CN114910501A - Method for detecting pH value of living body by using N-acetyl aspartic acid molecular magnetic resonance signal for non-diagnosis purpose - Google Patents
Method for detecting pH value of living body by using N-acetyl aspartic acid molecular magnetic resonance signal for non-diagnosis purpose Download PDFInfo
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- OTCCIMWXFLJLIA-UHFFFAOYSA-N N-acetyl-DL-aspartic acid Natural products CC(=O)NC(C(O)=O)CC(O)=O OTCCIMWXFLJLIA-UHFFFAOYSA-N 0.000 title claims abstract description 112
- OTCCIMWXFLJLIA-BYPYZUCNSA-N N-acetyl-L-aspartic acid Chemical compound CC(=O)N[C@H](C(O)=O)CC(O)=O OTCCIMWXFLJLIA-BYPYZUCNSA-N 0.000 title claims abstract description 112
- 238000000034 method Methods 0.000 title claims abstract description 50
- 238000003745 diagnosis Methods 0.000 title description 6
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims abstract description 80
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims abstract description 19
- KZMAWJRXKGLWGS-UHFFFAOYSA-N 2-chloro-n-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-n-(3-methoxypropyl)acetamide Chemical compound S1C(N(C(=O)CCl)CCCOC)=NC(C=2C=CC(OC)=CC=2)=C1 KZMAWJRXKGLWGS-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000005259 measurement Methods 0.000 claims abstract description 5
- 238000001208 nuclear magnetic resonance pulse sequence Methods 0.000 claims description 25
- 238000001228 spectrum Methods 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 12
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- 238000005859 coupling reaction Methods 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
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- 238000001514 detection method Methods 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 238000005457 optimization Methods 0.000 claims description 5
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- 235000012333 Vitis X labruscana Nutrition 0.000 description 6
- 235000014787 Vitis vinifera Nutrition 0.000 description 6
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
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- 235000013922 glutamic acid Nutrition 0.000 description 3
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- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 3
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
- G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
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Abstract
The invention discloses a method for measuring the pH value of a biological living body by using N-acetyl aspartic acid (NAA) molecular magnetic resonance signals. The method is prepared by preparing the compound from NAA molecules on methylene and methine 1 The nuclear spin singlet of a 3 spin system formed by H realizes the methylene of NAA molecules 1 Selective and accurate observation of H magnetic resonance signals. Due to the methylene group of the NAA molecule 1 H magnetic resonance signal is sensitive to environment pH value, and obtained NAA molecular methylene 1 The H magnetic resonance signal can realize accurate measurement of the pH value of the living organism. The method can rapidly measure the pH value of the living body organ of the human body in a non-invasive and non-radiative manner, has good accuracy and sensitivity, and has important application value in the aspects of biology, medicine and the like.
Description
Technical Field
The invention belongs to the technical field of magnetic resonance, and particularly relates to a method for detecting the pH value of a living body by using N-acetyl aspartic acid (NAA) molecular magnetic resonance signals for a non-diagnosis purpose.
Background
The normal human environment often has a certain acidity or alkalinity. When an acid-base imbalance (i.e., acid or base bias compared to normal) occurs in the human environment, it means that the health condition of the human body is changed. Through the observation of the acid-base property of the body environment, the early diagnosis of diseases is possible, and the judgment of the treatment effect in the treatment process of some diseases is facilitated.
The magnetic resonance signals of many biochemical molecules in the human body have a significant pH dependence. If the magnetic resonance signal of the biochemical molecule influenced by the pH value in the living organism can be accurately observed, and the relation between the pH value and the magnetic resonance signal of the biochemical molecule is established, the magnetic resonance living organism observation of the pH value of the environment where the biochemical molecule is positioned can be realized. N-acetyl aspartic acid (NAA) is a common biochemical molecule, widely exists in biological brains, and is an important index for evaluating neuron activity and brain cell metabolic activity. The chemical structure of NAA has a methylene chemical group, and the magnetic resonance signal (chemical shift and J coupling) of the group has obvious dependence on pH value. Therefore, if the methylene group of NAA molecule in vivo can be accurately observed 1 The chemical shift and J coupling of H signal will make it possible to realize the in vivo magnetic resonance observation of pH value of human body.
