A method for detecting pH value of living body using magnetic resonance signal of N-acetylaspartic acid molecule for non-diagnostic purpose

Abstract

The present invention discloses a method for measuring the pH value of a living organism using the magnetic resonance signal of N-acetyl aspartic acid (NAA) molecules. 1 The nuclear spin singlet of the three-spin system composed of H realizes the methylene of NAA molecule 1 Selective and precise observation of H magnetic resonance signals. 1 The H MR signal is sensitive to the environmental pH value, which is obtained by the methylene 1 The H magnetic resonance signal can realize the accurate measurement of the pH value of living organisms. The method of the present invention can measure the pH value of living human organs quickly, non-invasively and without radiation, has good accuracy and sensitivity, and has important application value in biology, medicine and other fields.

Description

Technical Field

[0001] The present invention belongs to the field of magnetic resonance technology, and in particular relates to a method for detecting pH value of a living body by using magnetic resonance signals of N-acetyl aspartic acid (NAA) molecules for non-diagnostic purposes. Background Art

[0002] The normal human body environment usually has a certain acidity and alkalinity. When the human body environment has an acid-base imbalance (i.e., it is more acidic or alkaline than normal), it means that the health of the human body has changed. By observing the acidity and alkalinity of the body environment, it is not only possible to achieve early diagnosis of diseases, but also helps to judge the treatment effect during the treatment of some diseases.

[0003] The magnetic resonance signals of many biochemical molecules in the human body have obvious pH dependence. If we can accurately observe the magnetic resonance signals of biochemical molecules affected by pH in living organisms and establish a connection between pH and the magnetic resonance signals of biochemical molecules, we can achieve in vivo magnetic resonance observation of the pH value of the environment in which the biochemical molecules are located. N-acetylaspartic acid (NAA) is a common biochemical molecule that is widely present in the biological brain and is an important indicator for evaluating neuronal activity and brain cell metabolic activity. There is a methylene chemical group in the chemical structure of NAA, and the magnetic resonance signal (chemical shift and J coupling) of this group has a significant dependence on pH. Therefore, if we can accurately observe the methylene shift of NAA molecules in vivo 1 The chemical shift and J coupling of the H signal will make it possible to realize in vivo magnetic resonance observation of the pH value of the human body.

[0004] However, classical in vivo magnetic resonance techniques (e.g., magnetic resonance spectroscopy, MRS) can usually only observe the methyl groups of NAA molecules in living organisms. 1 H signal, the methylene of NAA molecule cannot be observed 1 In particular, it is often impossible to obtain the J coupling value, chemical shift of the methylene group of the NAA molecule, and the difference between the chemical shift of the methylene group and the methyl group of the NAA molecule. Based on the classical in vivo magnetic resonance technology, it is impossible to accurately observe the methylene group of the NAA molecule. 1 The H signal is used to measure the pH value of living organisms. Summary of the invention

[0005] In order to solve the shortcomings of the prior art, the present invention proposes a method for detecting the pH value of a living body using the magnetic resonance signal of NAA molecules for non-diagnostic purposes. The method of the present invention cannot directly obtain the diagnosis result of the disease. 1 H signal was precisely observed, and based on the methylene1 The magnetic resonance signal of the H signal was compared with the magnetic resonance signal of the NAA molecule at different pH values, and the pH value of the brain area containing NAA in the human brain was observed. The experiment proved that this method is fast, non-invasive, can be applied to living organisms, and the measurement results have good stability and sensitivity.

[0006] The present invention is directed to the methylene and methine groups of the NAA molecule. 1 The magnetic resonance signal of the nuclear spin system has good sensitivity to the acidity and alkalinity of its surrounding environment. When the pH value changes, the chemical shift and J coupling of the methylene molecule will change. The present invention prepares the methylene and methine of NAA molecules by designing a new pulse sequence. 1 The nuclear spin singlet of the 3-spin system composed of H is used to realize the methylene of NAA molecule by taking advantage of the fact that the nuclear spin singlet is not affected by the gradient field and evolves. 1 Selective and precise observation of H magnetic resonance signals. 1 The correspondence between the H magnetic resonance signal and the acidity and alkalinity of the surrounding environment enables accurate measurement of the pH of the environment in which biochemical molecules in living organisms are located.

