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WO2003016951A1 - Procede et appareil destines a la spectroscopie par resonance magnetique nucleaire ex situ haute resolution - Google Patents

Procede et appareil destines a la spectroscopie par resonance magnetique nucleaire ex situ haute resolution Download PDF

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Publication number
WO2003016951A1
WO2003016951A1 PCT/US2002/025802 US0225802W WO03016951A1 WO 2003016951 A1 WO2003016951 A1 WO 2003016951A1 US 0225802 W US0225802 W US 0225802W WO 03016951 A1 WO03016951 A1 WO 03016951A1
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Prior art keywords
pulse
recited
sample
pulses
composite
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PCT/US2002/025802
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English (en)
Inventor
Alexander Pines
Carlos A. Meriles
Henrike Heise
Dimitrios Sakellariou
Adam Moule
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The Regents Of The University Of California
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Priority claimed from PCT/US2002/011049 external-priority patent/WO2002082116A1/fr
Application filed by The Regents Of The University Of California filed Critical The Regents Of The University Of California
Publication of WO2003016951A1 publication Critical patent/WO2003016951A1/fr

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    • 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
    • G01R33/483—NMR imaging systems with selection of signals or spectra from particular regions of the volume, e.g. in vivo spectroscopy
    • G01R33/485—NMR imaging systems with selection of signals or spectra from particular regions of the volume, e.g. in vivo spectroscopy based on chemical shift information [CSI] or spectroscopic imaging, e.g. to acquire the spatial distributions of metabolites
    • 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]
    • G01R33/46—NMR spectroscopy
    • 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]
    • G01R33/445—MR involving a non-standard magnetic field B0, e.g. of low magnitude as in the earth's magnetic field or in nanoTesla spectroscopy, comprising a polarizing magnetic field for pre-polarisation, B0 with a temporal variation of its magnitude or direction such as field cycling of B0 or rotation of the direction of B0, or spatially inhomogeneous B0 like in fringe-field MR or in stray-field 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]
    • G01R33/46—NMR spectroscopy
    • G01R33/4633—Sequences for multi-dimensional NMR

Definitions

  • the present invention pertains generally to high-resolution molecular spectroscopy and imaging devices and methods, and more particularly to an apparatus and method for ex-situ NMR spectroscopy and imaging.
  • Nuclear magnetic resonance spectroscopy is a sensitive tool for studying the physical, chemical and biological properties of matter at a molecular level.
  • One- dimensional and two-dimensional NMR imaging techniques are routinely used by chemists to determine the structure of simple and complicated molecules and such techniques are replacing traditional x-ray crystallography as the preferred method for determining smaller protein structures of 25 kDa or less.
  • the phenomenon called nuclear magnetic resonance (NMR) occurs when the nuclei of certain atoms are placed in a static magnetic field.
  • the nuclei of the atoms of elements with an odd atomic number possess spin (/) and have a nuclear magnetic moment.
  • the positively charged nucleus spins the moving charge creates a magnetic moment.
  • nuclei behave like magnets, the nuclei have a lower energy state when aligned with the applied magnetic field than when the nuclei are opposed to the magnetic field. In an applied magnetic field, the axis of rotation will precess around the magnetic field.
  • a nucleus in the low energy state may transition to a high-energy state by the absorption of a photon that has an energy that is exactly equal to the energy difference between the two energy states.
  • the energy of a photon is related to its frequency by Plank's constant.
  • the frequency of the photon and the equivalent frequency of precession are referred to as the resonance or Larmor frequency.
  • the nuclei can absorb and reemit energy at characteristic radiofrequencies (if). Furthermore, energy will be absorbed by the same nuclear species at slightly different frequencies depending on the molecular environment of the nucleus of a particular atom.
  • the precise resonant frequency of the nuclear species is dependent on the magnetic field at the nucleus that will vary depending on the types of nuclei and the bonds in the molecule involving the nuclei.
  • This characteristic variance in the resonance frequency depending on the chemical environment of the nucleus is called the chemical shift (S) and can be used to deduce the patterns of atomic bonding in the molecule.
  • Chemical shift is the frequency difference between the observed resonance and a resonance from a standard compound and is usually reported in parts per million (ppm) of the mean resonance frequency.
  • ppm parts per million
  • B 0 and the net magnetization vector (M z ) reside on the z-axis at equilibrium.
  • the applied radio frequency (rf) pulse has a stationary field vector in the xy plane within this reference frame with a direction governed by the phase of the radio frequency.
  • the application of an rf pulse along the -axis rotates the nuclear magnetization vector towards the y-axis at an angle that is proportional to the duration and intensity of the rf pulse.
  • a pulse that is of sufficient duration and intensity to rotate the magnetization vector clockwise 90 degrees about the -axis is termed a 90° or ⁇ /2-pulse.
  • a 180° pulse will rotate the magnetization vector, 180 degrees and is called a ⁇ pulse.
  • the populations of nuclei relax to equilibrium at an exponential rate after the termination of the pulse.
  • the magnetization vector Once the magnetization vector is placed onto the y-axis, it rotates in the xy plane at a resonant frequency ultimately decaying back to the z-axis emitting //radiation over time. This is typically the point of data acquisition (Acq.).
