Nuclear magnetic resonance signal measuring method and nuclear magnetic resonance apparatus

Abstract

To provide a new measuring method of a nuclear magnetic resonance signal as an NMR spectral method using a quantum sensor element for an NMR probe.SOLUTION: The method measures a nuclear magnetic resonance signal of a measuring object 9 using a quantum sensor element 1 changing by interaction 8 with the measuring object 9 as a magnetic field probe, and includes steps of: irradiating the quantum sensor element 1 with, as a first reference wave, an electromagnetic wave for manipulating an electron spin state of the quantum sensor element 1 in a first pulse sequence, and measuring a first magnetic resonance signal S0; irradiating the quantum sensor element 1 with, as a second reference wave obtained by changing the phase with respect to the first reference wave, an electromagnetic wave in a second pulse sequence obtained by shifting the timing of the first pulse sequence by ts, and measuring a second magnetic resonance signal S90; coupling the first and second magnetic resonance signals S0, S90 with one of them as a real part and the other as an imaginary part, and subjecting the coupled signal to complex Fourier transformation FFT.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a method and apparatus for measuring a nuclear magnetic resonance signal of a measurement object by using a quantum sensor element, which changes due to interaction with the measurement object, as a magnetic field probe. [Background technology]

[0002] Nuclear magnetic resonance (NMR) spectroscopy is one of the few structural analysis techniques that can measure biomolecules while the biological system is alive. However, NMR spectroscopy has low sensitivity and requires a large amount of sample for measurement, so it is difficult to perform local measurements on single cells.

[0003] In recent years, nitrogen vacancy centers (hereinafter referred to as NV centers) in diamond have been attracting attention. NV centers can be used as magnetic field sensor elements with ultra-high sensitivity and ultra-high spatial resolution at room temperature, and by using NV centers as NMR probes, structural analysis of extremely small samples is also being attempted. For example, in Non-Patent Document 1, NMR signals are measured from microscale samples using NV centers in diamond as a magnetic field probe.

[0004] In addition to the above-mentioned NV center, complex defects called silicon vacancy centers and complex defects called germanium vacancy centers can be found in the crystal structure of diamond, and these complex defects including NV centers are called color centers. These diamond color centers can also be used as magnetic field sensor elements. In addition to sensors using diamond color centers, there are various types of sensors used as magnetic field sensor elements, such as sensors using color centers in silicon carbide (SiC), optically pumped atomic magnetometers (OPMs), and superconducting quantum interference devices (SQUIDs). These diamond color centers, silicon carbide color centers, optically pumped magnetometers, and superconducting quantum interference devices are called quantum sensors because they use quantum effects to measure physical quantities. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Glenn, D., Bucher, D., Lee, J. et al., “High-resolution magnetic resonance spectroscopy using a solid-state spin sensor”, Nature 555, 351-354 (2018). https: / / doi.org / 10.1038 / nature25781 Summary of the Invention [Problem to be solved by the invention]

[0006] In NMR spectroscopy, the NMR frequency value is required to obtain structural information of a sample. The above-mentioned conventional measurement method using NV centers as NMR probes is based on heterodyne detection, but the detection is single-phase. Single-phase detection can obtain the deviation from the reference frequency as a measurement value, but it cannot measure whether the deviation is higher or lower than the reference frequency. In other words, the conventional measurement method is single-phase detection, and quadrature detection is required to obtain the NMR frequency including the positive and negative signs. However, in the measurement method using NV centers as NMR probes, sampling and heterodyne detection have been performed at the time when the fluorescence is measured as an optical signal. Therefore, in order to introduce quadrature detection in NMR spectroscopy using NV centers as NMR probes, it is necessary to develop a new quantum measurement method itself. A new measurement method for nuclear magnetic resonance signals is required.

[0007] An object of the present invention is to provide a new method for measuring nuclear magnetic resonance signals in NMR spectroscopy using a quantum sensor element as an NMR probe. [Means for solving the problem]

[0008] In order to achieve the above object, the present invention includes, for example, the following aspects.

[0009] (Section 1) A method for measuring a nuclear magnetic resonance signal of a measurement object using a quantum sensor element that changes due to an interaction with the measurement object as a magnetic field probe, comprising: a step of irradiating an electromagnetic wave for manipulating an electronic spin state of a quantum sensor element as a first reference wave to the quantum sensor element in a first pulse sequence, and measuring a first magnetic resonance signal; a step of irradiating the quantum sensor element with the electromagnetic wave using a second pulse sequence obtained by shifting the timing of the first pulse sequence as a second reference wave having a phase shifted relative to the first reference wave, and measuring a second magnetic resonance signal; combining the first and second magnetic resonance signals, one as a real part and the other as an imaginary part, and subjecting the combined signal to a complex Fourier transform; A method for measuring a nuclear magnetic resonance signal, comprising: (Section 2) Item 1. The measurement method according to item 1, wherein the first and second pulse sequences are dynamic decoupling pulse sequences. (Section 3) The phase difference Φ between the first and second reference waves is a timing shift t between the first and second pulse sequences. s and the pulse interval τ of the dynamic decoupling is expressed by the following equation.