[0007] The present invention provides a method for measuring the pH value of a living organism using N-acetyl aspartic acid (NAA) molecular magnetic resonance signals for non-diagnostic purposes. The method flow is as follows: Figure 2 As shown, specifically including:

[0008] Step i: Prepare the methylene and methine groups of NAA molecules using a pulse sequence 1 H constitutes a nuclear spin singlet of a 3-spin system; the nuclear spin singlet obtained by the preparation is R x S x +R y S y +I n ;

[0009] Step ii: Using the characteristic that the nuclear spin singlet is not affected by the pulse gradient field, the methylene group of the NAA molecule is 1 Selective observation of H magnetic resonance signals;

[0010] Step iii: The measured NAA molecules in the actual living organism are 1 The H magnetic resonance signal is compared with the magnetic resonance signal of NAA molecules at different pH values ​​to determine the pH value of the environment surrounding the NAA molecules;

[0011] The magnetic resonance signals include J coupling value, two methylene 1 H chemical shift (ω R ,ωS ), and these two methylene groups and the methyl group of the NAA molecule 1 The difference in H chemical shift (Δω R and Δω S ) etc.

[0012] In the step i, using Figure 3 The pulse sequence shown in FIG. 1 is used to prepare the spin singlet state of the NAA molecule 3 spin system, and the preparation steps include: 1 H spins (labeled R and S, see Figure 1 ) and 1 methine 1 H spin (labeled I, see Figure 1 ) is composed of a spin system, consisting of a thermal equilibrium state R z +S z +I z Transition to state R x S x +R y S y +I n , where n∈{x,y,z}.

[0013] In step ii, a pulse gradient field is used to eliminate or suppress the methylene groups of the NAA molecules. 1 Signals other than the singlet state signal of H nuclear spin can be used to detect the methylene group of NAA molecule 1 Selective observation of H magnetic resonance signals. Adjust the intensity, time, application times and position of the pulse gradient field to achieve selective observation of the methylene groups of the NAA molecule. 1 Optimization of selective observation of H magnetic resonance signals.

[0014] In step iii, the methylene group of the NAA molecule of the actual living organism is 1 Precise observation of H magnetic resonance signals to obtain methylene 1 H magnetic resonance signals, including: J coupling value, two 1 Chemical shift of H R and ω S , and these two 1 The difference between the chemical shifts of H and the methyl signal of NAA molecules, namely Δω R and Δω S By placing the methylene 1 H magnetic resonance signal and NAA molecules at different pH values 1 The pH value of the environment around the NAA molecule can be measured by comparing the H magnetic resonance signal.

[0015] In addition, the present invention also includes the following basic steps: (1) locating the area to be observed in the living organism by conventional magnetic resonance imaging technology. (2) if necessary, acquiring the MRS spectrum of the area to be observed by conventional magnetic resonance spectroscopy (MRS) technology.

[0016] Specifically, the present invention is directed to the methylene and methine groups in the NAA molecule. 1 The coupling characteristics of the three-spin system composed of H are designed. Figure 3 The pulse sequence shown in Figure 1 is mainly composed of the "Single State Preparation and Selection" module and the "Magnetic Resonance Spectroscopy" module.