  • a receiver coil resonant at the Larmor frequency generally located along the -axis, can detect this rotation called the free induction decay (FID).
  • FID free induction decay
  • Fourier transformation of the FID provides the NMR spectrum.
  • One time constant used to describe this return to equilibrium is called the longitudinal or spin lattice relaxation time (Ti). The time (Ti) will vary as a function of the magnetic field strength.
  • T 2 spin-spin relaxation time
  • M xy transverse magnetization
  • a spin-echo pulse sequence is normally required to measure T ⁇ .
  • the typical pulse-sequence consists of the application of a 90° pulse, which results in the rotation of the magnetization to the xy plane, followed by a 180° pulse that allows the magnetization to partially rephase producing a non-dephased signal called an echo.
  • Correlation Spectroscopy is a useful technique for determining the signals that may arise from nuclei coupled by a coupling interaction such as a scalar J coupling or a dipole coupling as well as nuclei in close proximity to one another.
  • COSY pulse sequences usually include two 90° pulses in succession and gives a signal that varies depending on the time between the application of the two pulses.
  • Nuclear Overhauser Effect Spectroscopy (NOESY) and Rotational Nuclear Overhauser Effect Spectroscopy (ROESY) have pulse sequences that are used to determine the signal produced from nuclei that are not connected by chemical bonds but are closely oriented in space in the subject molecule.
  • NMR nuclear magnetic resonance
  • the present invention provides an apparatus and methods for NMR spectroscopy and imaging of external samples by refocusing inhomogeneities through the use of correlated, composite z-rotation pulses, producing resolved NMR spectra of liquid and solid samples.
  • the observation of chemical shifts is regained through the use of multiple-pulse sequences of trains of composite z- rotation pulses inducing nutation echoes over a region of matched rf and static field gradients.
  • the pulse series ⁇ /2)_ y ( ⁇ (r)) x ⁇ /2) y with the constant rotation composite ⁇ /2-pulses tipping the spins back and forth between the xy and yz planes make a position-dependent phase correction possible.
  • a ( ⁇ r)) x pulse applied over the proper time period gives rise to an overall phase shift that exactly reverses the relative positions of (chemically equivalent) fast and slow spins and induces a subsequent nutation echo. Because the same phase shift equally affects nuclei with different chemical shifts, the echo amplitude fully preserves the accumulated phase differences between chemically inequivalent spins.
  • the initial dephasing induced by the pulse ⁇ (r)) x is refocused during the free evolution (or dwell time) period. A one- point acquisition takes place at the nutation echo maximum, just before the next ( ⁇ /2) pulse.
  • a phase alternation is performed in order to compensate for undesired evolution during the rf irradiation.
  • the entire / sequence is repeated, with stroboscopic detection providing the inhomogeneity-free free induction decay.
  • the constant phase shift ⁇ ° ⁇ ⁇ remaining at each step of the train can be corrected by sequentially adjusting the phase of the rf pulses or by a shift of the reference frequency in the measured spectrum following data processing.
  • the static field ( ⁇ 0 ) gradient and the rf field (Bi) gradient are matched along the sample (x) by a composite ⁇ ' pulse sequence that functionally depends from the nutation amplitude oo .
  • a composite ⁇ ' pulse sequence that functionally depends from the nutation amplitude oo .
  • full passage adiabatic pulses are consecutively applied.
  • a probe head having magnets creating a characteristic saddle point in the field and with at least one switchable coil is provided.
  • the sample is placed one side of the saddle point with the coils switched off.
  • One preferred pulse sequence begins with an excitation pulse followed by a short period of evolution.
  • the coils are then switched on so that the saddle point is displaced, and the sample lies now on the other side of the saddle point where the field has a complimentary profile (as a simple example: the gradient has an opposite sign). If necessary, the rf frequency can be shifted so that the spins of the sample continue to resonate.
  • a data point acquisition is made after a gradient cycle.
  • An object of the invention is to provide an apparatus and method for high- resolution ex-situ NMR spectroscopy. Another object of the invention is to provide a method of observing chemical shift information in an inhomogeneous magnetic field with a pulse sequence of correlated, composite z-rotation pulses that produce resolved NMR spectra of liquid samples. Another object of the invention is to provide a sequence of radio frequency pulses that have matched radio frequency and static field inhomogeneities to produce an echo that preserves the chemical shift information.
  • Yet another object of the invention is provide a pulse sequence comprising multiple adiabatic passages. Another object of the invention is to provide a method for reducing in-situ residual NMR line width due to static field inhomogeneities.
  • FIG. 1 is a schematic representation of a NMR probe head with the sample outside of the core of the probe head in inhomogeneous static and radio frequency fields.
  • FIG. 2A is a conventional one-pulse NMR spectrum of trans-2-pentenal.
  • FIG. 2B is a one-pulse NMR spectrum of trans-2-pentenal in the presence of a linear static field gradient of 0.12 mT/cm along the sample axis.
  • FIG. 2C is an NMR proton spectrum of trans-2-pentenal obtained after the application of a refocusing sequence according to the present invention as shown in FIG. 3B.
  • FIG. 3A is a rotating-frame diagram describing the spin evolution under a single sequence of z-rotation composite pulses according to the present invention at different positions along the sample and depicting spins with the same chemical shift for clarity.
