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Title:
SYSTEM AND METHOD FOR PROVIDING A ROTATING MAGNETIC FIELD
Document Type and Number:
WIPO Patent Application WO/2006/047580
Kind Code:
A2
Abstract:
Disclosed herein are systems and methods for generating a rotating magnetic field. The rotating magnetic field can be used to obtain rotating-field NMR spectra, such as magic angle spinning spectra, without having to rotate the sample physically. This result allows magic angle spinning NMR to be conducted on biological samples such as live animals, including humans.

Inventors:
Schlueter, Ross (780 Cragmont Avenue, Berkeley, CA, 94708, US)
Budinger, Thomas (966 Euclid, Berkeley, CA, 94708, US)
Application Number:
PCT/US2005/038536
Publication Date:
May 04, 2006
Filing Date:
October 26, 2005
Export Citation:
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Assignee:
Schlueter, Ross (780 Cragmont Avenue, Berkeley, CA, 94708, US)
Budinger, Thomas (966 Euclid, Berkeley, CA, 94708, US)
International Classes:
H02K23/60
Foreign References:
US20030210046A1
US5260657A
Attorney, Agent or Firm:
Hart, Daniel (Knobbe, Martens Olson & Bear, LLP, 14th floor, 2040 Main Stree, Irvine CA, 92614, US)
Download PDF:
Claims:
WE CLAIM:
1. An apparatus for generating an adjustable rotating magnetic field for use in acquiring a NMR spectrum, comprising: a rotating magnetic field generating device adapted to produce a rotating magnetic field; and a stationary magnetic field generating device, the stationary magnetic field generating device adapted to produce a stationary magnetic field at least partially superimposed upon the rotating magnetic field and at a substantially constant nonzero angle relative to the rotating magnetic field.
2. The apparatus of Claim 1 wherein the rotating magnetic field generating device comprises a permanent magnet, an electromagnet, or a combination thereof.
3. The apparatus of Claim 1 wherein the rotating magnetic field generating device is a permanent magnet and the rotating magnetic field generating device produces a rotating magnetic field by physically rotating.
4. The apparatus of Claim 1 wherein the rotating magnetic field generating device is an electromagnet, and the rotating magnetic field generating device produces a rotating magnetic field by electronically switching the electromagnet.
5. The apparatus of Claim 1 wherein the stationary magnetic field generating device comprises an electromagnet.
6. The apparatus of Claim 5 wherein the electromagnet has a stationary magnetic field strength and the stationary magnetic field strength is adjustable.
7. The apparatus of Claim 1 wherein the rotating magnetic field is substantially orthogonal to the stationary magnetic field.
8. The apparatus of Claim 1, further comprising a sample container, the sample container positioned in a region wherein the rotating magnetic field and the stationary magnetic field are superimposed and both the rotating magnetic field and the stationary magnetic field are substantially uniform.
9. An apparatus for generating an adjustable rotating magnetic field for use in acquiring a NMR spectrum, comprising: a solenoid that includes a bore, the solenoid having a longitudinal magnetic axis and the solenoid adapted for generating a substantially uniform stationary magnetic field within at least a portion of the bore; an annular magnet disposed within the bore, the annular magnet adapted for generating a substantially uniform rotating magnetic field around a rotation axis within at least a portion of the bore; and a rotation device coupled to the annular magnet, the rotation device adapted for rotating the rotating magnetic field.
10. The apparatus of Claim 9 wherein the annular magnet comprises at least one electromagnet, and the rotation device is an electronic switching device adapted to rotate the rotating magnetic field.
11. The apparatus of Claim 9 wherein the annular magnet comprises a plurality of magnetic segments.
12. The apparatus of Claim 11 , further comprising one or more magnetic segment adjusters adapted to change position or magnetic field vector of one or more magnetic segments.
13. The apparatus of Claim 9 wherein the longitudinal magnetic axis of the solenoid and the axis of rotation of the rotating magnetic field are substantially parallel.
14. The apparatus of Claim 9 wherein the stationary magnetic field is substantially orthogonal to the rotating magnetic field.
15. The apparatus of Claim 14 wherein the annular magnet comprises a permanent magnet, and the rotation device is a motor coupled to the annular magnet and adapted to rotate the annular magnet around the axis of rotation.
16. The apparatus of Claim 9, further comprising at least one tuner shim coupled to the annular magnet, wherein the tuner shim is adapted to increase uniformity of the rotating magnetic field.
17. The apparatus of Claim 9, further comprising at least one trim coil coupled to the annular magnet, wherein the trim coil is adapted to increase uniformity of the rotating magnetic field.
18. An apparatus for measuring a spinning NMR spectrum from a sample, comprising: a rotating magnetic field generating device that can generate within the sample a rotating magnetic field that rotates around an axis of rotation, the rotating magnetic field having a substantially timeinvariant strength; a stationary magnetic field generating device that can generate within the sample a stationary magnetic field at any one of a variety of adjustable timeinvariant strengths, the stationary magnetic field being substantially parallel to the axis of rotation and having a substantially constant nonzero angle relative to the rotating magnetic field; and an NMR probe adapted to measure the rotating magnetic field NMR spectrum of the sample.
19. The apparatus of Claim 18 wherein the rotating magnetic field and the stationary magnetic field are essentially uniform within the sample.
20. The apparatus of Claim 18 wherein superposition of the rotating magnetic field and the stationary magnetic field produces a resulting magnetic field that rotates at an angle between about 0° and 90° with respect to the stationary magnetic field.
21. The apparatus of Claim 18 wherein superposition of the rotating magnetic field and the stationary magnetic field produces a resulting magnetic field that rotates at an angle of about 54.7° with respect to the stationary magnetic field.
22. The apparatus of Claim 21 wherein the rotating magnetic field NMR spectrum from the sample is a magic angle spinning NMR spectrum measured without rotating the sample.
23. A method of acquiring a spinning NMR spectrum of a sample, comprising: generating a uniform rotating magnetic field within the sample; generating a uniform stationary field within the sample, the uniform stationary field having a nonzero angle with respect to the rotating magnetic field; adjusting the strength of the stationary magnetic field so that superposition of the rotating magnetic field and the stationary magnetic field produces a resulting magnetic field that rotates at a substantially constant angle between about 0° and 90° relative to the stationary magnetic field; and providing an NMR probe in proximity to the sample acquiring the NMR spectrum from the sample.
24. The method of Claim 23 wherein the angle is about 54.7° and the NMR spectrum is a magic angle spinning NMR spectrum.
Description:
SYSTEM AND METHOD FOR PROVIDING A ROTATING MAGNETIC FIELD