[0017] In the "single state preparation and selection" module, the present invention targets the methylene and methine groups in the NAA molecule. 1 Based on the characteristics of the 3-spin system composed of H, the optimized control pulse technology based on numerical calculation is used to design the preparation pulse of the single state of NAA molecule. The main idea of ​​the optimized control pulse technology is to divide the entire optimized control pulse into several small pulses, and improve the transfer efficiency from the initial state to the target state by continuously changing the phase and power of each small pulse. 1 The phase and power of the prepared pulse of the nuclear spin singlet state of the three-spin system composed of H are as follows Figure 4 As shown. Through this preparation pulse, the NAA molecule methylene 1 Preparation of H nuclear spin singlet, wherein the nuclear spin singlet obtained by the preparation is R x S x +R y S y +I n ; and then realize the methylene 1 Selection of H signal;

[0018] In the "Magnetic Resonance Spectroscopy" module, the methylene groups of the NAA molecules are 1 Based on the selection of H signal, the present invention designs a combination of radio frequency pulse and gradient pulse to achieve the specific spatial position of NAA molecule methylene 1 Selective observation of H signal.

[0019] The measured methylene groups of NAA molecules in actual living organisms 1 H magnetic resonance signal and NAA molecules at different pH values 1 By comparing the H magnetic resonance signals, the pH value of the observed specific spatial position can be obtained.

[0020] Furthermore, the Figure 3The "Single State Preparation and Selection" module in the pulse sequence can be mainly composed of "Saturation Pulse", "Optimized Control Pulse 1", "Decoupling Pulse", "Gradient Pulse" and "Optimized Control Pulse 2":

[0021] “Saturation pulse”: mainly used to suppress the signal of water in living tissues. “Saturation pulse” can be used or not according to the needs of system detection;

[0022] "Optimized Control Pulse 1": used to convert the two methylene groups of the NAA molecule 1 H spins (labeled R and S) and 1 of the methine 1 The spin system composed of H spins (labeled as I) is composed of the thermal equilibrium state S z +R z +I z Transition to state R x S x +R y S y +I n (n∈{x,y,z}), thereby achieving the methylene and methine of NAA molecules 1 The nuclear spin singlet state preparation of the H-composed spin system. The present invention designs "optimized control pulse 1" by using the optimized control pulse technology based on numerical calculation. Figure 4 A method for preparing the methylene group of NAA molecules is presented. 1 Example of optimized control pulse of H nuclear spin singlet, where Figure 4 a is the phase of an optimized control pulse, Figure 4 b is the power of the corresponding pulse.

[0023] "Decoupling pulse": used to preserve the nuclear spin singlet state of NAA molecules and eliminate the magnetic resonance signal of some non-nuclear spin singlet states in the analyte. In natural abundance samples, this purpose can be achieved with conventional homonuclear decoupling pulses.

[0024] “Gradient pulse”: used to further eliminate other signals in the object to be tested except the nuclear spin singlet state.

[0025] "Optimized Control Pulse 2": used to convert the methylene and methine groups of NAA molecules 1 The H nuclear spin single state signal is converted to a thermal equilibrium state. The present invention designs "optimized control pulse 2" by using the optimized control pulse technology based on numerical calculation. Figure 5 An example of optimized control pulses for converting the nuclear spin singlet signals of the methylene and methine groups of NAA molecules to thermal equilibrium is shown, where Figure 5 a is the phase of an optimized control pulse, Figure 5 b is the power of the corresponding pulse.

[0026] Figure 3The "Magnetic Resonance Spectroscopy" module in the pulse sequence is mainly composed of radio frequency gradient pulses and selected layer pulses, the purpose of which is to achieve the detection of the methylene groups of NAA molecules in a specific spatial position. 1 In order to achieve selective observation of the H signal, the methylene groups of NAA molecules in specific spatial positions 1 The selection of H signal can use the conventional T1 weighted sequence to locate the position of the living organism in the magnetic field. This part of knowledge is well known in the field and will not be further elaborated in the present invention.