  • FIG. 3B is a is a rotating-frame diagram describing the spin evolution under a train of single sequences of z-rotation composite pulses according to the present invention at different positions along the sample and depicting spins with the same chemical shift for clarity.
  • FIG. 4A is correlation spectrum in absolute value mode of a trans-2-pentenal obtained through the use of the train of pulse sequences shown in FIG. 4B.
  • FIG. 4B is an adapted COSY sequence under conditions identical to those of FIG. 2B and providing the spectrum of FIG. 4B.
  • FIG. 5 is a two-dimensional H, C HETCOR NMR correlation spectrum of ethanol in a static field gradient using pulse sequences according to the present invention.
  • FIG. 6 is an alternative embodiment of a probe head with permanent magnets and switchable coil providing a variable saddle point.
  • FIG. 7 is a schematic diagram of one pulse sequence using a variable saddle point according to one embodiment of the present invention wherein the sample experiences a reversed static field gradient at the saddle point during the sequence.
  • FIG. 8 is a schematic diagram of an alternative pulse sequence using a variable saddle point according to one embodiment of the present invention when the static field gradient cannot be reversed.
  • FIG. 9A is a graph of typical rf and static field profiles along the sample with the rf-profile shown as a solid line.
  • FIG. 9B is a graph of the defocusing angle as a function of the nutation amplitude with the actual response shown as a solid line and the desired response shown as a dashed line.
  • FIG. 9C is a graph of 360° pulse as a function of nutation amplitude.
  • FIG. 9D is a graph of a composite pulse profile as a function of nutation amplitude that ultimately provides for the desired spatial response.
  • FIG. 10A is a graph of a standard one-pulse NMR spectrum of pure ethanol is shown as a reference.
  • FIG. 10B is a graph of a standard one-pulse spectrum in the presence of a linear Bo gradient showing the line broadening caused by the intrinsic inhomogeneity of the external magnetic field.
  • FIG. 10C is a graph of the spectra of FIG. 10B after the sample was exposed to a pulse train to detect the chemical shift.
  • FIG. 10D shows a progressively higher field gradient pointing along the chain.
  • FIG. 10E is a graph of the spectra of the calculated response when a refocusing pulse train is applied according to the present invention.
  • FIG. 11 A is a spectrum of a nutation echo from an acetone/benzene mixture induced after a single pulse excitation.
  • FIG. 11 B is a Fourier transformation of FIG. 11 A showing an rf dependent phase shift.
  • FIG. 11C shows a free induction signal immediately after an excitation pulse and subsequent free evolution periods after each double passage of the pulse train. Echo centers are shown as open circles.
  • FIG. 11 D is a Fourier transformation of the signal shown in FIG. 11 C.
  • DETAILED DESCRIPTION OF THE INVENTION Referring more specifically to the drawings, for illustrative purposes the present invention is embodied in the apparatus and methods generally shown in FIG. 1 through FIG. 11 D. It will be appreciated that the apparatus may vary as to configuration and as to details of the components, and that the method may vary as to the specific steps and sequence, without departing from the basic concepts as disclosed herein.
  • the present invention concerns a method of overcoming the presence of strong radio frequency and static field inhomogeneities that are located outside or inside the bore of a homogeneous magnet by using static and excitation field gradients at different points in the sample to refocus the inhomogeneities thereby allowing the undistorted analysis of the free induction decay (FID) of the ex-situ sample. Additionally, the capability of recording undistorted free induction decay from an ex-situ sample allows the extension of the present methods to multidimensional NMR spectroscopy.
  • the method generally includes an adaptation of nutation echoes, preferably in the presence of matched inhomogeneous static and radio frequency fields to provide spectra. Chemical shift information is regained through the use of sequences of multiple correlated, composite z-rotation pulses to resolve the NMR spectra.
  • NMR conditions was compared with that of a sample placed outside of the bore of the magnet and then subjected to sequences of correlated z-rotation pulses to resolve the NMR spectra.
  • FIG. 1 A schematic representation of one embodiment of a probe head 10 is shown in FIG. 1.
  • a static B 0 field gradient was produced by driving a current into the x-gradient coils of the probe head.
  • the sample 12 may then be attached outside the rf-coil 14.
  • a single solenoid serves to irradiate and detect the NMR proton signal from a sample of trans-2-pentenal contained in a glass tube inside the bore of a super-conducting magnet 16.
  • the sample is placed completely outside the solenoid central cavity when a static field gradient is applied.
  • An imaging coil set is used to generate a linear gradient of the static field along the solenoid axis.
  • the conventional 1 H (proton) NMR spectra of trans- 2-pentenal in a tube of 5 mm diameter and 2 cm length is shown as a standard for purposes of comparison. It can be seen that the "normal" one-pulse free induction decay (FID) proton NMR spectrum in a rather homogeneous B 0 field, exhibits five resolved lines at 9.5, 7.0, 6.1 , 2.4 and 1.1 parts per million (ppm) with relative intensities of 1 :1 :1 :2:3 that correspond, respectively, to the formylic, the two olefinic, and the two aliphatic protons. The linewidths (-60 Hz) come essentially from the intrinsic residual inhomogeneity of the magnet.