BACKGROUND OF THE INVENTION Field of the Invention

[0001] The invention relates to systems and methods for generating rotating magnetic fields. In some embodiments, the rotating magnetic fields may be used to acquire NMR spectra. Description of the Related Art

[0002] Dipole coupling and chemical shift anisotropy in systems containing molecules that are unable to tumble freely and rapidly (e.g., solid state systems or biological systems containing large biomolecules or cellular or tissue material) result in magnetic field anisotropy that obscures the nuclear magnetic resonance (NMR) spectra of such systems due to line broadening. These line broadening effects can be minimized by spinning the sample about an axis that is at an angle with respect to the Z magnetic field axis in an NMR spectrometer, which causes the Z component of the magnetic field due to dipole coupling and chemical shift anisotropy to be zero. This angle is 54.7°, the so called "magic angle," due to the presence of a 1 - 3cos 2 θ term in the dipole coupling and chemical shift anisotropy magnetic field equations. Magic angle spinning (MAS) NMR spectroscopy has been used with success for obtaining spectra of solid state samples. However, spinning of biological samples is not feasible. Spinning of ex vivo tissue at typical 4 to 5 kHz MAS rates can result in damage and component separation due to centrifugal forces during spectrum acquisition. Furthermore, spinning of live animals can be deadly to the animal. Accordingly, there is a need for systems and methods that provide magnetic field rotation through a sample without having to rotate the sample itself.

SUMMARY OF THE INVENTION

[0003] One embodiment disclosed herein includes an apparatus for generating a rotating magnetic field that includes a rotating magnetic field generating device adapted to generate a rotating magnetic field and a stationary magnetic field generating device adapted to generate a stationary magnetic field at a non-zero angle relative to the rotating magnetic field.