[0027] In some specific embodiments, a conventional T1-weighted sequence (or a similar pulse sequence that can provide in vivo magnetic resonance images) is first used to locate the position of the living organ in the magnetic field, and the region of the living organ to be measured is selected. Figure 3 The pulses are shown. Among them, the "saturation pulse" is applied to suppress the water signal in the human body; the "optimized control pulse 1" is used to prepare the nuclear spin singlet signal of the methylene and methine of the NAA molecule. This pulse is obtained by the optimized control pulse technology based on numerical calculation. The action time is 40ms and it consists of 1000 40μs independent pulses. The phase and power of each pulse are shown in Figure 4 a and 4b; "decoupling pulse" is used to preserve the single state of NAA molecules. In some specific embodiments, the present invention uses a continuous wave decoupling pulse. Among them, the power of the decoupling pulse is 400Hz and the time is 1ms; the intensity of the "gradient pulse" is 2Gauss / cm and the action time is 2ms. This pulse is used to suppress other signals except the NAA spin single state signal; "optimization control pulse 2" is used to convert the nuclear spin single state signal of the methylene and methine of the NAA molecule to a thermal equilibrium state. The total pulse time is 40ms, consisting of 1000 independent pulses of 40μs. The phase and power of each pulse are shown in Figure 5 a and 5b.

[0028] In the "Magnetic Resonance Spectroscopy" module, a pulse combination of one 90-degree and two 180-degree sinc pulses enables the selection of voxels in living organs.

[0029] Under the above conditions, Figure 3 The pulses shown are applied to the human body to obtain Figure 6 b 1 H spectrum. In this spectrum, there is an obvious 7-fold peak with J coupling characteristics between 2.2ppm and 3.0ppm. This signal is the methylene of NAA molecules. 1 H magnetic resonance signal. 1 H MR signal and methylene groups of NAA molecules at different pH values 1 By comparing the H magnetic resonance signals, the pH value at the corresponding position of the relevant human living organ can be obtained.

[0030] The beneficial effect of the present invention is that the present invention is based on magnetic resonance technology and has a significant feature and innovation point that is different from other previous magnetic resonance spectroscopy technologies: that is, it realizes the detection of the methylene groups of NAA molecules in the living human brain. 1 The precise observation of H signals and the methylene groups of NAA molecules in the living human brain 1 The H signal realizes the measurement of brain pH value. The method of the present invention can measure the pH value of living human organs quickly, non-invasively and without radiation, has good accuracy, sensitivity and stability, has important application value in biology, medicine and other aspects, and is a new and original technology. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The schematic diagram of the molecular structure of NAA of the present invention is shown in FIG. 1 , wherein R and S represent the two methylene groups on the NAA molecule. 1 H proton, I marks a methine 1 H proton.

[0032] Figure 2 The specific implementation process of the present invention includes: (1) preparing the methylene and methine groups in the NAA molecule by a suitable pulse sequence; 1 The nuclear spin singlet of the three-spin system composed of H; (2) based on the prepared nuclear spin singlet, the methylene 1 Selective observation of H signal; (3) by measuring the methylene groups of NAA molecules in actual living organisms 1 By comparing the H magnetic resonance signal with the magnetic resonance signal of NAA molecules at different pH values, the pH value of the environment surrounding the NAA molecules in the observation space can be obtained.

[0033] Figure 3 The present invention is used to accurately observe the methylene groups of NAA molecules in living bodies 1 Schematic diagram of the pulse sequence of H signal. 1 H represents hydrogen channel, G x ,G y and G z They represent the pulse gradient channels in the x, y, and z directions respectively, g1 is the gradient pulse, 90 x ,180 y ,180 y are the pulse and phase used for the layer selection pulse respectively.

[0034] Figure 4 Schematic diagram of the phase and power changes of the pulse sequence of the "optimized control pulse one" of the present invention. Figure 4 a is a schematic diagram of the phase change of the pulse sequence of "optimized control pulse one", Figure 4b is a schematic diagram of the pulse sequence power variation of “optimized control pulse one”.