  • FID one-pulse free induction decay
  • FIG. 2B the 1 H (proton) NMR spectra of trans-2-pentenal in a tube of 5 mm diameter and 2 cm length outside of the bore of the magnet is shown.
  • the spectrum of trans-2-pentenal 64 scans, 2.2 kHz full-width at half maximum line broadening) in the presence of a linear static field gradient of 0.12 mT/cm ( ⁇ 5 kHz/cm) along the sample axis is shown.
  • An exponential apodization of 50 Hz was applied to enhance the signal to noise ratio.
  • FIG. 2C it can be seen that the spectral resolution can be recovered and full chemical shift information can be obtained in a sample subjected to strong static field inhomogeneity and excited by a surface coil.
  • the spectrum shown in FIG. 2C was obtained by the use of an appropriately designed train of composite z-rotation pulses according to the present invention in the presence of the same field inhomogeneity as shown in FIG. 2B.
  • trains of z-rotation pulses inducing nutation echoes over a region of matched rf and static field gradients revives the spectroscopic resolution of all five proton NMR lines seen in the standard spectra shown in FIG. 2A.
  • the proton spectrum was obtained using the refocusing sequence seen schematically in FIG. 4B after 64 scans, in the presence of the same field gradient that produced FIG. 2B.
  • Constant-rotation composite ⁇ l2 -pulses were implemented by the series (2 ⁇ )g . 2 (4 ⁇ ) 2 g ⁇ . 5 (27)97.2(7)0 where ⁇ represents a nominal ⁇ /2-pulse.
  • the total duration was 117 ⁇ s;
  • x ⁇ the length of the ⁇ -pulse, was 23 ⁇ s for an evolution time ⁇ d w set at 250 ⁇ s.
  • the frequency units were shifted so that the position of the most intense peak matched the corresponding peak observed in standard reference shown in FIG.
  • ⁇ (r) is the strength of the /f-field at point r
  • ⁇ p the duration of the pulse.
  • the resulting spectrum contains the full chemical shift information.
  • This sequence induces an overall frequency shift of ⁇ x -z p l ⁇ which can be corrected either during the pulse sequence by a phase shift at each step or by numerical correction while processing the FID.
  • a refinement of this pulse sequence involves the symmetrization ⁇ 90% r 90% ⁇ _ x 90 ⁇ 90 ) , which corrects for the evolution during the ⁇ pulses.
  • FIG. 3A The basic mechanism underlying the use of composite z-rotation pulses can be visualized by means of a classical vector diagram in the rotating frame as seen in FIG. 3A illustrating spin evolution under a sequence of z-rotation composite pulses.
  • FIG. 3A only depicts nuclear spins with the same chemical shift but spread over different positions along the sample. "Faster” or “slower” spins, located closer to or away from the excitation coil, have been labeled by a small f(s) in FIG. 3A.
  • different Larmor frequencies ⁇ Q (r) throughout the sample give rise to progressive dephasing during a free-evolution period.
  • phase differences accumulated during the evolution and arising from the chemical shifts and scalar J couplings are maintained.
  • FIG. 3B A generalization of the principle that combines the repeated application of composite z-rotation pulses with stroboscopic acquisition enables the direct detection of resolved NMR spectra in inhomogeneous fields is shown schematically in FIG. 3B.
  • Point-by-point acquisition with a sequential increment of the ⁇ -pulse length is contemplated as well.
  • incomplete refocusing due to molecular diffusion is best suppressed by keeping the free evolution time sufficiently short.
  • the magnetization is initially dephased by a ⁇ -pulse of duration ⁇ ⁇ prior to the free evolution period ⁇ dw .
  • a nutation echo takes place and a single point acquisition is made.
  • ⁇ /2-pulse tips the magnetization back onto zy plane and the cycle starts again.
  • the phase shift introduced at each step of the train can be easily corrected by properly changing the phase of the synthesizer or by a frequency shift of the whole spectrum after processing the FID. In either case, this procedure provides a spectrum that, despite strong field inhomogeneities, still contains the full chemical shift information of the sample.
  • FIG. 4A shows a two-dimensional (2D) correlation spectrum (absolute value mode) of trans-2-pentenal that was obtained through an adapted COSY sequence under conditions identical to those of FIG. 2B.
  • the adapted COSY sequence is shown schematically in FIG. 4B.
  • the evolution period is made insensitive to field inhomogeneities by the use of a pulse ( ⁇ (r)) ⁇ . before the standard ⁇ /2) excitation pulse.
  • the duration of ⁇ c( ⁇ r)) x is sequentially incremented in a manner proportional to .
  • the ratio is adjusted so that the next ⁇ /2) mixing pulse occurs synchronously with the nutation echo.
  • the detection is made stroboscopically in a way similar to that of FIG. 3C.
  • a composite z- pulse is applied and the dephasing due to inhomogeneities is reversed.
  • a single point acquisition takes place at the expected nutation echo time between the pulses of the train. All diagonal peaks as well as most of the cross peaks for J-coupled protons are regained (a higher level contour for peaks belonging to aliphatic protons has been used to improve resolution).
  • the number of increments for was 64 in steps of 250 ⁇ s in the example shown. This was also the value assigned to ⁇ dw ensuring the same bandwidth for both dimensions.