[0004] Another embodiment disclosed herein includes an apparatus for generating a rotating magnetic field that includes a solenoid adapted to generate a substantially uniform magnetic field within a volume contained inside the solenoid's bore, an annular permanent magnet disposed within the solenoid's bore, wherein the permanent magnet is adapted to generate a substantially uniform magnetic field within a volume contained inside the permanent magnet's bore, wherein the volume contained inside the solenoid's bore substantially overlaps with the volume contained inside the permanent magnet's bore, and a motor operatively coupled to the

permanent magnet and adapted to rotate the annular permanent magnet within the solenoid. The term "annular" is used herein to mean having an overall shape like an annulus. The term also includes configurations whose overall shape is that of an annulus even though the shape may be discontinuous, i.e., there may be sections missing from what would be considered a continuous annular shape.

[0005] Another embodiment disclosed herein includes an apparatus for measuring a rotating magnetic field NMR spectrum of a sample that includes a rotating magnetic field generating device adapted to generate a rotating magnetic field having a substantially time- invariant strength within a sample volume, a stationary magnetic field generating device adapted to generate a strength-adjustable, time-invariant magnetic field at a non-zero angle relative to the rotating magnetic field within the sample volume, and an NMR probe adapted to measure an NMR spectrum of a sample contained within the sample volume.

[0006] Another embodiment disclosed herein includes a method of obtaining a magic angle spinning NMR spectrum of a sample that includes generating a rotating magnetic field within the sample, generating a stationary magnetic field within the sample at a non-zero angle with respect to the rotating magnetic field, adjusting the strength of the stationary magnetic field such that superposition of the rotating and stationary magnetic fields produces a magnetic field rotating at an angle of about 54.7° with respect to the stationary magnetic filed axis, and obtaining an NMR spectrum of the sample.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007] FIG. IA is a vector diagram of rotating and stationary magnetic fields.

[0008] FIG. IB is a vector diagram of the rotating magnetic field resulting from the superposition of the fields depicted in FIG. IA.

[0009] FIG. 2 is a cross-section of a segmented permanent magnet.

[0010] FIG. 3 is an exploded view of permanent magnet and solenoid system for generating rotating magnetic fields.

[0011] FIG. 4 is a cross-section of the system of FIG. 3.

[0012] FIG. 5 is a flow chart illustrating a method for adjusting the angle of a rotating magnetic field.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0013] One embodiment is a system for providing a rotating magnetic field using multiple magnetic field generating devices. The magnetic fields generated by each magnetic field generating device can be such that superposition of the magnetic fields from all of the magnetic field generating devices produces the desired rotating magnetic field. In one such embodiment, two magnetic field generating devices are used. One of the devices is adapted to generate a rotating magnetic field and the second device generates a stationary magnetic field. In one

embodiment, the two devices can be aligned in such a manner that the fields combine. In one embodiment, the devices are aligned such that the stationary magnetic field is at a substantially constant non-zero angle with respect to the rotating magnetic field. By "substantially constant non¬ zero angle" it is meant that the axis of rotation of the rotating magnetic field is substantially parallel with the stationary magnetic field. In one embodiment, "substantially parallel" is used to mean parallel to within about 500 millionths of a radian. In other embodiments, "substantially parallel" is used to mean parallel to within about 100 millionths, 50 millionths or 20 millionths of a radian.

[0014] Figure IA depicts a vector diagram of the magnetic fields generated by such a device. A stationary magnetic field generating device generates a magnetic field 102. A rotating magnetic field generating device generates a magnetic field 100. The magnetic field 100 rotates about a rotation axis that may be coincident with vector 102 through a cone 101. The term "around a rotation axis" is used interchangeably throughout this disclosure with the more common term "about a rotation axis." These terms are intended to have the same meaning and to avoid confusion with other uses of the word "about.". The stationary magnetic field 102 may be aligned with the rotation axis of the rotating magnetic field 100 such that a substantially constant (non-zero) angle 104 is made between the stationary magnetic field 102 and the rotating magnetic field 100. In one arrangement, "substantially constant angle" is used to mean constant to within about 500 millionths of a radian. In other arrangements, "substantially constant angle" is used to mean constant to within about 100 millionths, 50 millionths or 20 millionths of a radian. In one embodiment, the non-zero angle 104 is about 90° such that the rotating 100 and stationary 102 fields are substantially orthogonal. In such an embodiment, the rotating magnetic field 100 rotates in a plane making the cone 101 a substantially planar circle.

