Method for measuring nuclear magnetic resonance signal and nuclear magnetic resonance device

Abstract

Provided is a new measurement method for a nuclear magnetic resonance signal in an NMR spectroscopy in which a quantum sensor element is used for an NMR probe. The measurement method is a method for measuring a nuclear magnetic resonance signal of a measurement object 9 by using, as a magnetic field probe, a quantum sensor element 1 that varies with an interaction 8 with the measurement object 9. The measurement method comprises: a step for irradiating the quantum sensor element 1 with, as a first reference wave, an electromagnetic wave for operating an electron spin state of the quantum sensor element 1 in a first pulse sequence, and measuring a first magnetic resonance signal S0; a step for irradiating the quantum sensor element 1 with, as a second reference wave with the phase changing from that of the first reference wave, an electromagnetic wave in a second pulse sequence in which the timing of the first pulse sequence is shifted by ts, and measuring a second magnetic resonance signal S90; and a step for combining the first and second magnetic resonance signals S0, S90 using one as a real part and the other one as an imaginary part, and performing complex Fourier transform FFT on the combined signal.

Description

Nuclear magnetic resonance signal measuring method and nuclear magnetic resonance apparatus

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

[0002] Nuclear magnetic resonance (NMR) spectroscopy is one of the few structural analysis techniques that can measure biomolecules in living organisms. However, NMR spectroscopy has low sensitivity and requires a large amount of sample for measurement, making it 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, efforts are being made to analyze the structure of extremely small samples. 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 NV centers described above, complex defects called silicon vacancy centers and germanium vacancy centers can also be found in the crystal structure of diamond. 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 other 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 (SQUIDs) are called quantum sensors because they measure physical quantities using quantum effects.

[0005] 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

[0006] In NMR spectroscopy, NMR frequency values ​​are required to obtain structural information about a sample. The conventional measurement techniques described above, using NV centers as NMR probes, are based on heterodyne detection, but the detection is single-phase. Single-phase detection can obtain the deviation from a reference frequency as a measurement value, but it cannot determine whether the deviation is higher or lower than the reference frequency. In other words, conventional measurement techniques use single-phase detection, and quadrature detection is required to obtain NMR frequencies that include positive and negative signs. However, in measurement techniques using NV centers as NMR probes, sampling and heterodyne detection have already been performed at the time the fluorescence is measured as an optical signal. Therefore, to introduce quadrature detection into NMR spectroscopy using NV centers as NMR probes, a new quantum measurement technique itself must be developed. A new measurement technique for nuclear magnetic resonance signals is needed.

[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.