  • the number of scans for each evolution time was 8. Thus, in FIG. 4A, cross peaks indicating J-coupled proton spins are still recognizable even though the field inhomogeneity is sufficient to completely erase any spectroscopic information.
  • EXAMPLE 3 Similarly, as seen in FIG. 5, a first two-dimensional H,C HETCOR NMR correlation spectrum of ethanol in a static field gradient was obtained.
  • a linear static field gradient of 0.24 mT/cm ( 10 kHz/cm) along the sample axis spreads the Larmor frequencies in the proton dimension over a range of 75 ppm, in the carbon dimension over a range of 180 ppm, and absolutely no relevant spectroscopic information can be recorded with a standard experiment.
  • the number of scans for each evolution time was 128.
  • the refocusing HETCOR sequence was similar to the COSY sequence displayed in FIG. 4A, with direct polarization on the protons and stroboscopic detection of the carbon magnetization.
  • Probe head 20 has an antenna 22 and three permanent magnets 24 that collectively generate a static magnetic field whose spatial dependence exhibits a saddle point 26. Due to the smooth variation of the static magnetic field, the on- resonant detection is usually made at the saddle point 26.
  • the location of the saddle point 26 depends on the relative positions and intensities of the magnets 24, and, to some extent, can be controlled by adding solenoids at proper positions. Accordingly, a probe head with a variable saddle point may be provided.
  • Step 1 of the sequence the rf frequency is tuned so that on-resonance spins lie on the surface and then, an inhomogeneity free excitation pulse is applied.
  • Step 2 the coils 28 are switched on so that the saddle point 26 is displaced deeper towards the sample in Step 2.
  • the frequency is reset so that spins located on the surface of the sample are still on resonance.
  • This gradient train can be combined with the former rf-pulse sequence now used as a shim to properly "shape" the effective gradients affecting the spin evolution at each step of the sequence. It will be further understood that by simply extending the length of the first free evolution period, a one-dimensional chemical shift resolved image is possible.
  • FIG. 8 one possible sequence for use when the field gradient cannot be reversed by the use of a saddle point is schematically illustrated.
  • spectroscopic information can still be obtained if a field cycle is applied that affects the ratio between the field and the gradient.
  • a field cycle is applied that affects the ratio between the field and the gradient.
  • a constant rotation ⁇ pulse is then applied and the gradient is changed and, if necessary, the reference frequency is readjusted).
  • a free evolution t 2 over a different (and properly selected) time period takes place that refocus all static field inhomogeneities.
  • phase differences due to chemical shift are not completely erased.
  • a new ⁇ pulse is applied and a single point acquisition is made whose amplitude and phase represent the chemical shift evolved over an effective period proportional to the difference t 2 -t ⁇ .
  • FIG. 9A shows the static field (B 0 ) gradient, shown in the solid line and the rf field (B-i) gradient, shown in dashed lines, are mismatched along the sample (x). If a plain ⁇ pulse is applied refocus the magnetization, those spins located on the sample where the gradients are mismatched will experience an //gradient larger than expected and the refocusing will be imperfect as seen in FIG. 9B.
  • FIG. 9B shows the defocusing angle ⁇ as a function ⁇ i and the actual response is shown in solid lines while the desired response is shown in dashed lines.
  • the noted refocusing errors may be overcome by the application of a pulse with a nominal value of 360°, labeled as ⁇ in FIG. 9C, immediately after the ⁇ pulse if the pulse dependence on ⁇ i is properly designed.
  • the composite pulse ⁇ ' i.e. ( ⁇ + ⁇ ) in combination with the previously known //profile provides the desired spatial response.
  • the modified performance of the refocusing composite pulse is shown in FIG. 9D and it can be seen that the desired and effective responses are matched. In this setting there is no need to separate corrective 360° pulses from the plain ⁇ pulse.
  • integrated composite ⁇ pulses with more involved ⁇ i dependencies are also possible.
  • the same principle can be applied to the mobile saddle points sequence as well. Corrective spatially dependent phase shifts can be applied during the refocusing period in order to improve the effective matching on both sides of the saddle point.
  • pulse schemes based on variable rotation composite pulses can be used to perform z-rotations that are proportional to the rf-inhomogeneities.
  • Radio- frequency inhomogeneity may be exploited through a pulse scheme to provide a less demanding duty cycle than with constant rotation ⁇ /2 composite pulses.
  • One way to achieve this is through the use of composite radio-frequency pulses that have the net effect of a negative sign rotation of the magnetization around the z-axis of the rotating reading frame, which compensates for the development of the magnetization under the influence of the inhomogeneous magnetic field.
  • the rotation of in-plane magnetization about an angle ⁇ around the z-axis can be achieved with the following composite pulse:
  • P z ( ⁇ ) P y ( ⁇ /2) R x ( ⁇ ) P.y ( ⁇ l2)
  • R a ( ⁇ ) and P a ( ⁇ ) respectively represent an ordinary square pulse and a composite pulse around the a axis of the flip angle ⁇ .
  • the P y ( ⁇ l2) and P -y ( ⁇ /2) pulses are constant rotation composite ⁇ /2 pulses which ideally compensate for the //and static magnetic field inhomogeneities, while R x ( ⁇ ) ideally depends only upon Bi (r). Inversion pulses induce inversion of the z magnetization over a wide range of rf and/or offset imperfections.