[0015] The resulting magnetic field generated by the superposition of the rotating 100 and stationary 102 fields is depicted in Figure IB. The result is a rotating magnetic field 110 rotating through a cone 112. The cone 112 has a narrower angle than the cone 101 due to the addition of the stationary magnetic field 102 to the rotating magnetic field 100. The angle that the resultant rotating magnetic field 110 makes with respect to its rotation axis will depend on the angle 104 of the initial cone 101 and the relative strengths of the rotating 100 and stationary 102 magnetic fields. In some embodiments, the strengths of the stationary 102 and/or rotating 100 magnetic fields are adjustable such that angle between the rotating magnetic field 110 and the stationary field 102 is adjustable. In one embodiment, the magnetic fields are adjusted such that the angle between the rotating magnetic field 110 and the stationary field 102 is the "magic angle" of about 54.7°.

[0016] The magnetic field generating devices for both the rotating and the stationary magnetic fields may be any suitable device for generating magnetic fields including one or more

permanent magnets or electromagnets. Suitable permanent magnets may include multiple magnet segments so that the resulting field has a desired shape and uniformity. Electromagnets may be constructed using any suitable coil design. In one embodiment, a solenoid is utilized.

[0017] Magnetic field generating devices may be adapted to produce rotating magnetic fields by mechanically rotating a magnetic field generating device that produces a constant magnetic field. For example, a peπnanent magnet, an electromagnetic producing a constant magnetic field, or a combination thereof may be rotated by a motor to produce a rotating magnetic field. In various embodiments, the rotating magnetic field rotates at a rate of at least about 1 Hz, 10 Hz, 50 Hz, 100 Hz, 500 Hz, or 1000 Hz. Alternatively, multiple stationary electromagnets may be driven by an appropriate driving scheme, such as by electronic switching, so that the superposition of the fields produced by the electromagnets is a rotating magnetic field. For example, three orthogonal Helmholtz coils may be dynamically driven so that a rotating magnetic field is produced such as described in Meriles et al., "High-resolution NMR of static samples by rotation of the magnetic field," J. Magnetic Resonance, 169 (2004), 13-18, which is incorporated herein by reference in its entirety.

[0018] In one embodiment, magnetic field generating devices are used that generate substantially uniform magnetic fields within a desired volume, such as a sample volume. By "uniform," it is meant that the magnetic fields are spatially constant to within approximately 500 ppm over the desired volume. In some embodiments, magnetic fields having approximately 100 ppm, 50 ppm, or 20 ppm uniformity are used. When a magnetic field generating device is adapted to produce a rotating magnetic field, substantial uniformity refers to the uniformity of the magnetic field produced by the device prior to rotation (e.g., prior to mechanically rotating the device or electronically rotating the field).

[0019] In one embodiment, magnetic field generating devices are used that generate substantially time-invariant magnetic fields. By a "substantially time-invariant magnetic field," it is meant that the magnetic field strength is substantially constant over a relevant data collection time. In one arrangement, the magnetic field strength is constant during data collection time to within approximately 500 ppm. In other arrangements, the magnetic field strength is constant during data collection time to within approximately 100 ppm, 50 ppm, and or 20 ppm.

[0020] In some embodiments, the magnetic field generating devices are positioned such that the resulting rotating magnetic field is produced in a sample volume in which an NMR spectrum may be detected with a suitable NMR probe. Those of skill in the art will recognize NMR probes and systems suitable for obtaining NMR spectra of samples within the sample volume. In one such embodiment, the magnetic field generating devices produce substantially uniform and time-invariant magnetic fields within the sample.