However, classical in vivo magnetic resonance techniques (e.g., magnetic resonance spectroscopy, MRS) typically only allow visualization of the methyl group of the NAA molecule in vivo 1 H signal, no observable methylene of NAA molecule 1 The H signal. In particular, J-coupling values, chemical shifts of the methylene groups of the NAA molecules, and differences in the chemical shifts of the methylene and methyl signals of the NAA molecules are often not obtained. Based on the fact that the classical in-vivo magnetic resonance technology cannot accurately observe the NAA molecular methylene 1 The H signal enables measurement of pH of the living organism.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides a method for detecting the pH value of a living body by using NAA molecular magnetic resonance signals, which is not used for diagnosis, and the method can not directly obtain the diagnosis result of the disease. By using the method, the invention can carry out the treatment on the NAA molecular methylene in the brain of the living human 1 The H signal is accurately observed and is based on the methylene 1 The magnetic resonance signal of the H signal is compared with the magnetic resonance signal of the NAA molecule under different pH values, so that the pH value of the brain region containing the NAA in the human brain is observed. Experiments prove that the method is rapid and noninvasive, can be applied to living organisms, and has good and stable measurement resultsSex and sensitivity.
The invention aims at the NAA molecules methylene and methine 1 A 3 spin system consisting of H. The magnetic resonance signal of the nuclear spin system has good sensitivity to the acidity and alkalinity of the surrounding environment. When the pH is changed, both the chemical shift and J-coupling of the methylene molecule are changed. The invention prepares NAA molecular methylene and methine by designing a novel pulse sequence 1 The nuclear spin singlet of a 3 spin system consisting of H utilizes the characteristic that the nuclear spin singlet evolves without the action of a gradient field to realize the methylene of NAA molecules 1 Selective and accurate observation of H magnetic resonance signals. Using the obtained NAA molecular methylene 1 The pH value of the environment where the biochemical molecules in the living organism are located is accurately measured by the corresponding relation between the H magnetic resonance signal and the pH value of the surrounding environment.
The invention provides a method for measuring pH value of a biological living body by using N-acetyl aspartic acid (NAA) molecular magnetic resonance signals for non-diagnosis purposes, wherein the flow of the method is shown in figure 2, and the method specifically comprises the following steps:
step i: preparation of NAA molecules on methylene and methine groups by using pulse sequence 1 H forms a 3 spin system nuclear spin singlet state; the nuclear spin singlet state obtained by the preparation is R x S x +R y S y +I n ；
Step ii: utilizes the characteristic that nuclear spin singlet state is not influenced by pulse gradient field to realize methylene of NAA molecule 1 Selective observation of H magnetic resonance signals;
step iii: measuring the methylene of NAA molecules in the living body of the actual organism 1 Comparing the H magnetic resonance signal with the magnetic resonance signal of the NAA molecules under different pH values to determine the pH value of the environment around the NAA molecules;
the magnetic resonance signal comprises a J coupling value and two methylene groups 1 H chemical shift (omega) R 、ω S ) And the two methylene groups and the NAA molecule methyl 1 Difference in H chemical shifts (Δ ω [. omega. ]) R And Δ ω S ) And the like.
In the step i, the first step is carried out,preparing the spin singlet state of the NAA molecule 3 spin system by using a pulse sequence shown in figure 3, wherein the preparation steps comprise: 2 of methylene are substituted 1 H spin (labeled R and S, see FIG. 1) and 1 of methine 1 Spin system consisting of H spins (labeled I, see FIG. 1), consisting of a thermal equilibrium state R z +S z +I z Conversion to state R x S x +R y S y +I n Where n ∈ { x, y, z }.
In the step ii, eliminating or suppressing NAA molecular methylene by using a pulse gradient field 1 Signals other than H nuclear spin singlet signals realize methylene to NAA molecules 1 Selective observation of H magnetic resonance signals. Adjusting the strength, time, application times and position of the pulse gradient field to realize methylene of the NAA molecule 1 Optimization of the selective observation of H magnetic resonance signals.