[0035] Figure 5 Schematic diagram of the phase and power changes of the pulse sequence of the "optimized control pulse 2" of the present invention. Figure 5 a is a schematic diagram of the phase change of the pulse sequence of "optimized control pulse 2", Figure 5 b is a schematic diagram of the pulse sequence power variation of “optimized control pulse two”.

[0036] Figure 6 This is a T1-weighted image of human brain magnetic resonance imaging and a magnetic resonance spectrum image of a selected region according to an embodiment of the present invention. Figure 6 a is a conventional T1-weighted image of a normal human brain. The box in the figure indicates the area observed by the magnetic resonance spectrum. Figure 6 b is used Figure 3 Pulse selection Figure 6 a The area indicated by the box 1 H magnetic resonance spectroscopy.

[0037] Figure 7 is the NAA molecule at different pH values 1 H magnetic resonance spectrum. The top grey line is the magnetic resonance signal of a normal human brain measured using the pulse of the present invention, and the grey frame is the signal of the methylene group of the NAA molecule.

[0038] Figure 8 It is a schematic flow chart of the main steps of an implementation method of the present invention.

[0039] Fig. 9 The conventional T1-weighted image, conventional MRS magnetic resonance spectrum and the conventional T1-weighted image of the water film sample (comprising a concentrated solution of 1.2% NAA, 0.4% glutamic acid and 1.2% glutamine) of the embodiment of the present invention are shown in FIG. Figure 3 Pulse magnetic resonance spectrum. Among them, Fig. 9 a is a conventional T1-weighted image of a water film sample. The box in the figure indicates the area observed by the magnetic resonance spectrum. Fig. 9 b is selected for conventional magnetic resonance spectroscopy (MRS) Fig. 9 a Magnetic resonance spectrum obtained in the area indicated by the box, Fig. 9 c is used Figure 3 Pulse Pair Fig. 9 a Magnetic resonance spectrum obtained in the area indicated by the box.

[0040] Fig.10 In Example 3 of the present invention, different subjects were tested using Figure 3 Pulse magnetic resonance spectroscopy. Fig.10 a is for normal 25-year-old women, using Figure 3 Pulse acquisition of magnetic resonance spectra; Fig.10b is for normal 24-year-old males, using Figure 3 Pulse acquisition of magnetic resonance spectra; Fig.10 c is for normal 25-year-old males, using Figure 3 Pulse-acquired magnetic resonance spectrum. The gray box shows the signal of the methylene group of the NAA molecule. DETAILED DESCRIPTION

[0041] The invention is further described in detail with reference to the following specific embodiments and drawings. The process, conditions, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art and are not particularly limited by the present invention.

[0042] The main steps of the implementation process are as follows Figure 8 As shown:

[0043] 1. Use a conventional T1-weighted sequence (or a similar pulse sequence that can provide in vivo magnetic resonance images) to locate the position of a living organ (such as the human brain) in the magnetic field and select the region of the living organ to be tested.

[0044] 2. Apply Figure 3 The pulse shown above obtains the NAA methylene group in the area to be tested in the living body. 1 H signal.

[0045] 3. The methylene groups of NAA molecules in the living body are obtained 1 H signal and methylene groups of NAA molecules at different pH values 1 By comparing the H signal, the pH value of the observed area in the living body is obtained.

[0046] In the implementation process, a localized in vivo magnetic resonance image is provided, which can be obtained by various conventional pulse sequences. The present invention is applicable to the preparation and detection of singlet states of 3 spins and is not limited to Figure 3 , 4, 5 described in the optimized pulse method.

[0047] Example 1

[0048] Experimental subjects: normal 25-year-old women.

[0049] Measuring instrument: Siemens 3T Prisma nuclear magnetic resonance instrument, the detection coil used is Siemens 64-channel head coil.

[0050] Determination method: Figure 3 Pulse sequence shown.