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

[0009] (Item 1) A method for measuring a nuclear magnetic resonance signal of a measurement object using a quantum sensor element that changes due to interaction with the measurement object as a magnetic field probe, the method comprising the steps of: irradiating the quantum sensor element with an electromagnetic wave for manipulating the electron spin state of the quantum sensor element as a first reference wave in a first pulse sequence, and measuring a first magnetic resonance signal; irradiating the quantum sensor element with an electromagnetic wave as a second reference wave whose phase is changed relative to the first reference wave in a second pulse sequence in which the timing of the first pulse sequence is shifted, and measuring a second magnetic resonance signal; and combining the first and second magnetic resonance signals, one as a real part and the other as an imaginary part, and performing a complex Fourier transform on the combined signal. (Item 2) The measurement method according to Item 1, wherein the first and second pulse sequences are dynamic decoupling pulse sequences. (Item 3) The phase difference Φ between the first and second reference waves is determined by the amount of 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. (Item 4) The measurement method according to any one of Items 1 to 3, wherein the phase difference between the first and second reference waves is π / 2. (Item 5) The measurement method according to any one of Items 1 to 4, further comprising a step of calculating a value, including positive and negative, of the frequency of the nuclear magnetic resonance signal based on the spectrum of the nuclear magnetic resonance signal of the measurement target obtained by the complex Fourier transform. (Item 6) The measurement method according to any one of Items 1 to 5, wherein the frequencies of the first and second reference waves are made to correspond to a peak frequency of a solvent that dissolves the sample of the measurement target. (Item 7) The measurement method according to any one of Items 1 to 6, wherein the step of measuring the first and second magnetic resonance signals measures the magnetic resonance signals by setting the phases of the first and second reference waves according to each step while fixing the phase difference between the first and second reference waves at π / 2 and changing the phase of a pulse that excites the magnetic resonance signals in a stepwise manner, and the step of performing complex Fourier transform combines the first and second magnetic resonance signals in accordance with the phase difference between the pulses that excite the magnetic resonance signals that has been changed in a stepwise manner. (Item 8) A method of measuring multidimensional nuclear magnetic resonance signals by the method of measuring nuclear magnetic resonance signals according to any one of Items 1 to 7. (Item 9) An apparatus for measuring a nuclear magnetic resonance signal of an object to be measured using a quantum sensor element that changes due to an interaction with the object to be measured as a magnetic field probe, the apparatus 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 in a first pulse sequence as a first reference wave, and irradiates the quantum sensor element with the electromagnetic wave in a second pulse sequence obtained by shifting the timing of the first pulse sequence as a second reference wave that has a phase shifted relative to the first reference wave; 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; and a complex Fourier transform unit that 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.(Item 10) The nuclear magnetic resonance apparatus according to Item 9, wherein the signal measurement unit comprises: 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 caused in the quantum sensor element by the light irradiation, and a data processing unit that reads out information about the electron spin state from the detected change. (Item 11) The nuclear magnetic resonance apparatus according to Item 9 or 10, further comprising a frequency calculation unit that 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 of the measurement object obtained by the complex Fourier transform.

[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.

[0011] FIG. 4 is a diagram for explaining a method for measuring nuclear magnetic resonance signals according to the present invention. FIG. 5 is a diagram schematically showing a general configuration of a nuclear magnetic resonance apparatus according to an embodiment. FIG. 6 is a diagram schematically showing an example of a specific configuration of the nuclear magnetic resonance apparatus shown in FIG. 2. FIG. 7 is a diagram showing an example of a specific configuration around the probe shown in FIG. 3. FIG. 8 is a flowchart showing the procedure of a method for measuring nuclear magnetic resonance signals according to an embodiment. FIG. 9 is a pulse sequence and a result of Fourier transform used in Example 1. FIG. 10 is a result of complex Fourier transform in Example 1. FIG. 11 is a pulse sequence of phase rotation used in Example 2. FIG. 12 is a diagram for explaining a set of four phase rotations used in Example 2. FIG. 13 is a result of complex Fourier transform in Example 2. FIG. 14 is a pulse sequence used in Example 3. FIG. 15 is a measurement result and a simulation result of two-dimensional NMR performed in Example 3.

[0012] Hereinafter, embodiments 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 will denote the same or similar components, and therefore, redundant descriptions of the same or similar components will be omitted.

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

[0014] In the present invention, a freely variable reference wave phase is introduced into the quantum heterodyne (Qdyne) method based on heterodyne detection, which enables the application of phase-based techniques used in conventional NMR spectroscopy, such as quadrature detection and phase rotation, to measurement techniques that use NV centers as NMR probes.

[0015] In the illustrated example, the magnetic resonance signal from the NV center is detected by optically detected magnetic resonance (ODMR). That is, the illustrated Qdyne pulse sequence is a pulse sequence including irradiation with laser light and microwave pulses. First, the electron spin state of the NV center is initialized by irradiation with laser light. Next, the electron spin state of the NV center is manipulated by irradiation with microwave pulses. Finally, the electron spin state of the NV center is read out by irradiation with laser light and initialized for the next pulse sequence. Other methods capable of measuring the spin state of the NV center, such as electrically detected magnetic resonance (EDMR), 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. That is, 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 part of the figure and the pulse sequence shown in the lower part of the figure. ｓ and the pulse interval τ of the dynamic decoupling, it is expressed by the following equation.