  • An effective inversion pulse can be visualized as a series of ⁇ rotations occurring around a wide distribution of axes on the xy plane.
  • a spatially variable phase shift can be attained if a first ⁇ pulse is linked with a second inversion pulse displaying a new set of axes.
  • a first ⁇ pulse is linked with a second inversion pulse displaying a new set of axes.
  • the pulse behaves as a ⁇ rotation about an axis shifted from the nominal axis by an amount proportional to the //variation.
  • the sign of the phase shift depends on the relative phases within the composite ⁇ pulse. Accordingly, it can be seen that a variable phase shift on spins subjected to an inhomogeneous //field can be created from the following pulse:
  • a whole set of compensated pulses having different features can be devised with a z-rotation pulse comprising a combination of variable rotation inversion pulses.
  • a z-rotation pulse comprising a combination of variable rotation inversion pulses.
  • FIG 10A a standard one-pulse NMR spectrum of pure ethanol is shown as a reference. This experiment was conducted in a super-widebore imaging magnet and NMR spectrometer operating at a proton frequency of 179.12 MHz and an imaging probe head with three perpendicular gradient coils. A variable gradient of d ⁇ o/dx of 6.5 to 50 kHz/cm along the x-axis was applied.
  • FIG. 10B the standard one-pulse spectra in the presence of a linear B 0 gradient showing the line broadening caused by the intrinsic inhomogeneity of the external magnetic field. It can be seen that the spread in Larmor frequency ranges from 40 to 350 ppm obscuring the chemical shift.
  • the sample was exposed to a pulse train to detect the chemical shift as seen in FIG. 10C.
  • a variable phase shift was created through a pulse series composed of an integral number of z rotation P z pulses.
  • the dwell time was set to that a nutation echo is formed at the end of the period.
  • the amplitude of the echo was modulated with the chemical shift. It can be seen that the stroboscopic detection of the refocused echo points gives an inhomogeneity free FID.
  • FIG. 10D and FIG. 10E numerical simulations were performed using stronger rf amplitudes and field gradients than produced the data presented in FIG. 10B and FIG. 10C.
  • An ensemble of 200 "molecules" (1200 spins 1/2) were placed in a one dimensional arrangement under constant linear B 0 and rf gradients. The latter was set so that the last molecule in the chain experiences no rf gradient at all.
  • the spectrum is has three lines spread over 6 ppm and has a linewidth of 0.3 ppm, introduced by a phenomenological T 2 (5ms) damping in the FID.
  • the progressively higher field gradient pointing along the chain is shown in FIG. 10D.
  • the calculated response when the refocusing pulse train is applied is shown in FIG. 10E.
  • the nominal //amplitude of 83 kHz was used for spins located closest to the coil. It can be seen that the chemical shift information is left unaltered in the presence of very high gradients in the order of 170 kHz/cm.
  • EXAMPLE 7 An alternative pulse scheme according to the present invention is based on the use of multiple adiabatic passages that manipulate the pulse of the excitation over a large bandwidth of radio frequencies and amplitudes.
  • One pulse for example, is an adiabatic double passage pulse where the second passage is performed using an amplitude that is one half of the amplitude of the first passage.
  • an essentially linear phase roll is observed that is proportional to the rf amplitude at each point of the sample.
  • the resulting excitation profile is independent of the frequency of the excited spin, providing that the adiabatic condition is fulfilled throughout each pulse.
  • phase shaping may be achieved by modifying the characteristics of the rf pulse.
  • an adiabatic double passage sweeping through asymmetric limits, produces a non-linear phase encoding that is dependent on the //amplitude and the frequency of each spin.
  • the excitation profile can be adapted to any physical setting through the control over these parameters.
  • Multiple adiabatic pulses may be used in ex-situ NMR, Magnetic Resonance Imaging, Optical Spectroscopy, Quantum Computing and similar applications.
  • radio frequency pulses have been described as an example, it will be understood that the procedure can be utilized with magnetic field (dc) pulses as well.
  • FIG. 11A through FIG. 11 D the results of tests using two full passage adiabatic pulses is shown.
  • the embodiment shown is particularly suited for use with wide open scanners or, alternatively, one-sided magnets able to provide spectroscopic information would be extremely useful in areas ranging from health, food technology, geology and other industrial applications.
  • FIG. 11 A shows the FID of an acetone/benzene mixture recorded in the presence of a 20 kHz cm field gradient.
  • a single hard 90° pulse (10 ⁇ s hard ⁇ /2, 20 kHz maximum rf) was used to provide initial excitation, and a weak but long adiabatic double passage was applied immediately after to encode the phase of the sample magnetization.
  • Each full passage was a 20 ms hyperbolic secant pulse and the amplitude ratio between the first and the second passage was 0.5.
  • the peak rf power was 3 kHz whereas the static field gradient (present during and after the pulses) was 20 kHz/cm.
  • the combined presence of matched rf and static field gradients results in a sharp nutation echo taking place at 1 ms.
  • the echo position can be controlled by the relative amplitude of each adiabatic full passage.