number

[0010] According to the present invention, it is possible to provide a new method for measuring nuclear magnetic resonance signals in NMR spectroscopy using a quantum sensor element as an NMR probe. [Brief description of the drawings]

[0011] [Figure 1] 1 is a diagram for explaining a method for measuring a nuclear magnetic resonance signal according to the present invention. [Diagram 2] 1 is a diagram showing a schematic configuration of a nuclear magnetic resonance apparatus according to an embodiment; [Diagram 3] FIG. 3 is a diagram illustrating an example of a specific configuration of the nuclear magnetic resonance spectrometer shown in FIG. 2. [Figure 4] FIG. 4 is a diagram showing an example of a specific configuration around the probe shown in FIG. 3. [Diagram 5] 3 is a flowchart showing the procedure of a method for measuring a nuclear magnetic resonance signal according to an embodiment. [Figure 6] 1 shows the pulse sequence and Fourier transform results used in Example 1. [Figure 7] 1 shows a result of a complex Fourier transform in the first embodiment. [Figure 8] 13 shows a phase rotation pulse sequence used in the second embodiment. [Figure 9] FIG. 11 is a diagram for explaining a set of four phase rotations used in the second embodiment. [Figure 10] 11 is a result of a complex Fourier transform in the second embodiment. [Figure 11] 13 shows a pulse sequence used in Example 3. [Figure 12] 13 shows the measurement results and simulation results of two-dimensional NMR carried out in Example 3. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Hereinafter, an embodiment of the present invention will be described in detail with reference to the accompanying drawings. In the following description and drawings, the same reference numerals denote the same or similar components, and therefore, redundant description of the same or similar components will be omitted.

[0013] [Measurement method] FIG. 1 is a diagram for explaining a method for measuring a nuclear magnetic resonance signal according to the present invention.

[0014] In the present invention, a freely variable reference wave phase is introduced in the quantum heterodyne (Qdyne) method based on heterodyne detection, which makes it possible to apply phase-based techniques used in conventional NMR spectroscopy, such as orthogonal detection and phase rotation, to a measurement technique using an NV center as an NMR probe.

[0015] In the illustrated example, the magnetic resonance signal from the NV center is detected by the optically detected magnetic resonance (ODMR) method. That is, the illustrated Qdyne pulse sequence is a pulse sequence including irradiation with laser light and irradiation with a microwave pulse. First, the electronic spin state of the NV center is initialized by irradiation with laser light. Next, the electronic spin state of the NV center is manipulated by irradiation with a microwave pulse. Finally, the electronic spin state of the NV center is read out and initialized for the next pulse sequence by irradiation with laser light. Other methods capable of measuring the spin state of the NV center, such as the electrically detected magnetic resonance (EDMR) method, can also be used.

[0016] In the present invention, in such a Qdyne pulse sequence, the phase of the reference wave is changed by shifting the timing of the pulse sequence as a whole. The reference wave here does not refer to each microwave pulse, but rather to the entire microwave pulse sequence enclosed in square brackets "[···]" in the figure. In other words, the reference wave in the present invention is a standard having elements of frequency and phase for obtaining measurement results in heterodyne detection, and in the method proposed in the present invention, the frequency of the reference wave is controlled by the pulse interval in the sequence, and the phase of the reference wave is controlled by the timing of the start of the sequence. The phase difference Φ between two reference waves whose timing is shifted as a whole is calculated by the amount of timing shift t between the pulse sequence shown in the upper row and the pulse sequence shown in the lower row in the figure. s and the pulse interval τ of the dynamic decoupling is expressed by the following equation.

[0017]

number

[0018] In the illustrated example, as an example of a shift, quadrature detection with a relative phase shift of 90° (π / 2) is shown. The phase shift between the pulse sequence shown in the upper part of the figure and the pulse sequence shown in the lower part of the figure is 90°. The magnetic resonance signal S0 obtained by the pulse sequence shown in the upper part of the figure is the real part, and the magnetic resonance signal S 90 These signals are combined with the imaginary part, and the combined signal is subjected to a complex Fourier transform. This realizes quadrature detection in measurements using NV centers as NMR probes, and makes it possible to calculate NMR frequencies including positive and negative signs, which cannot be obtained with conventional measurement methods using single-phase detection.

[0019] The microwave pulse sequence shown in the figure is a pulse sequence of the XY-8 method, which is a type of dynamic decoupling. Multiple (N) pulse sequences are required for measurement, and at least the same number of pulse sequences with different shift amounts are required. This is because pulse sequences with different shift amounts cannot be measured simultaneously.

