured to provide a static bias field oriented parallel to a first axis, the static bias field passing through the imaging zone; at least a first driving coil configured to provide an alternating magnetic field along a second axis, the alternating magnetic field passing through the imaging zone, the second axis perpendicular to the first axis; apparatus for providing at least one static magnetic field gradient with the field oriented along the first or second axis, and the gradient in the field along at least one axis selected from the first axis, the second axis, and a third axis mutually perpendicular to the first and second axis; at least one sensing coil oriented to provide a detected signal by sensing changes in a magnetic field parallel to the first axis, and further oriented to minimize sensing of changes in a magnetic field parallel to the second axis; and a signal processing subsystem configured to determine a response of magnetic nanoparticles in the
  • a system designated AAA including the system designated A wherein the field of the magnetic field gradient is oriented along the second axis.
  • a system designated AAB including the system designated A or AAA wherein the field of the magnetic field gradient has a gradient along the second axis.
  • AAC including the system designated A wherein the field of the magnetic field gradient is oriented along the first axis.
  • a system designated AA including the system designated A, AAA, AAB, or AAC wherein the static magnet is configured to provide a bias field of strength greater than or equal to two ten thousandths tesla.
  • a system designated AB including the system designated A or AA wherein the static magnet is configured to provide a bias field of strength greater than or equal to two tenths tesla.
  • a system designated AC including the system designated A, AAB, AAC, or AB wherein the static magnet is a main magnet of a magnetic resonance imaging system, and further comprising apparatus for applying radio frequency signals to tissue and apparatus for sensing a response of tissue to the radio frequency signals.
  • a system designated AD including the system designated A, AAA, AAB, AAC, AA, AB, or AC wherein the signal processing subsystem is configured to determine a voxel-based model of magnetic nanoparticle distribution in the imaging zone.
  • a system designated AE including the system designated AD wherein the voxel-based model is three-dimensional.
  • a system designated AF including the system designated A, AAA, AAB, AAC, AA, AB, AC, AD, or AE further including at least a second AC driving coil configured to provide an AC magnetic field along the third axis, the AC magnetic field passing through the imaging zone, and comprising apparatus allowing the direction of an alternating field resulting from energizing the first and second AC driving coils to be steered electronically.
  • a system designated AG including the system designated A, AAA, AAB, AAC, AA, AB, AC, AD, AE, or AG wherein the at least one sensing coil is electrically coupled to a center tap node, the center tap node being coupled to a balance coil disposed to be less sensitive to magnetic nanoparticles in the imaging zone than is the sensing coil, and the center tap node is coupled to an input of a differential amplifier; and wherein a first resistor is electrically coupled between a second input of the differential amplifier and across the sensing coil; and a second resistor between the second input of the differential amplifier and across the balance coil; and wherein at least one of the first and second resistors is an adjustable resistor.
  • a system designated AH including the system designated AG wherein the adjustable resistor is automatically adjusted.
  • a method designated B of producing magnetic nanoparticle data includes applying a DC bias magnetic field along a first axis to nanoparticles in a sensing zone;
  • a method designated BA including the method designated B wherein the nanoparticle data comprises magnetic spectroscopy of Brownian motion data.
  • a method designated BB including the method designated B or BA further including determining a voxel-based model of nanoparticle distribution in the sensing zone.
  • a method designated BC including the method designated B, BA, or BB, and further including applying a second AC magnetic field along a third axis to the nanoparticles, the third axis perpendicular to the first axis; and while the DC and second AC magnetic fields are applied, sensing a response from the nanoparticles with a sensing coil oriented to respond primarily to field perturbations along the first axis, while minimizing response to field perturbations along the third axis.
  • a method designated BD including the method designated B, BA, BB, or BC, wherein the nanoparticle data comprises Magnetic Spectroscopy of Brownian motion data
  • a method designated BE including the method designated B, BA, BB, BC, or BD wherein the nanoparticle data comprises magnetic particle imaging data.
  • a method designated BF including the method designated B, BA, BB, BC, BD, or BE wherein the DC magnetic field has strength at least two tenths millitesla.
  • a method designated BG including the method designated BE wherein the DC magnetic field has strength at least two tenths tesla.
  • a method designated BH including the method designated B, BA, BB,
  • the nanoparticle data comprises a signal from magnetic nanoparticles that relax with the Neel relaxation mechanism at a resonant frequency of the nanoparticles.
  • a method designated BI including the method designated B, BA, BB, BC,
  • BD BD, BE, BF, or BG wherein the sensing coils are sensed with a bridge circuit.

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Abstract

La présente invention concerne un système permettant de mesurer des réponses de nanoparticules magnétiques, et qui comporte un champ de polarisation magnétique statique le long d'un premier axe, et des bobines d'attaque à courant alternatif fournissant un champ magnétique à courant alternatif le long d'un second axe perpendiculaire au premier axe, les deux champs traversant une zone d'imagerie. Des bobines de détection sont orientées de sorte à détecter des champs parallèles au premier axe, mais qui ne sont pas parallèles au second axe. Un processeur détermine des réponses de nanoparticules dans la zone d'imagerie vers le champ à courant alternatif. Un autre système présente une polarisation en courant continu sur le premier axe et des bobines d'attaque à courant alternatif fournissant un champ magnétique à courant alternatif le long d'un second axe, un gradient magnétique orienté le long du premier et/ou du second axe, le second axe étant mis en rotation de manière mécanique ou électronique. Le processeur de signal fournit un modèle à base de voxel de distribution de nanoparticules magnétiques dans une zone d'imagerie. Dans certains modes de réalisation, l'aimant statique est un aimant principal d'un système d'imagerie par résonance magnétique.
PCT/US2013/068082 2012-11-01 2013-11-01 Système et appareil d'imagerie par résonance magnétique combinée à une spectroscopie magnétique de mouvement brownien et/ou à une imagerie de nanoparticules magnétiques WO2014071196A1 (fr)

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