  • FIG. 11 B a Fourier transformation of the FID of FIG. 11A providing an rf-weighted image of the encoded phase is shown.
  • the adiabatic double passage encodes an //dependent phase shift. As the offset frequency goes from positive to negative values, the rf amplitude diminishes accordingly. This, in turn, translates into a change of the local phase of the magnetization and a corresponding modulation of the spectrum. For very low rf amplitudes, the adiabatic condition is not fulfilled anymore leading to an uncontrolled behavior. However, because the signal contribution is also very low from these points, the latter does not represent a serious distortion of the echo.
  • two full-passage adiabatic pulses are applied immediately one after the other. Both pulses are identical with the exception of the peak amplitude whose relative variation determines the degree (and sense) of the modulation.
  • the first passage induces a modulation of the transverse magnetization that strongly depends on the local value of the //field and, to a lesser extent, on the offset relative to the central frequency.
  • the beginning of the second passage is seen as an inversion of the effective field that reverses the sense of the modulation.
  • the rf amplitude is different, the accumulated phase during the first passage is not completely canceled during the second one. The difference is roughly proportional to the local //field value resulting in a modulation that reproduces its spatial variation.
  • the offset dependence, already weak, is canceled out since the frequency sweep during the second passage is identical to the first one.
  • FIG. 11 C the same procedure can be repeated to create a train of adiabatic refocusing pulses.
  • the evolution of the magnetization in the inter- pulse intervals along the train is shown.
  • the free induction signal immediately after the excitation pulse and in subsequent free evolution periods after each double passage of the pulse train can be seen.
  • the field gradient used was 20 kHz/cm and the pulses where >10 ms hyperbolic secant type pulses.
  • the amplitude ratio (0.7:1 ) was adjusted so that the echoes took place in the middle of the free evolution interval.
  • FIG. 11D if the acquisition is restricted to the centers of each echo (open circles), the resulting FID is inhomogeneity-free and contains the full spectral information. It can be seen that the amplitude of the first echoes is comparable to the signal immediately following the excitation pulse indicating that almost the whole sample constructively contributes to the echo. Comparatively, this represents a considerable improvement with respect to the performance of composite z-pulses where, mainly due to limitations created by the offset, only a small fraction of the sample can be successfully refocused. For example, FIG. 11 B shows that the inhomogeneous broadening along the sample reaches 20 kHz.
  • This value is considerably higher than the 3 kHz available during the peak of the adiabatic pulse in the region of maximum rf.
  • the gradual decay of the amplitude in subsequent echoes mainly derives from the repeated accumulation of errors in the refocusing. This is caused by an imperfect correspondence between the modulation induced by the pulses and that induced by the field gradient.
  • the resulting spectrum is free of inhomogeneities and compares well with the unperturbed spectrum recorded in the absence of field gradients.
  • a series of spectra of decreasing resolution can be obtained with the same sequence if the amplitude of the second passage is altered beyond the minimum required in FIG. 11C.
  • the echo takes place earlier and the stroboscopic acquisition in the center of the free evolution interval should provide free induction decays in the presence of effective gradients controlled by rf.
  • Variable gradient imaging along the axis of dominant inhomogeneity arises as an interesting possibility, specially for one-sided scanners where the field decay is usually not a parameter under control.
  • the sample spins can be imagined as forming a curve with positive slope. If the modulation created by the pulse is strictly proportional to the local rf, only a fraction of the sample is refocused when this curve is not a straight line. However, the spin response to the rf amplitude can itself be modified to encode a phase modulation proportional to the static field at each point. In the present case, the modulation can be altered if, besides the amplitude, other parameters like the central frequency or the bandwidth of the sweep are modified during the second passage.
  • Compensating for the static inhomogeneities with matched radio frequency inhomogeneities can reduce the residual line-width and provide ultra high-resolution NMR spectra.
  • This procedure can also be applied to very strong hybrid magnets lacking static magnetic field homogeneity and imaging scanners.
  • the ex-situ methodology can be applied in typical NMR cases where the sample resides within the bore of a superconducting magnet experiencing imperfect static field homogeneities in order to obtain high resolution NMR spectra and images.
  • EXAMPLE 9 Spinning a sample at high speeds at a well defined angle (magic angle) to the main magnetic field has proven to be a powerful tool in the study of heterogeneous samples such as powdered solids and heterogeneous solid-liquid mixtures.
  • Magic angle spinning was developed to minimize the spectral line broadening that is observed from intermolecular and intra-molecular dipole couplings, quadrupolar couplings, chemical shift anisotropy, sample inhomogeneity and magnetic susceptibility.
  • MAS Magic angle spinning
  • This embodiment may be used in traditional in-situ experiments as well as with ex-situ applications.
  • the magnetic field may be rotated either through the mechanical rotation of electromagnets or permanent magnets or by cycling currents in a configuration of fixed electromagnets.
  • a sample could be placed in the center of three perpendicular pairs of regular or superconducting coils.
  • one pair of coils would have a constant current applied while the current in the two other pairs would be oscillating. It can be seen that other current modulations are possible that can give the same effect with a higher degree of imperfection compensation.
  • Such a probe head can be utilized to perform magic angle spinning on samples lying physically outside of the center of the coils and resolve the data through the use of trains of pulses.