[0020] In the Qdyne pulse sequence, it is possible to change the reference wave phase Φ for each XY-8. Using this, pseudo-quadrature detection measurement is also possible, in which the phase is changed by 90° each time the magnetic resonance signal is sampled.

[0021] In the illustrated example, the phase shift between the pulse sequence shown in the upper part and the pulse sequence shown in the lower part is 90°, but the phase shift is not limited to 90° (π / 2) and can be changed arbitrarily. Here, to determine the reference for the absolute phase, a Qdyne measurement is performed on an NMR signal starting from phase 0, and when the vibration phase of the measurement result becomes 0, that sequence is regarded as the reference wave 0°.

[0022] Preferably, the frequencies of the first and second reference waves correspond to the peak frequency of the solvent that dissolves the sample to be measured. This makes it possible to reduce the solvent peak that is often a problem in the measurement of an actual sample. The solvent is, for example, water (H2O), and the peak frequency in this case is about 4.7 ppm.

[0023] [Device configuration] Fig. 2 is a diagram showing a schematic configuration of a nuclear magnetic resonance apparatus according to an embodiment. Fig. 3 is a diagram showing a schematic example of a specific configuration of the nuclear magnetic resonance apparatus shown in Fig. 2. Fig. 4 is a diagram showing an example of a specific configuration around the probe shown in Fig. 3.

[0024] A nuclear magnetic resonance apparatus 10 (hereinafter simply referred to as apparatus 10) according to one embodiment is an apparatus that measures a nuclear magnetic resonance (NMR) signal of a measurement object 9 using a sensor element 1 that changes due to an interaction 8 with the measurement object 9 as a magnetic field probe. The apparatus 10 includes the sensor element 1, an electromagnetic wave irradiation unit 2, and a signal measurement unit 3. In this embodiment, the sensor element 1 is attached to the tip of a probe 11 of the apparatus 10.

[0025] The sensor element 1 is a quantum sensor element. In this embodiment, the sensor element 1 is a diamond crystal having a color center, and an NV center is used as the color center. The NV center is a complex (complex defect) of nitrogen (N) substituting a carbon atom and a vacancy (V) adjacent to the nitrogen. In this embodiment, the sensor element 1 is generated in advance by a known method, for example in a layer shape, in a predetermined region on the diamond crystal 12. Illustratively, there are roughly several thousand particles (concentration: 1×10 12 / cm -3 ) A plurality of sensor elements 1 are generated. In this embodiment, the sensor elements 1 are ensemble NV centers.

[0026] The electron spin state of the sensor element 1 is changed by an interaction 8 with the nuclear spin of a measurement object 9. In this embodiment, the measurement object 9 is a sample of an organic or inorganic molecule or a biomolecule, and any molecular sample can be the measurement object 9. The interaction 8 is an interaction due to a magnetic field.

[0027] The electromagnetic wave application unit 2 applies electromagnetic waves to the sensor element 1 for manipulating the electronic spin state of the sensor element 1 by magnetic resonance. As an example, in this embodiment, the electromagnetic wave application unit 2 includes a known microwave (MW) oscillator 21, a switch 22 for applying electromagnetic waves in a pulsed form, and an amplifier 23. The switch 22 and the amplifier 23 may have any configuration. In this embodiment, the electromagnetic wave application unit 2 applies electromagnetic waves to the sensor element 1 in a pulsed form for manipulating the electronic spin state of the sensor element 1.

[0028] The electromagnetic wave irradiation unit 2 irradiates the sensor element 1 with electromagnetic waves in different pulse sequences with shifted timing. In this embodiment, the electromagnetic wave irradiation unit 2 irradiates the sensor element 1 with electromagnetic waves in a first pulse sequence as a first reference wave, and irradiates the sensor element 1 with electromagnetic waves in a second pulse sequence with the timing of the first pulse sequence shifted as a second reference wave with a phase shifted relative to the first reference wave. Preferably, the first and second pulse sequences are pulse sequences of dynamic decoupling, and more preferably, are pulse sequences of the XY-8 method of dynamic decoupling.

[0029] The electromagnetic wave irradiating unit 2 irradiates the sensor element 1 with electromagnetic waves through an antenna 14 for irradiating electromagnetic waves that is arranged in the vicinity of the sensor element 1. The antenna 14 can be formed on the diamond crystal 12 using, for example, a coaxial wire, or using, for example, a lithography technique, using a conductive metal.

[0030] As shown in FIG. 4(A), in this embodiment, a CVD-synthesized diamond 12 with a (100) plane orientation is attached to a right-angle prism 13. The NV center 1 of the diamond is formed in a layer in the diamond crystal 12. The laser light (exemplarily about 532 nm) for initializing and detecting the state of the NV center 1 is incident from the side of the polished prism 13, passes through the back surface of the diamond crystal 12, and is totally reflected on the surface of the diamond crystal 12. This allows measurement to be performed without exposing the sample to the laser light even if the sample of the measurement object 9 is placed on the surface of the diamond 12. A static magnetic field B0 is applied to the sample of the measurement object 9 and the probe 11 by the electromagnet 7. The magnetic field direction of the static magnetic field B0 is aligned with one of the axial directions of the NV center 1.