[0051] The experimental steps are as follows:

[0052] 1. Use conventional T1-weighted sequences to locate the position of the human brain in the magnetic field and select the living organ area to be tested. See the MRI image of the human brain and the selected area. Figure 6a.

[0053] 2. Apply Figure 3 During the experiment, the "saturation pulse" used to suppress the water signal consists of 4 Gaussian pulses with a pulse width of 250ms and a power of 35Hz; the "optimized control pulse 1" is obtained by the optimized control pulse technology based on the numerical calculation GRAPE method, with an action time of 40ms and composed of 1000 40μs independent pulses. The phase and power of these pulses are shown in Figure 4 a and 4b. The RF center of "optimized control pulse 1" is 2.66ppm, and the total power is 100Hz. "Decoupling pulse" uses continuous wave decoupling, where the RF center is 2.66ppm, the power is 400Hz, and the application time is 1ms; the power of "gradient pulse" is 2Gauss / cm, and the action time is 2ms; "optimized control pulse 2" is obtained by the optimized control pulse technology based on the numerical calculation GRAPE method, with an action time of 40ms, and consists of 1000 40μs independent pulses. The phase and power of these pulses are shown in Figure 5 a and 5b. The RF center of the "optimized control pulse 2" is 2.66ppm and the total power is 100Hz. The "magnetic resonance spectroscopy" pulse module contains one 90-degree and two 180-degree sinc pulses with pulse times of 1ms, 2ms and 2ms respectively. The power of these pulses is 250Hz. During the experiment, the power and RF center of the optimized control pulse can be fine-tuned to optimize the methylene group of the NAA molecule. 1 H signal.

[0054] 3. Then the obtained human brain NAA molecule methylene 1 The H signal was compared with the previously obtained methylene signals of NAA molecules at different pH values ​​(see Figure 7 ) to obtain the observed area in the living brain (see Figure 6 ) has a pH value of about 7.4.

[0055] Example 2

[0056] Experimental subjects: 35 mL of a neutral mixed aqueous solution of 0.4% glutamic acid, 1.2% glutamine and 1.2% NAA by mass fraction of solute.

[0057] Measuring instrument: Siemens 3T Prisma nuclear magnetic resonance instrument, the detection coil used is Siemens 64-channel head coil.

[0058] Determination method: Figure 3 Pulse sequence shown.

[0059] The experimental steps are as follows:

[0060] 1. Use conventional T1-weighted sequences to locate the position of the water film sample in the magnetic field and select the water film sample area to be tested. See the water film magnetic resonance image and selected area. Fig. 9 a.

[0061] 2. Apply Figure 3 During the experiment, the "saturation pulse" used to suppress the water signal consists of 4 Gaussian pulses with a pulse width of 250ms and a power of 35Hz; the "optimized control pulse 1" is obtained by the optimized control pulse technology based on the numerical calculation GRAPE method, with an action time of 40ms and composed of 1000 40μs independent pulses. The phase and power of these pulses are shown in Figure 4 a and 4b. The RF center of "optimized control pulse 1" is 2.66ppm, and the total power is 100Hz. "Decoupling pulse" uses continuous wave decoupling, where the RF center is 2.66ppm, the power is 400Hz, and the application time is 1ms; the power of "gradient pulse" is 2Gauss / cm, and the action time is 2ms; "optimized control pulse 2" is obtained by the optimized control pulse technology based on the numerical calculation GRAPE method, with an action time of 40ms, and consists of 1000 40μs independent pulses. The phase and power of these pulses are shown in Figure 5 a and 5b. The RF center of the "optimized control pulse 2" is 2.66ppm and the total power is 100Hz. The "magnetic resonance spectroscopy" pulse module contains one 90-degree and two 180-degree sinc pulses with pulse times of 1ms, 2ms and 2ms respectively. The power of these pulses is 250Hz. During the experiment, the power and RF center of the optimized control pulse can be fine-tuned to optimize the methylene group of the NAA molecule. 1 H signal.