  • the geometry would preferably correspond to the inhomogeneous static magnetic field head described in FIG. 6 with the additional feature of rotating magnetic fields.
  • such a probe head would produce a time dependent magnetic field rotating at a virtually and variable angle including the magic angle.
  • a series of spectra would be obtained from the magnetic field rotating at different angles and used to reconstruct the isotropic and subsequently the anisotropic spectral information from the sample. This may be particularly useful in ex-situ settings where the access to the object might be limited by spatial constraints.
  • the field variation concept may be applied to the use of permanent magnets or electromagnets to generate a magnetic field spinning at the magic angle with respect to static in-situ or ex-situ samples.
  • the combination of spinning with high resolution in the inhomogeneous fields serves to overcome spectral broadening due to orientational anisotropy, and could be extended to the enhanced ex-situ NMR of hyperpolarized gases.
  • Mechanical problems related to complex rotations of the sample could be obviated, opening the way to high resolution ex-situ NMR of solids and other systems in which in-situ magic-angle spinning is known to be of benefit.
  • Such systems include fluids contained within the pores of solid materials or inside organisms, where resolution is often compromised by orientation-dependent magnetic susceptibility.
  • a time dependent magnetic field can be rotated at variable angles in both in-situ and ex-situ applications.
  • the spectra and images provided would contain chemical shift information that is free of field inhomogeneities and anisotropies using the methods described herein.
  • the magnetic field at the magic angle it is not necessary to rotate the magnetic field at the magic angle in order to obtain isotropic NMR data.
  • a series of spectra obtained from rotation of the magnetic field at different angles can be used to reconstruct isotropic and subsequently anisotropic data from a sample.
  • Limited angle spinning away from the magic angle may be accomplished through several methods with Switched Angle Spinning (SAS) with a direct 2D transform being preferred.
  • SAS Switched Angle Spinning
  • the small angle SAS example assumes that there are two angles.
  • the first angle, ⁇ is spinning along the magnetic field and a second angle, 02, spinning close to the magic angle.
  • VACSY Variable Angle Correlation Spectroscopy with data filling may be used.
  • VACSY is a two dimensional NMR technique that provides spectra with isotropic chemical shifts resolved in one dimension and corresponding shielding anisotropies resolved in a second dimension.
  • the invention provides an apparatus and method for obtaining chemical shift information from a sample outside the bore of a magnet in an inhomogeneous static field and pulse field. Subjects that could not be placed previously in a large super-conducting magnet may now be accessible with the present invention.

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  • High Energy & Nuclear Physics (AREA)
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  • General Physics & Mathematics (AREA)
  • Optics & Photonics (AREA)
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Abstract

L'invention concerne un procédé et un appareil destinés à la spectroscopie par résonance magnétique nucléaire (RMN). Selon l'invention, un échantillon (12) est fixé à l'extérieur d'une bobine RF (14). Une tête de sonde (10) utilise un solénoïde unique afin d'irradier et de détecter les signaux de protons RMN de l'échantillon (12).
PCT/US2002/025802 2001-08-14 2002-08-13 Procede et appareil destines a la spectroscopie par resonance magnetique nucleaire ex situ haute resolution WO2003016951A1 (fr)

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PCT/US2002/011049 WO2002082116A1 (fr) 2001-04-09 2002-04-09 Procede et appareil pour spectrometrie rmn ex-situ haute resolution
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2386953A (en) * 2001-12-18 2003-10-01 Schlumberger Holdings Method for determining molecular properties of hydrocarbon mixtures from nmr data
WO2006042120A3 (fr) * 2004-10-06 2006-09-08 Univ Minnesota Contraste d'une relaxation de cadre tournant par impulsions adiabatiques
CN116413649A (zh) * 2023-01-04 2023-07-11 中国科学院精密测量科学与技术创新研究院 一种基于绝热射频脉冲的磁共振相位成像方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5935065A (en) * 1997-06-27 1999-08-10 Panacea Medical Laboratories MRI system with peripheral access and inhomogeneous field
US6100688A (en) * 1991-06-07 2000-08-08 Btg International Limited Methods and apparatus for NQR testing

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6100688A (en) * 1991-06-07 2000-08-08 Btg International Limited Methods and apparatus for NQR testing
US5935065A (en) * 1997-06-27 1999-08-10 Panacea Medical Laboratories MRI system with peripheral access and inhomogeneous field

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2386953A (en) * 2001-12-18 2003-10-01 Schlumberger Holdings Method for determining molecular properties of hydrocarbon mixtures from nmr data
GB2386953B (en) * 2001-12-18 2004-04-28 Schlumberger Holdings Method for determining molecular properties of hydrocarbon mixtures from NMR data
US6859032B2 (en) 2001-12-18 2005-02-22 Schlumberger Technology Corporation Method for determining molecular properties of hydrocarbon mixtures from NMR data
WO2006042120A3 (fr) * 2004-10-06 2006-09-08 Univ Minnesota Contraste d'une relaxation de cadre tournant par impulsions adiabatiques
CN116413649A (zh) * 2023-01-04 2023-07-11 中国科学院精密测量科学与技术创新研究院 一种基于绝热射频脉冲的磁共振相位成像方法

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