[0031] As shown in Fig. 4(B), the fluorescence FL from the NV center 1 passes through a prism 13 with a mirror-coated slanted surface, is collected by the light-collecting optical system 15, and is detected by the detection unit 32. In this embodiment, the light-collecting optical system 15 includes a CPC (Compound Parabolic Concentrator) lens 151, a condenser lens 152, and a long-pass filter 153 (exemplary about 633 nm). Illustratively, the detection volume of the sample to be measured 9 is about 20 µm 3 It is.

[0032] 2 and 3 again. The signal measurement unit 3 measures magnetic resonance signals corresponding to the respective pulse sequences from the sensor element 1 irradiated with electromagnetic waves in different pulse sequences with shifted timing, combines the measured signals, and performs complex Fourier transformation. In this embodiment, the signal measurement unit 3 measures a first magnetic resonance signal from the sensor element 1 irradiated with electromagnetic waves in a first pulse sequence, and measures a second magnetic resonance signal from the sensor element 1 irradiated with electromagnetic waves in a second pulse sequence. The signal measurement unit 3 includes a light irradiation unit 31, a detection unit 32, and a data processing unit 33.

[0033] The light irradiating unit 31 irradiates the sensor element 1 with light for reading out phase information of the electron spin state of the sensor element 1 after interacting with the measurement target 9. The light irradiating unit 31 also irradiates the sensor element 1 with light for initializing the electron spin state of the sensor element 1. As an example, in this embodiment, the light irradiating unit 31 includes a light source 311 and an acousto-optical modulator (AOM) 312. The acousto-optical modulator 312 can have any configuration.

[0034] The light source 311 emits light for reading out phase information of the electron spin state of the sensor element 1 after interaction with the measurement target 9. The light source 311 also emits light for exciting and initializing the electron spin state of the sensor element 1. The wavelength of the light emitted by the light source 311 is determined according to the type of the sensor element 1. In this embodiment, the light source 311 emits laser light having a wavelength of about 532 nm (green). For example, various known laser generating devices can be used as the light source 311. In this embodiment, the light source 311 is a semiconductor laser that emits green laser light.

[0035] The detection unit 32 detects the change occurring in the sensor element 1. In this embodiment, the detection unit 32 detects the light emitted from the sensor element 1, and detects the magnetic resonance signal as a change in light emission intensity by a known optically detected magnetic resonance (ODMR) method. In this case, for example, a known photodiode can be used for the detection unit 32. For example, an avalanche photodiode can be used for the photodiode. In this embodiment, the electromagnetic wave irradiation unit 2 irradiates the electromagnetic wave for operation in a pulsed form. Therefore, in this embodiment, specifically, detection is performed by a Pulsed Optically Detected Magnetic Resonance (pODMR) method.

[0036] The data processing unit 33 is connected to the detection unit 32, reads out phase information of the electron spin state of the sensor element 1 after interaction with the measurement target 9 from the change detected by the detection unit 32, and performs various data processing based on the read out phase information. The data processing unit 33 includes a complex Fourier transform unit 331 and a frequency calculation unit 332.

[0037] For example, a known general-purpose computer or various information terminal devices such as a smartphone can be used for the data processing unit 33. The data processing unit 33 may be configured to be integrated with the device 10, or may be provided outside the device 10 and connected to the device 10 via a wired or wireless network 99 as shown in the figure.

[0038] The complex Fourier transform unit 331 combines the magnetic resonance signals corresponding to the respective pulse sequences, and performs a complex Fourier transform on the combined signal. In this embodiment, the complex Fourier transform unit 331 combines the first and second magnetic resonance signals, one as a real part and the other as an imaginary part, and performs a complex Fourier transform on the combined signal.

[0039] The frequency calculation section 332 calculates a value including positive and negative values ​​of the frequency of the nuclear magnetic resonance signal based on the spectrum of the nuclear magnetic resonance signal (NMR signal) of the measurement object 9 obtained by complex Fourier transform.

[0040] [Measurement procedure] FIG. 5 is a flowchart showing the procedure of a method for measuring a nuclear magnetic resonance signal according to an embodiment.

[0041] A method for measuring a nuclear magnetic resonance signal according to one embodiment is a method for measuring a nuclear magnetic resonance (NMR) signal of a measurement object 9 using a sensor element 1 that changes due to an interaction 8 with the measurement object 9 as a magnetic field probe. An example of a measurement procedure will be described below with reference to Figs. 5 and 1.