In the step iii, the NAA molecules are methylene-substituted by the actual living organisms 1 Accurate observation of H magnetic resonance signals to obtain methylene 1 H magnetic resonance signals comprising: j coupling number, two on methylene 1 Chemical shift ω of H R And omega S And both of these 1 Difference in chemical shift between H and the methyl signal of NAA molecules, i.e. Δ ω R And Δ ω S And the like. By reacting the methylene group 1 H magnetic resonance signal and NAA molecule under different pH values 1 And H magnetic resonance signals are compared to realize the measurement of the pH value of the environment around the NAA molecules.
In addition, the invention also comprises the following basic steps: (1) the region to be observed of the living organism is located by conventional magnetic resonance imaging techniques. (2) If desired, the MRS spectrum of the region under test is acquired by conventional Magnetic Resonance Spectroscopy (MRS) techniques.
In particular, the invention is directed to the methine and methine positions of the NAA molecule 1 The coupling characteristic of the 3 spin system consisting of H, a pulse sequence as shown in fig. 3 was designed. The pulse sequence is functionally mainly composed of a 'singlet preparation and selection' module and a 'magnetic resonance spectrum' module.
In the "singlet preparation and selection" module, the inventionAgainst methylene and methine groups in the NAA molecule 1 The characteristic of a 3-spin system consisting of H utilizes an optimized control pulse technology based on numerical calculation to design a preparation pulse of NAA molecular singlet state. The main idea of the optimized control pulse technology is as follows: the whole optimized control pulse is divided into a plurality of small pulses, and the phase and power of each small pulse are continuously changed to improve the transfer efficiency from the initial state to the target state, for methylene and methine in NAA molecules 1 The phase and power of the prepared pulse of the 3 spin system nuclear spin singlet state composed of H are shown in FIG. 4. Through the preparation pulse, NAA molecular methylene can be realized 1 Preparation of H nuclear spin singlet, the nuclear spin singlet obtained by said preparation being R x S x +R y S y +I n (ii) a And further realize methylene of NAA molecules 1 Selecting an H signal;
in the magnetic resonance spectroscopy module, the NAA molecules are methylene-paired based on the preamble 1 On the basis of H signal selection, the invention designs the combination of radio frequency pulse and gradient pulse, and realizes the methylene of NAA molecules at specific spatial positions 1 Selective observation of H signal.
Measuring the methylene of NAA molecules in actual living organisms 1 H magnetic resonance signal and NAA molecule under different pH values 1 And H magnetic resonance signals are compared to obtain the pH value of the observed specific space position.
Further, the "singlet preparation and selection" module in the pulse sequence of fig. 3 may be mainly composed of "saturation pulse", "optimal control pulse one", "decoupled pulse", "gradient pulse", and "optimal control pulse two":
"saturation pulse": the device is mainly used for suppressing the signal of water in living tissues, and can use or not use a 'saturation pulse' according to the system detection requirement;
"optimal control pulse one": for methylene modification of 2 of NAA molecules 1 1 of H spin (labeled R and S) and methine 1 Spin system consisting of H spins (labeled I), consisting of the thermal equilibrium state S z +R z +I z Conversion to state R x S x +R y S y +I n (n is belonged to { x, y, z }), thereby realizing methylene and methine of NAA molecules 1 H constitutes the nuclear spin singlet preparation of the spin system. The invention designs the optimal control pulse I by utilizing the optimal control pulse technology based on numerical calculation. FIG. 4 shows a methylene group useful for the preparation of NAA molecules 1 An example of an optimized control pulse for H-nuclear spin singlet state, where fig. 4a is the phase of one optimized control pulse and fig. 4b is the power of the corresponding pulse.
"decoupled pulses": the magnetic resonance method is used for storing the nuclear spin singlet state of the NAA molecules and eliminating a part of non-nuclear spin singlet state magnetic resonance signals in the object to be detected. In natural abundance samples, conventional homonuclear decoupling pulses can be used for this purpose.
"gradient pulse": for further eliminating other signals except the nuclear spin singlet state in the object to be measured.
"optimal control pulse two": for methylene and methine conversion of NAA molecules 1 The H nuclear spin singlet signal is converted to a thermal equilibrium state. The invention designs an optimal control pulse II by utilizing an optimal control pulse technology based on numerical calculation. Fig. 5 shows an example of an optimized control pulse for converting the nuclear spin singlet signal of methylene and methine of NAA molecules to thermal equilibrium, where fig. 5a is the phase of an optimized control pulse and fig. 5b is the power of the corresponding pulse.