[0062] 3. Conclusions of conventional MRS experiments Fig. 9 As shown in b, the signal at 2.1 ppm is the signal of the methyl group of the NAA molecule, and the signals at 2.2 and 2.3 ppm are glutamic acid and glutamine, among which the glutamine signal overlaps with the methylene signal of the NAA molecule; Fig. 9 c is used Figure 3 Pulse selection Fig. 9 From the magnetic resonance spectrum obtained in the area indicated by the box a, it can be seen that the signals of glutamate and glutamine are greatly suppressed, and only the signal of the methylene group of the NAA molecule is retained. 1 The H signal is compared with the previously obtained NAA molecule methylene signal at different pH values ​​to obtain the observed area in the water film sample (see Fig. 9 a) pH value.

[0063] Example 3

[0064] Experimental subjects: normal 25-year-old female, normal 24-year-old male, normal 25-year-old male

[0065] Measuring instrument: Siemens 3T Prisma nuclear magnetic resonance instrument, the detection coil used is Siemens 64-channel head coil.

[0066] Determination method: Figure 3 Pulse sequence shown.

[0067] The experimental steps are as follows:

[0068] 1. Use conventional T1-weighted sequences to locate the position of different human living brains in the magnetic field and select the living brain area of ​​the sample to be tested. See the magnetic resonance images of the living brain and the selected area. Figure 6 a.

[0069] 2. Apply Figure 3 During the experiment, the "saturation pulse" used to suppress the water signal consists of 4 Gaussian pulses with a pulse width of 250ms and a power of 35Hz; the "optimized control pulse 1" is obtained by the optimized control pulse technology based on the numerical calculation GRAPE method, with an action time of 40ms and composed of 1000 40μs independent pulses. The phase and power of these pulses are shown in Figure 4 a and 4b. The RF center of "optimized control pulse 1" is 2.66ppm, and the total power is 100Hz. "Decoupling pulse" uses continuous wave decoupling, where the RF center is 2.66ppm, the power is 400Hz, and the application time is 1ms; the power of "gradient pulse" is 2Gauss / cm, and the action time is 2ms; "optimized control pulse 2" is obtained by the optimized control pulse technology based on the numerical calculation GRAPE method, with an action time of 40ms, and consists of 1000 40μs independent pulses. The phase and power of these pulses are shown in Figure 5 a and 5b. The RF center of the "optimized control pulse 2" is 2.66ppm and the total power is 100Hz. The "magnetic resonance spectroscopy" pulse module contains one 90-degree and two 180-degree sinc pulses with pulse times of 1ms, 2ms and 2ms respectively. The power of these pulses is 250Hz. During the experiment, the power and RF center of the optimized control pulse can be fine-tuned to optimize the methylene group of the NAA molecule. 1 H signal.

[0070] 3. Fig.10 a is a normal 25-year-old female Figure 3 Pulse acquisition of magnetic resonance spectra; Fig.10 b is a normal 24-year-old male Figure 3 Pulse acquisition of magnetic resonance spectra; Fig.10 c is a normal 25-year-old male Figure 3The magnetic resonance spectrum is obtained by pulse. As can be seen from the figure, the position and peak shape of the methylene signal of the NAA molecule in the normal human brain are exactly the same, so the pH value of the normal human brain is neutral, about 7.4.

[0071] The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention and are protected by the attached claims.