[0042] In step S1, an electromagnetic wave for manipulating the electronic spin state of the sensor element 1 is irradiated to the sensor element 1 as a first reference wave with a first pulse sequence, and a first magnetic resonance signal is measured from the sensor element 1. In this embodiment, the pulse sequence shown in the upper part of Fig. 1 is applied as the first pulse sequence.

[0043] In step S2, an electromagnetic wave for manipulating the electronic spin state of the sensor element 1 is irradiated to the sensor element 1 as a second reference wave in a second pulse sequence, and a second magnetic resonance signal is measured from the sensor element 1. The second reference wave is a reference wave whose phase is changed with respect to the first reference wave. In this embodiment, the pulse sequence shown in the lower part of FIG. 1 is applied as the second pulse sequence. The second pulse sequence is a pulse sequence in which the timing of the first pulse sequence is shifted. In this embodiment, the phase shift between the first and second pulse sequences is 90°.

[0044] In step S3, the first and second magnetic resonance signals obtained by the measurement are combined, one as a real part and the other as an imaginary part, and the combined signal is subjected to a complex Fourier transform. The complex Fourier transform provides a spectrum of the nuclear magnetic resonance signal (NMR signal) of the measurement object 9.

[0045] The phase shift between the first and second pulse sequences is 90°. If the first magnetic resonance signal is a signal S0 with a phase of 0°, the second magnetic resonance signal is a signal S1 with a phase of 90°. 90 In this embodiment, the first magnetic resonance signal S0 is a real part, and the second magnetic resonance signal S 90 The imaginary part of the combined signal (S0+iS 90 ) is the complex Fourier transform.

[0046] In step S4, a value including positive and negative frequencies of the nuclear magnetic resonance signal is calculated based on the spectrum of the nuclear magnetic resonance signal (NMR signal) of the measurement target 9 obtained by complex Fourier transform. The frequency at which the intensity peaks in the spectrum of the NMR signal is calculated from the spectrum.

[0047] The process of step S4 is optional. There are cases where it is not always necessary to calculate values ​​including positive and negative frequencies of the nuclear magnetic resonance signal (NMR signal) of the measurement object 9, such as in phase rotation and applications to multidimensional NMR described later.

[0048] [Phase Rotation] A method of measuring a nuclear magnetic resonance signal according to an embodiment can introduce a method of phase rotation in nuclear magnetic resonance. The content of the method of phase rotation is established, and is realized by interlocking an excitation pulse and a receiver phase. For example, a well-known method of phase rotation is to change the phase of an excitation pulse in increments of 90° from 0° while interlocking the receiver phase in increments of 90° from 0° (CYCLically-Ordered Phase-Sequence: CYCLOPS). In this embodiment, the method of phase rotation is introduced by interlocking the phase of a reference wave irradiated as an excitation pulse with the phase of the receiver.

[0049] That is, in one embodiment of the method for measuring a nuclear magnetic resonance signal, The step of measuring the first and second magnetic resonance signals includes measuring the magnetic resonance signals by setting the first and second reference wave phases according to each step while fixing the phase difference between the first and second reference waves at π / 2 and gradually changing the phase of the pulse that excites the magnetic resonance signals; The step of complex Fourier transforming can combine the first and second magnetic resonance signals in response to a phase difference of pulses exciting the magnetic resonance signals which is varied in stages.

[0050] An example of a method for changing the receiver phase in increments of 90° from 0° will be described. In this embodiment, the complex Fourier transform unit 331 changes a combination pattern of which of the first and second magnetic resonance signals is the real part and which is the imaginary part, and a sign inversion pattern of the entire combined signal, and combines the first and second magnetic resonance signals to change the receiver phase. Please refer to the examples described later for actual examples of the combination pattern and the sign inversion pattern.

[0051] [Multidimensional NMR] The method for measuring nuclear magnetic resonance signals according to an embodiment can be applied to one-dimensional NMR measurement, which is a unit of measurement in two-dimensional NMR measurement. That is, the method for measuring nuclear magnetic resonance signals according to an embodiment can be applied to COSY (COrrelation SpectroscopY) and TOCSY (TOtal Correlation SpectroscopY), which are known as two-dimensional NMR and are intended for the correlation of homonuclei, and HSQC (Heteronuclear Single Quantum Correlation) and HMBC (Heteronuclear Multiple Bond Correlation), which are intended for the correlation of heteronuclei. Similarly, the method can be applied to multidimensional NMR.

[0052] As described above, according to the nuclear magnetic resonance apparatus or the method for measuring a nuclear magnetic resonance signal according to an embodiment, a new method for measuring a nuclear magnetic resonance signal in NMR spectroscopy using a quantum sensor element as an NMR probe can be provided. This makes it possible to apply phase-based methods used in conventional NMR spectroscopy, such as orthogonal detection and phase rotation, to a measurement method using a quantum sensor element as an NMR probe. Since quantum sensor elements such as NV centers are highly sensitive magnetic field sensors, using such quantum sensor elements as an NMR probe makes it possible to perform structural analysis on a much smaller amount of sample than before. It is also possible to calculate a value including the positive and negative frequencies of the nuclear magnetic resonance signal (NMR signal) of the measurement object 9.