[0017]

[0018] In the illustrated example, quadrature detection with a relative phase shift of 90° (π / 2) is shown as an example of a shift. 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 S obtained by the pulse sequence shown in the upper part of the figure ０ is the real part, and the magnetic resonance signal S obtained by the pulse sequence shown in the lower part of the figure ９０ These signals are combined, with the imaginary part being , and the combined signal is subjected to a complex Fourier transform. This enables quadrature detection in measurements using the NV center as an NMR probe, and makes it possible to calculate the NMR frequency including positive and negative signs, which cannot be obtained using conventional measurement techniques that use 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 also possible to change the reference wave phase Φ for each XY-8. By utilizing 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 of the figure and the pulse sequence shown in the lower part of the figure 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, Qdyne measurement is performed on an NMR signal starting from phase 0, and when the vibration phase of the measurement result is 0, that sequence is considered to be the reference wave 0°.

[0022] Preferably, the frequencies of the first and second reference waves are set to 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 measuring an actual sample. The solvent is, for example, water (H ２ 0), in which case the peak frequency is about 4.7 ppm.

[0023] [Device Configuration] Fig. 2 is a diagram schematically showing a general configuration of a nuclear magnetic resonance apparatus according to one embodiment. Fig. 3 is a diagram schematically showing an 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 the 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 produced in advance by a known method, for example in the form of a layer, in a predetermined region on the diamond crystal 12. Illustratively, the region contains 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 the measurement object 9. In this embodiment, the measurement object 9 is a sample of organic or inorganic molecules or biomolecules, and any molecular sample can be used as the measurement object 9. The interaction 8 is an interaction due to a magnetic field.

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

[0028] The electromagnetic wave irradiating unit 2 irradiates the sensor element 1 with electromagnetic waves using different pulse sequences with shifted timing. In this embodiment, the electromagnetic wave irradiating unit 2 irradiates the sensor element 1 with electromagnetic waves using a first pulse sequence as a first reference wave, and irradiates the sensor element 1 with electromagnetic waves using a second pulse sequence obtained by shifting the timing of the first pulse sequence 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 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, lithography technology, using a conductive metal.

[0030] As shown in Figure 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 centers 1 of the diamond are formed in layers in the diamond crystal 12. Laser light (exemplary, about 532 nm) for initializing and detecting the state of the NV centers 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 at the surface of the diamond crystal 12. This allows measurement to be performed without exposing the sample to laser light, even if the sample to be measured 9 is placed on the surface of the diamond 12. A static magnetic field B is applied to the sample to be measured 9 and the probe 11 by an electromagnet 7. ０ is applied. ０ The magnetic field direction is aligned with one of the axial directions of the NV center 1.

[0031] As shown in Fig. 4B, the fluorescence FL from the NV center 1 passes through a prism 13 with a mirror-coated slope, 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 (e.g., about 633 nm). Illustratively, the detection volume of the sample of the measurement target 9 is about 20 µm ３ is.

[0032] 2 and 3 again. The signal measurement unit 3 measures magnetic resonance signals corresponding to the respective pulse sequences from the sensor elements 1 irradiated with electromagnetic waves using different pulse sequences with shifted timing, combines the measured signals, and performs a complex Fourier transform. In this embodiment, the signal measurement unit 3 measures a first magnetic resonance signal from the sensor elements 1 irradiated with electromagnetic waves using a first pulse sequence, and measures a second magnetic resonance signal from the sensor elements 1 irradiated with electromagnetic waves using 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 object 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 object 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 depending on the type of the sensor element 1. In this embodiment, the light source 311 emits laser light with a wavelength of approximately 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 changes occurring in the sensor element 1. In this embodiment, the detection unit 32 detects light emitted from the sensor element 1, and detects a magnetic resonance signal as a change in light emission intensity using a known optically detected magnetic resonance (ODMR) method. In this case, the detection unit 32 can be, for example, a known photodiode. The photodiode can be, for example, an avalanche photodiode. In this embodiment, the electromagnetic wave irradiation unit 2 irradiates the operating electromagnetic wave in a pulsed form. Therefore, in this embodiment, detection is specifically performed using 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 interacting with the measurement object 9 from the changes 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] Various information terminal devices such as a known general-purpose computer or a smartphone can be used as the data processing unit 33. The data processing unit 33 may be configured as an integral part of the device 10, or as shown in the figure, may be provided externally to the device 10 and connected to the device 10 via a wired or wireless network 99.