Claims

1. A method for measuring the pH value of a living organism using the magnetic resonance signal of N-acetylaspartic acid molecules for non-diagnostic purposes, characterized in that: The method comprises: Step i: Prepare the methylene and methine groups of N-acetylaspartic acid using a pulse sequence 1 H constitutes a nuclear spin singlet of a 3-spin system; the nuclear spin singlet obtained by the preparation is R x S x +R y S y +I n ; The pulse sequence includes: a single state preparation and selection module, a magnetic resonance spectroscopy module; wherein, The single state preparation and selection module includes: a saturation pulse, an optimized control pulse 1, a decoupling pulse, a gradient pulse and an optimized control pulse 2; the optimized control pulse 1 and the optimized control pulse 2 divide the entire control pulse into a number of small pulses, and improve the transfer efficiency from the initial state to the target state by continuously changing the phase and power of each small pulse; the optimized control pulse 1 and the optimized control pulse 2 have an action time of 40ms respectively, and are composed of 1000 independent pulses of 40μs; The saturation pulse is used to suppress the signal of water in living tissue; The optimized control pulse 1 is used to convert the two methylene groups of the N-acetylaspartic acid molecule labeled R and S into 1 H spin and 1 of the methine labeled I 1 The three-spin coupling system composed of H spins is composed of thermal equilibrium state R z +S z +I z Transform to state R x S x +R y S y +I n , where n∈{x,y,z}, thereby achieving the methylene and methine groups of N-acetylaspartic acid molecules 1 Preparation of nuclear spin singlets of a spin system composed of H; the pulse is obtained by an optimized controlled pulse technology based on numerical calculation; The decoupling pulse is used to preserve the nuclear spin singlet state of the N-acetylaspartic acid molecule and eliminate the magnetic resonance signal of a part of the non-nuclear spin singlet state in the object to be tested; the power of the decoupling pulse is 400 Hz and the time is 1 ms; The gradient pulse is used to further eliminate other signals in the object to be tested except the nuclear spin singlet state; the intensity of the gradient pulse is 2 Gauss / cm, and the action time is 2 ms; The optimized control pulse 2 is used to convert the methylene and methine groups of the N-acetylaspartic acid molecule into 1 The H nuclear spin singlet signal is converted to a thermal equilibrium state; the pulse is obtained by an optimized control pulse technology based on numerical calculation; The magnetic resonance spectroscopy module includes: radio frequency gradient pulses and slice selection pulses; Step ii: Using the characteristic that the nuclear spin singlet state is not affected by the pulse gradient field, the methylene group of N-acetylaspartic acid molecule is cleaved. 1 Selective observation of H magnetic resonance signals; Step iii: The measured N-acetylaspartic acid molecule methylene 1 The H magnetic resonance signal is compared with the magnetic resonance signal of the N-acetylaspartic acid molecule at different pH values ​​to determine the pH value of the environment surrounding the N-acetylaspartic acid molecule.

2. The method according to claim 1, characterized in that In step ii, the pulse gradient field is used to eliminate or suppress the methylene groups of the N-acetylaspartic acid molecules. 1 Signals other than the singlet state signal of H nuclear spin can be used to detect the methylene group of N-acetylaspartic acid molecule 1 Selective observation of H magnetic resonance signals; adjusting the intensity, time, application times and position of the pulse gradient field to achieve selective observation of the methylene groups of N-acetylaspartic acid molecules 1 Optimization of selective observation of H magnetic resonance signals.

3. The method according to claim 1, characterized in that In the step iii, the methylene group of the N-acetylaspartic acid molecule of the actual living organism is 1 Precise observation of H magnetic resonance signals to obtain the methylene group of N-acetylaspartic acid molecules 1 H magnetic resonance signal; by 1 H MR signal and N-acetylaspartate molecules at different pH values 1 By comparing the H magnetic resonance signals, the pH value of the environment surrounding the N-acetylaspartic acid molecule can be measured.

4. The method according to claim 1, characterized in that The N-acetylaspartate molecule 1 H magnetic resonance signals include J coupling value, methylene 1 H chemical shift, methylene 1 H and N-acetylaspartate molecule methyl 1 One or more of the H signal chemical shift differences.

5. Use of the method according to any one of claims 1 to 4 in the detection of pH in living organisms for non-diagnostic purposes.

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