[0053] [Other formats] Although the present invention has been described above with reference to specific embodiments, the present invention is not limited to the above-described embodiments.

[0054] In the above embodiment, diamond crystal is used as the sensor element 1, and NV center is used as the color center of diamond, but the color center used is not limited to NV center. Instead of NV center, silicon-vacancy center or germanium-vacancy center can be used as the color center of diamond of the sensor element 1. In addition, the color center is not limited to the color center of diamond crystal, and color centers of various crystals can be used for the sensor element 1.

[0055] In the above embodiment, the color center of diamond is used for the sensor element 1, but the sensor element 1 used is not limited to the color center of diamond. Instead of the color center of diamond, various quantum sensors such as color centers of silicon carbide (SiC), optically pumped magnetometers (OPM), and superconducting quantum interference meters (SQUID) can be used for the sensor element 1 as long as the electronic spin state can be manipulated by irradiating the sensor element 1 with electromagnetic waves.

[0056] In the above embodiment, the magnetic resonance signal from the sensor element 1 is detected by the optically detected magnetic resonance (ODMR) method, but the method used to detect the magnetic resonance signal is not limited to the optically detected magnetic resonance (ODMR) method. Instead of the optically detected magnetic resonance (ODMR) method, the magnetic resonance signal can also be detected by, for example, the well-known electrically detected magnetic resonance (EDMR) method.

[0057] In the electrically detected magnetic resonance (EDMR) method, a pair of measurement electrodes for detecting a magnetic resonance signal is electrically connected to the sensor element 1. A bias voltage is applied between the pair of measurement electrodes, and an electric field is applied to the sensor element 1 through the measurement electrodes. Photoexcitation of the sensor element 1 generates a photocurrent that depends on the spin state. This photocurrent is generated due to the difference in lifetime of the excited state that depends on the spin state. The detection unit 32 detects the magnetic resonance signal as a change in electrical resistivity (or a change in photocurrent due to light irradiation) by detecting the electrical resistance of the sensor element 1 (or the photocurrent generated in the sensor element 1). That is, the detection unit 32 functions as an electrical detection unit. For example, a known ammeter can be used as the detection unit 32.

[0058] The following examples of the present invention will make the features of the present invention clearer. EXAMPLES

[0059] In the first embodiment, an AC magnetic field having a frequency simulating a signal of proton nuclear spin was measured, and it was verified that quadrature detection is possible.

[0060] The pulse sequence used in Example 1 is shown in the upper part of Fig. 6(A). In Example 1, two types of reference wave phases, 0° and 90°, were used. The pulse sequence was a pulse sequence for quadrature detection. The magnetic resonance signal obtained by measurement is shown in the lower part of Fig. 6(A). The phase changed in the obtained signal waveform.

[0061] The result of Fourier transforming the magnetic resonance signal shown in the lower part of Fig. 6(A) is shown in Fig. 6(B). The lower part of Fig. 6(B) shows a signal S=S0+iS, which is a complex number combining the signal S0 from the reference wave phase 0° and the signal S90 from the reference wave phase 90°. 90 6B shows the result of performing a complex Fourier transform on only the signal S0 from the reference wave phase 0° as a comparative example.

[0062] As shown in the upper part of Figure 6(B), when only the signal S0 from the reference wave phase of 0° was used, the signal folded back on the frequency axis appeared as a peak at the mirror image position. In contrast, as shown in the lower part of Figure 6(B), when the signal S0 from the reference wave phase of 0° and the signal S90 from the reference wave phase of 90° were combined as a complex number, the mirror image with the same difference from the reference wave but different sign was removed. This made it possible to perform quadrature detection, and it was possible to obtain values ​​including both positive and negative frequencies.

[0063] Additionally, the following three benefits of orthogonal detection were confirmed:

[0064] First advantage The first advantage is that it is possible to distinguish between positive and negative spectra near the reference frequency because the mirror image can be simply removed. With quadrature detection, measurements are possible without generating dummy peaks due to mirror images. Figure 7(A) shows the results of complex Fourier transform of data measured with single-phase detection and quadrature detection for a signal containing five reference frequencies (-50Hz, -20Hz, 20Hz, 40Hz, 60Hz) around the 0 point. With single-phase detection, there were two triplet peaks that tend to appear in NMR. The more unknown and complex the peak, the more important it is to use quadrature detection near 0 Hz.