[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 unit 332 calculates values ​​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 nuclear magnetic resonance signals according to one 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 the measurement procedure will be described below with reference to FIGS. 5 and 1 .

[0042] In step S1, an electromagnetic wave for manipulating the electron spin state of the sensor element 1 is irradiated to the sensor element 1 as a first reference wave using 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 electron spin state of the sensor element 1 is irradiated onto the sensor element 1 using a second pulse sequence as a second reference wave, and a second magnetic resonance signal is measured from the sensor element 1. The second reference wave is a reference wave whose phase is shifted relative 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, which provides a spectrum of the nuclear magnetic resonance signal (NMR signal) of the object 9 to be measured.

[0045] The phase shift between the first and second pulse sequences is 90°. The first magnetic resonance signal is converted into a signal S ０ Then, the second magnetic resonance signal is a signal S ９０ In this embodiment, the first magnetic resonance signal S ０ is the real part, and the second magnetic resonance signal S ９０ The signal (S ０ +iS ９０ ) is subjected to 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 object 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 processing of step S4 is optional. There are cases where it is not always necessary to calculate values ​​including the positive and negative frequencies of the nuclear magnetic resonance signal (NMR signal) of the measurement object 9, such as in applications to phase rotation and multidimensional NMR, which will be described later.

[0048] [Phase Rotation] A method for measuring nuclear magnetic resonance signals according to one embodiment can incorporate a phase rotation technique in nuclear magnetic resonance. The details of the phase rotation technique are well established and are achieved by interlocking the excitation pulse and receiver phase. For example, a well-known phase rotation technique is a method in which the phase of the excitation pulse is changed in increments of 0° to 90° while the receiver phase is also changed in increments of 0° to 90° (cyclically-ordered phase-sequence: CYCLOPS). In this embodiment, the phase rotation technique is introduced by interlocking the phase of a reference wave irradiated as an excitation pulse with the receiver phase.

[0049] That is, in one embodiment of the method for measuring nuclear magnetic resonance signals, the step of measuring the first and second magnetic resonance signals can measure 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; and the step of performing complex Fourier transform can combine the first and second magnetic resonance signals according to the phase difference between the pulse that excites the magnetic resonance signals that has been gradually changed.

[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 these first and second magnetic resonance signals to change the receiver phase. For actual examples of the combination pattern and the sign inversion pattern, see the examples described below.

[0051] [Multidimensional NMR] The method for measuring nuclear magnetic resonance signals according to an embodiment can be applied to, for example, one-dimensional NMR measurement, which serves as the 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, for example, COSY (COrrelation Spectroscopy) and TOCSY (Total Correlation Spectroscopy), which are known as two-dimensional NMR and target homonuclear correlation, and HSQC (Heteronuclear Single Quantum Correlation) and HMBC (Heteronuclear Multiple Bond Correlation), which target heteronuclear correlation. Similarly, the method can also be applied to multidimensional NMR.