[0021] In one embodiment, the magnetic field generating device that produces the rotating magnetic field includes a plurality of permanent magnet segments in an annular arrangement. Figure 2 depicts a cross-section of one such annular permanent magnet arrangement consisting of 16 wedge shaped segments 150 defining an opening 152. The dipole directions 154 of each permanent magnet segment 150 may be selected to produce the desired magnetic field shape within the opening 152. For example, the dipoles depicted in Figure 2 generate a substantially uniform transverse magnetic field 156 within the opening 152. The uniformity of the transverse magnetic field 156 is enhanced by using multiple magnet segments 150 with fine-tuned dipole directions. The orientations of each dipole may be such that the magnetic field generated by each segment 150 within the bore 152 is substantially in a single direction, thus producing a uniform lateral magnetic field over a significant volume within the bore 156. This type of segmented annular magnet is described in more detail in Halbach, K., "Design of Permanent Multipole Magnets with Oriented Rare Earth Cobalt Material," Nuclear Instruments and Methods, 169 (1980) 1-10, which is incorporated herein by reference in its entirety.

[0022] Multiple segments can also be used in the longitudinal direction of the annular magnet, i.e., the direction into or out of the page in Figure 2. For example, stacks of arrangements such as the one depicted in Figure 2 may be used in order to provide transverse magnetic field uniformity along the length or long axis of the opening 152 in the annular magnet. In other arrangements some or all of the multiple segments can have different dipole directions that can add together to provide a desired resultant magnetic filed uniformly along the long axis of the opening 152 in the annular magnet.

[0023] If the permanent magnet depicted in Figure 2 is mechanically rotated about the longitudinal axis of the opening 152, the transverse magnetic field 156 will rotate with the magnet. In one embodiment, the uniformity of the resultant magnetic field is enhanced by inserting a magnet yoke sleeve (not shown) inside the opening 152. In one embodiment, magnetic field adjusters can be used to adjust and tune the uniformity of the magnetic fields and field gradients produced by the permanent by adjusting the position and orientation of one or more permanent magnet segments 150. Accordingly, in some embodiments, features are incorporated within the permanent magnet assembly, which allow for adjustability of one or more permanent magnet segments 150. For example, the permanent magnet segments 150 may be held in place by adjustment screws (not shown) that allow their orientation to be selectively adjusted.

[0024] Those of skill in the art will appreciate that by appropriately selecting the magnet segments and dipole directions, a resultant magnetic field may be generated at any angle relative to the long axis of the opening 152. In one embodiment, a transverse magnetic field is generated that is substantially orthogonal to the long axis of the opening 152. In one embodiment, the magnet segments consist of NdFeB magnets. However, any suitable magnetic material may be

used. In another embodiment, the magnet segments consist of electromagnets. In another embodiment, the transverse magnetic field is generated by only one electromagnet. In yet another embodiment, the transverse magnetic field is generated by a small number of electromagnets or by a combination of permanent magnets and electromagnets. In one embodiment, each segment is sized so that the entire assembly has an outer diameter of 8 cm with a 5 cm diameter opening 152, however, any suitable dimensions may be used. The size of the sample to be examined may detennine the size of the opening 152 and the size of the entire apparatus that are most useful. In one embodiment, four stacks of segments are used, and the magnet has an overall length of about 10 cm, however, any suitable number of stacks may be used. In one embodiment, the field strength of the substantially transverse magnetic field 156 is approximately 0.5 T (tesla).

[0025] Figure 3 depicts an exploded view of a system utilizing a permanent magnet such as depicted in Figure 2. The permanent magnet 200 consists of four stacks of permanent magnet segments 202 arranged in the annular arrangement depicted in Figure 2. A transverse magnetic field 204 is generated within the opening 206 in the magnet 200. The magnet 200 is coupled via a shaft 208 to a motor 210. The motor 210 may be used to rotate the magnet 200 and thus the magnetic field 204 in the opening 206. The magnet 200 may be inserted into a bore 212 of an electromagnet or solenoid 214. The solenoid 214 may contain wire coils configured to generate a magnetic field 216 substantially parallel to the axes of the opening 206 and the bore 212. In some embodiments, the solenoid 214 is adapted to generate a substantially uniform magnetic field along the axis of bore 212. In some embodiments, the solenoid 214 is also adapted to provide a substantially time-invariant magnetic field. This time-invariance can be accomplished by providing a stable power supply to supply stable current to the solenoid 214. In yet other embodiments, a permanent magnet that has an approximate solenoid shape can take the place of the solenoid 214.