[0065] Second advantage The second benefit is that the bandwidth is doubled. With single-phase detection, as mentioned above, a mirror image occurs, so in order to prevent the origin from being crossed after the complex Fourier transform, it is necessary to shift the entire spectrum to either the positive or negative side during measurement. In contrast, with quadrature detection, this is not necessary, so twice the bandwidth can be used even with the same sampling rate. Figure 7(B) shows the results of a comparison of bandwidth between single-phase detection and quadrature detection. The top row shows the results for single-phase detection, and the bottom row shows the results for quadrature detection.

[0066] The third benefit The third advantage is that it is possible to reduce the solvent peaks that are often problematic in the measurement of actual samples. The most typical example is the water (H2O) peak that appears around 4.7 ppm. The concentration of pure water is very high, which causes a peak that is overwhelmingly larger than the sample molecules to be measured, and the signal peaks around water are covered by the huge peak, or the baseline of the spectrum is distorted. The simplest and most basic method for this solvent peak is to set the reference wave frequency to match the frequency of the solvent peak. The water peak that most often appears in measurements of biological systems is 4.7 ppm, which is located in the center of the spectrum, so orthogonal detection that does not produce mirror images is desirable. EXAMPLES

[0067] In the second embodiment, a phase rotation technique known as CYCLOPS is introduced, and the effect of correction by CYCLOPS is verified.

[0068] The pulse sequence of phase rotation used in the second embodiment is shown in Fig. 8. More specifically, in the second embodiment, as shown in Fig. 9, the phase Φ of the excitation pulse is rotated by four sets of phase rotations of 0°, 90°, 180°, and 270°. pulse and the receiver phase Φ receiver The changes were made in conjunction with the above.

[0069] The result of the complex Fourier transform is shown in Fig. 10. The graph on the right side of Fig. 10 shows the measurement result when phase rotation is applied by the pulse sequence shown in Fig. 8 and Fig. 9. The graph on the left side of Fig. 10 shows the measurement result when no phase rotation is applied and the phase Φ pulse and the receiver phase Φ receiver Both are measurement results for 0° only. In the graph on the right, where phase rotation was applied, there is some disruption in the signal phase compared to the graph on the left, where phase rotation was not applied, but it was confirmed that distortion at the origin and mirror image point was suppressed. EXAMPLES

[0070] In Example 3, two-dimensional NMR measurements were performed and compared with the simulation results. Two-dimensional NMR measures various correlations between nuclear spins in molecules, and enables complex structural analysis of macromolecules by exploring the positional relationships between functional groups and atoms. It is particularly useful for structural analysis of biomolecules.

[0071] The pulse sequence used in Example 3 is shown in FIG. 11. In Example 3, a homonuclear correlation COSY sequence was used. A 90° nuclear spin pulse was applied, and after a time t1 was inserted as a development period, a 90° pulse was applied again to measure the free induction decay (FID) signal. Measurements were performed in the detection period t2 while increasing the time t1 in sequence to obtain a two-dimensional matrix, and then Fourier transformation was performed on the t2 axis and the t1 axis in that order. In two-dimensional NMR, the data thus obtained is usually plotted as contour lines.

[0072] The molecular sample measured in Example 3 is acetaldehyde. Acetaldehyde has chemical shifts at 2.206 ppm and 9.789 ppm. The J coupling value is 2.9 Hz. It is an A3X system, and as a result of COSY, a correlation signal appears as a cross peak at the intersection of 2 ppm and 10 ppm due to coupling via bonds between two types of protons.

[0073] In Example 3, a simulation was performed using SPINACH, and the detected FID data was obtained as a complex number, and then an AC magnetic field was created by upconverting the data to the proton Larmor frequency of 3.571 MHz at 83 mT, which is the experimental environment for the NV center. A sampling rate of 25 MHz or 50 MHz was used. The signal thus obtained was output from an arbitrary waveform generator (AWG) and measured using a quadrature detection Qdyne, thereby demonstrating two-dimensional NMR measurement. The observation center was set to 6 ppm, which is the central part of the spectrum. By using quadrature detection, it is possible to perform measurement while avoiding the generation of a mirror image symmetrical with respect to the t2 axis. The States method was used for the folding back of the t1 axis. The phase of the first 90-degree pulse was set to 0° and 90°, and the obtained signals were designated as P0 and P90, respectively. At this time, after complex Fourier transform on the t2 axis, the data having the imaginary component of the signal P0 as a real number and the real component of the signal P90 as an imaginary number is complex Fourier transformed on the t1 axis, thereby making it possible to remove the mirror image on the t1 axis.

[0074] The measured data and simulation results are shown in Figure 12. Figure 12(A) shows the measurement results using the Qdyne method in the case of single-phase detection (without quadrature detection). Figure 12(B) shows the simulation results, and Figure 12(C) shows the measurement results using the quadrature detection Qdyne method.

[0075] The results shown in (B) and (C) of Figure 12 were compared. Referring to the measurement result shown in (C), the J coupling, signal phase, and chemical shift were reproduced in the cross peak. No aliasing signals were generated on both the t1 and t2 axes.