[0052] As described above, the nuclear magnetic resonance apparatus or nuclear magnetic resonance signal measurement method according to one embodiment provides a new method for measuring nuclear magnetic resonance signals in NMR spectroscopy using a quantum sensor element as an NMR probe. This makes it possible to apply phase-based techniques used in conventional NMR spectroscopy, such as quadrature detection and phase rotation, to measurement techniques using a quantum sensor element as an NMR probe. Because quantum sensor elements, including NV centers, are highly sensitive magnetic field sensors, using such quantum sensor elements as an NMR probe enables structural analysis of much smaller samples than conventional methods. It is also possible to calculate values, including both positive and negative frequencies, of the nuclear magnetic resonance signal (NMR signal) of the measurement object 9.

[0053] [Other Embodiments] 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-described embodiment, a diamond crystal is used as the sensor element 1, and an NV center is used as the color center of the diamond, but the color center used is not limited to the NV center. Instead of the NV center, a silicon-vacancy center or a germanium-vacancy center can be used as the color center of the diamond in the sensor element 1. In addition, the color center is not limited to the color center of a diamond crystal, and color centers of various crystals can be used in the sensor element 1.

[0055] In the above-described embodiment, a diamond color center is used for the sensor element 1, but the sensor element 1 used is not limited to a diamond color center. Instead of a diamond color center, various quantum sensors such as a silicon carbide (SiC) color center, an optically pumped magnetometer (OPM), or a superconducting quantum interference device (SQUID) can be used for the sensor element 1, as long as the electron spin state can be manipulated by irradiating the sensor element 1 with electromagnetic waves.

[0056] In the above-described 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 magnetic resonance signals 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 differences in the lifetime of the excited state, which depends on the spin state. The detection unit 32 detects the electrical resistance of the sensor element 1 (or the photocurrent generated in the sensor element 1) to detect the magnetic resonance signal as a change in electrical resistivity (or a change in photocurrent due to light irradiation). In other words, the detection unit 32 functions as an electrical detection unit. A known ammeter, for example, can be used as the detection unit 32.

[0058] Examples of the present invention will be described below to clarify the features of the present invention.

[0059] In Example 1, an AC magnetic field having a frequency simulating a signal of proton nuclear spin was measured, and it was verified that quadrature detection was 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 transform of 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 the signal S from the reference wave phase 0°. ０ and the signal S90 from the reference wave phase 90° are combined as a complex number to form a signal S=S ０ +iS ９０ The upper part of FIG. 6B shows the result of complex Fourier transform of the signal S from the reference wave phase 0° as a comparative example. ０ This is the result of Fourier transforming only

[0062] As shown in the upper part of FIG. 6B, the signal S ０ In contrast, as shown in the lower part of FIG. 6B, when the signal S ０ When the signal S90 from the reference wave phase 90° was combined as a complex number, the mirror image with the same difference from the reference wave but with a different sign was removed. This enabled quadrature detection, and values ​​including both positive and negative frequencies could be obtained.

[0063] We were also able to confirm the following three benefits of quadrature detection.

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

[0065] Second Advantage The second advantage 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 advantage is that it is possible to reduce the solvent peak that is often a problem in the measurement of actual samples. The most typical example is water (H ２ The solvent peak is the 4.7 ppm (4.7 ppm) peak. The concentration of pure water is so high that it produces a peak that is overwhelmingly larger than the sample molecules being measured, and the signal peaks around the water are obscured by the huge peak, or the spectrum baseline is distorted. The simplest and most basic method for dealing with this solvent peak is to set the reference wave frequency to match the frequency of the solvent peak. In measurements of biological systems, the most common water peak is 4.7 ppm, located in the center of the spectrum, so orthogonal detection, which does not produce mirror images, is desirable.

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

[0068] The phase rotation pulse sequence used in Example 2 is shown in Fig. 8. More specifically, in Example 2, as shown in Fig. 9, the phase Φ of the excitation pulse is rotated by a set of four 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 results of the complex Fourier transform are shown in Fig. 10. The graph on the right side of Fig. 10 shows the measurement results when phase rotation is applied using the pulse sequences shown in Fig. 8 and Fig. 9. The graph on the left side of Fig. 10 shows the measurement results when no phase rotation is applied and the phase Φ of the excitation pulse is ｐｕｌｓｅ and the receiver phase Φ ｒｅｃｅｉｖｅｒ Both are measurement results for only 0°. In the graph on the right, where phase rotation was applied, there is some disruption of 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.