[0026] When the rotating magnet 200 is inserted into the bore 212, the superposition of the rotating transverse magnetic field 204 and the stationary axial magnetic field 216 yields a resulting rotating magnetic field 230 within the opening 206. The resulting magnetic field 230 has an angle between 0° and 90° with respect to the stationary field 216. The angle of the resulting magnetic field 230 depends on the relative strengths of the fields 204 and 216. In one embodiment, current driven through the solenoid 214 may be adjusted to produce a variety of axial magnetic field strengths 216, thus allowing the angle of the resulting magnetic field 230 to be tuned to a desired angle. For example, the desired angle may be the "magic angle," 54.7°, which can be used to obtain magic angle spinning (MAS) NMR spectra. In one embodiment, the strength of the magnetic field 216 generated by the solenoid 214 is between about 0.1 and 1.0 T. A sample (e.g., an animal 218) may be inserted into a sample holder 220 for insertion into the opening 206 of the permanent magnet 200. The sample holder 220 may be coupled to a rod 222 to allow for insertion

and removal of the sample holder 220 into the opening 206. For NMR spectroscopy applications, a suitable probe coil (not shown) may be included such that it surrounds the sample holder 220.

[0027] In some embodiments, the uniformity of the rotating transverse magnetic field 204 can be increased using one or more tuning devices such as permanent magnet tuner shims (not shown) that rotate in synchronization with the rotating magnet 200. The tuner shims may be adjusted to provide a desired magnetic field or field gradient correction. Alternative tuning devices such as one or more electromagnetic trim coils (not shown) may be used to increase the uniformity of the field or field gradient in the rotating magnetic field 204. In some arrangements, both permanent magnet tuner shims and electromagnetic trim coils can be used.

[0028] Figure 4 depicts a cross-sectional view of the assembled apparatus depicted in Figure 3. The permanent magnet segments 202 and the solenoid 214 may be contained within an iron yoke 250 to increase the flux of the magnetic fields. An aperture 252 may be made in the yoke 250 so that the shaft 208 can extend to the motor 210. Another aperture 254 may be provided for introducing a sample holder 220. Removable plugs 256 may be provided to cover a significant part of the aperture 254 after insertion of the sample holder 220. For NMR spectroscopy applications, a suitable NMR probe (not shown) may also be included. In some embodiments, the sizes of the sample holder 220 and the entire apparatus are adapted to hold an animal such as a mouse 208 as depicted in Figure 4. In some embodiments, the sample holder 220 is adapted to hold ex vivo biological samples such as cellular or tissue matter. Such a system can be used to analyze NMR spectra of cells, living tissues, and organs. For example, NMR spectra of membrane phospholipids in in vivo brain tissue can be analyzed to determine if neurodegeneration is present. Accordingly, the apparatus depicted in Figure 4 can be used to obtain magic angle spinning NMR spectra or magic angle spinning (MAS) NMR spectra of samples that cannot themselves be spun without changing or damaging the samples. The apparatus shown in Figure 4 can be used also to obtain spinning NMR or MAS NMR spectra for any other biological or non-biological sample of interest.

[0029] In some embodiments, a method is provided for tuning an apparatus, such as described above, to obtain a resulting rotating magnetic field rotating at a desired angle. The resulting field may then be used to obtain a rotating magnetic field NMR spectrum. Such a method is depicted in the flow chart of Figure 5. First, at block 250, a rotating magnetic field is generated. Next at block 252 a stationary magnetic field is generated such that the superposition of the stationary magnetic field and the rotating magnetic field produces a resulting rotating magnetic field. Then at block 254 the strength of the stationary magnetic field is adjusted until the resulting rotating magnetic field is rotating at a desired angle. In one embodiment, the strength of the stationary magnetic field is adjusted to produce a resulting rotating magnetic field at an angle of about 54.7°. In some embodiments, other angles between about 0° and 90° are chosen. Finally, at block 256, a spinning NMR spectrum of a sample within the rotating magnetic field is obtained. In

the case where the resulting rotating magnetic field is at an angle of about 54.7°, a MAS NMR spectrum is obtained.

[0030] Although the invention has been described with reference to embodiments and examples, it should be understood that numerous and various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.