[0076] In addition, some of the measurement results shown in (C) are unclear, but this is thought to be due to bit errors in the arbitrary waveform generator, insufficient integration time, and broadening due to the damping term multiplied by the AC magnetic field. [Explanation of symbols]

[0077] 1. Sensor element (Nano-Voltage center in diamond) 2 Electromagnetic wave irradiation section 3. Signal Measurement Section 7. Electromagnets 8 Interaction 9. Measurement target (sample) 10. Nuclear Magnetic Resonance Spectrometer 11 Probe 12 Diamond Crystal 13 Prism 14 Antenna 15 Light collecting optical system 151 CPC (Compound Parabolic Concentrator) lens 152 Condenser Lens 153 Longpass Filter 21 Microwave (MW) Oscillator 22 Switch 23 Amplifier 31 Light irradiation unit 311 Light source 312 Acousto-optic Modulator (AOM) 32 Detection unit 33 Data Processing Section 331 Complex Fourier Transform Section 332 Frequency Calculation Unit 99 Network

Claims

1. A method for measuring a nuclear magnetic resonance signal of a measurement object using a quantum sensor element that changes due to an interaction with the measurement object as a magnetic field probe, comprising: a step of irradiating an electromagnetic wave for manipulating an electronic spin state of a quantum sensor element as a first reference wave to the quantum sensor element in a first pulse sequence, and measuring a first magnetic resonance signal; a step of irradiating the quantum sensor element with the electromagnetic wave using a second pulse sequence obtained by shifting the timing of the first pulse sequence as a second reference wave having a phase shifted relative to the first reference wave, and measuring a second magnetic resonance signal; combining the first and second magnetic resonance signals, one as a real part and the other as an imaginary part, and subjecting the combined signal to a complex Fourier transform.

2. The measurement method of claim 1 , wherein the first and second pulse sequences are dynamic decoupling pulse sequences.

3. The phase difference Φ between the first and second reference waves is a timing shift amount t between the first and second pulse sequences. ｓ and a pulse interval τ of the dynamic decoupling, [0010]

4. The measurement method according to claim 1 , wherein the phase difference between the first and second reference waves is π / 2.

5. The measurement method according to claim 1 , further comprising the step of calculating a value including positive and negative frequencies of the nuclear magnetic resonance signal based on a spectrum of the nuclear magnetic resonance signal of the measurement object obtained by the complex Fourier transform.

6. The measurement method according to claim 1 , wherein the frequencies of the first and second reference waves are set to correspond to a peak frequency of a solvent that dissolves the sample to be measured.

7. The step of measuring the first and second magnetic resonance signals includes measuring the magnetic resonance signals by changing the phase of a pulse for exciting the magnetic resonance signals in a stepwise manner while fixing a phase difference between the first and second reference waves at π / 2, and setting the phase of the first and second reference waves according to each step; 2. The measurement method according to claim 1, wherein the step of performing a complex Fourier transform combines the first and second magnetic resonance signals in accordance with a phase difference between pulses that excite the magnetic resonance signals, the phase difference being changed in stages.

8. A method for measuring multidimensional nuclear magnetic resonance signals by the method for measuring nuclear magnetic resonance signals according to any one of claims 1 to 7.

9. An apparatus for measuring a nuclear magnetic resonance signal of a measurement object using a quantum sensor element that changes due to an interaction with the measurement object as a magnetic field probe, comprising: an electromagnetic wave irradiation unit that irradiates the quantum sensor element with an electromagnetic wave for manipulating an electronic spin state of the quantum sensor element as a first reference wave in a first pulse sequence, and irradiates the quantum sensor element with an electromagnetic wave as a second reference wave in which the phase of the first reference wave is changed, in a second pulse sequence in which the timing of the first pulse sequence is shifted; a signal measurement unit that measures a first magnetic resonance signal from the quantum sensor element irradiated with the electromagnetic wave in the first pulse sequence, and measures a second magnetic resonance signal from the quantum sensor element irradiated with the electromagnetic wave in the second pulse sequence; a complex Fourier transform unit that combines the first and second magnetic resonance signals, one of which is a real part and the other is an imaginary part, and performs a complex Fourier transform on the combined signal; A nuclear magnetic resonance apparatus comprising:

10. The signal measurement unit a light irradiation unit that irradiates the quantum sensor element with light for reading out the electron spin state; a detection unit that detects a change that occurs in the quantum sensor element due to the irradiation of the light; a data processing unit that reads out information about the electron spin state from the detected change; The nuclear magnetic resonance apparatus according to claim 9 .

11. 11. The nuclear magnetic resonance apparatus according to claim 9, further comprising a frequency calculation unit that calculates a value including positive and negative frequencies of the nuclear magnetic resonance signal based on a spectrum of the nuclear magnetic resonance signal of the measurement object obtained by the complex Fourier transform.

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