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

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

[0072] The molecular sample measured in Example 3 was acetaldehyde. Acetaldehyde has chemical shifts at 2.206 ppm and 9.789 ppm. The J coupling value is 2.9 Hz. This 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 a bond between two types of protons.

[0073] In Example 3, a simulation was performed using SPINACH to obtain detected FID data as complex numbers. An AC magnetic field was then created by upconverting the data to the proton Larmor frequency of 3.571 MHz at 83 mT, 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 quadrature detection (Qdyne) to demonstrate two-dimensional NMR measurements. The observation center was set to 6 ppm, the central part of the spectrum. The use of quadrature detection allows measurements to be performed while avoiding the generation of mirror images symmetrical about the t2 axis. The States method was used to fold the t1 axis. Measurements were performed with the phase of the first 90-degree pulse set to 0° and 90°, and the resulting signals were designated P0 and P90, respectively. In this case, after complex Fourier transform on the t2 axis, by complex Fourier transforming the data having the imaginary components of signal P0 as real numbers and the real components of signal P90 as imaginary numbers on the t1 axis, it becomes 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 Figure 12 (B) and (C) were compared. Referring to the measurement results shown in (C), the J coupling, signal phase, and chemical shift were reproduced in the cross peaks. No aliasing signals were generated on either the t1 or t2 axes.

[0076] The measurement results shown in (C) are somewhat unclear, but this is thought to be due to bit errors in the arbitrary waveform generator, insufficient integration time, and broadening due to the attenuation term multiplied by the AC magnetic field.

[0077] REFERENCE SIGNS LIST 1 Sensor element (diamond NV center) 2 Electromagnetic wave irradiation unit 3 Signal measurement unit 7 Electromagnet 8 Interaction 9 Measurement object (sample) 10 Nuclear magnetic resonance apparatus 11 Probe 12 Diamond crystal 13 Prism 14 Antenna 15 Focusing optical system 151 CPC (Compound Parabolic Concentrator) lens 152 Condenser lens 153 Long-pass filter 21 Microwave (MW) oscillator 22 Switch 23 Amplifier 31 Light irradiation unit 311 Light source 312 Acousto-optical modulator (AOM) 32 Detection unit 33 Data processing unit 331 Complex Fourier transform unit 332 Frequency calculation unit 99 Network

Claims

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

2. The measurement method according to 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 t between the first and second pulse sequences. ｓ and a pulse interval τ of the dynamic decoupling, 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 a 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 correspond to a peak frequency of a solvent that dissolves the sample to be measured.

7. The measurement method according to claim 1, wherein the step of measuring the first and second magnetic resonance signals comprises: fixing a phase difference between the first and second reference waves at π / 2; varying the phase of a pulse for exciting a magnetic resonance signal in stages; setting the phase of the first and second reference waves in accordance with each stage; and measuring the magnetic resonance signal; and the step of performing complex Fourier transform combines the first and second magnetic resonance signals in accordance with the phase difference of the pulse for exciting the magnetic resonance signal that has been changed in stages.

8. A method for measuring multidimensional nuclear magnetic resonance signals using 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 the electronic spin state of the quantum sensor element in a first pulse sequence as a first reference wave, and irradiates the quantum sensor element with the electromagnetic wave in a second pulse sequence in which the timing of the first pulse sequence is shifted as a second reference wave in which the phase is changed relative to the first reference wave; 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; and a complex Fourier transform unit that 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.

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

11. The nuclear magnetic resonance apparatus according to claim 9 or 10, further comprising a frequency calculation unit that 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 of the measurement object obtained by the complex Fourier transform.

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