The magnetic resonance spectrum module in the pulse sequence of FIG. 3 is mainly composed of RF gradient pulse and layer-selecting pulse, and is aimed at implementing methylene group of NAA molecule in specific spatial position 1 Selective observation of H signal. To achieve methylene group to NAA molecule in a specific spatial position 1 H signal is selected by using conventional T 1 The weighting sequence locates the position of the living organism in the magnetic field. This part of knowledge is known in the art and will not be described further.
In some embodiments, conventional T is first utilized 1 The weighting sequence (or similar pulse sequence providing magnetic resonance images of the living organism) locates the position of the living organism in the magnetic field and selects the living organism to be measuredAn organ region. Then, the pulse shown in fig. 3 is applied to the living organism. Wherein, applying 'saturation pulse' suppresses water signal in human body; the optimized control pulse I is used for preparing nuclear spin singlet signals of methylene and methine of NAA molecules, is obtained by an optimized control pulse technology based on numerical calculation, has the action time of 40ms and consists of 1000 independent pulses of 40 mu s, and the phase and the power of each pulse are shown in figures 4a and 4 b; the "decoupling pulses" are used to preserve the singlet state of the NAA molecule, and in some embodiments, the present invention uses continuous wave decoupling pulses. Wherein, the power of the decoupling pulse is 400Hz, and the time is 1 ms; the strength of the gradient pulse is 2Gauss/cm, the action time is 2ms, and the gradient pulse is used for suppressing other signals except for NAA spin singlet signals; the 'optimization control pulse two' is used for converting nuclear spin singlet signals of methylene and methine of the NAA molecules into a thermal equilibrium state. The total pulse time was 40ms, consisting of 1000 individual pulses of 40 mus. The phase and power of each pulse is shown in figures 5a and 5 b.
In the "magnetic resonance spectroscopy" module, selection of voxels in a living organism is achieved by a combination of one 90-degree and two 180-degree sinc pulses.
Under the above conditions, the pulse shown in FIG. 3 is applied to the human body, and the pulse shown in FIG. 6b can be obtained 1 And H, spectrum. In this spectrum, a distinct 7-fold peak with J-coupling characteristics appears between 2.2ppm and 3.0 ppm. The signal is a methylene group of NAA molecules 1 H magnetic resonance signals. By methylene-coupling of NAA molecules in the spectrum 1 H magnetic resonance signal and method for preparing NAA molecular methylene under different pH values 1 And H magnetic resonance signals are compared to obtain the pH value of the corresponding position of the relevant human living organ.
The invention has the beneficial effects that: the invention is based on the magnetic resonance technology, and has a remarkable characteristic and innovation point which are different from other magnetic resonance spectrum technologies in the past: namely, the methylene group of the NAA molecule in the human living brain is realized 1 Accurate observation of H signal, and based on the obtained NAA molecular methylene in human living brain 1 The H signal enables measurement of brain pH. The method of the invention can be used for realizing rapidness, no wound and no radiationThe pH value of the living body organ of the human body is measured, and the method has good accuracy, sensitivity and stability, has important application value in the aspects of biology, medicine and the like, and is a novel original technology.
Drawings
FIG. 1 is a schematic diagram of the molecular structure of NAA of the present invention. Wherein R, S mark two methylene groups on NAA molecule 1 H proton, I denotes one of the methines 1 And H protons.
FIG. 2 is a flow chart of the present invention. The method specifically comprises the following steps: (1) preparation of the methylene and methine groups in the NAA molecule by appropriate pulse sequences 1 Nuclear spin singlet of the 3 spin system consisting of H; (2) realization of N-NAA molecular methylene based on prepared nuclear spin singlet state 1 Selective observation of H signals; (3) by measuring the methylene of NAA molecules in actual living organisms 1 And comparing the H magnetic resonance signal with the magnetic resonance signal of the NAA molecule under different pH values to obtain the pH value of the environment around the NAA molecule in the observation space.
FIG. 3 shows the application of the present invention in the precise observation of NAA molecular methylene in vivo 1 Schematic diagram of the pulse sequence of the H signal. Wherein, 1 h represents a hydrogen channel, G x ,G y And G z Respectively representing the pulse gradient channels in the x, y, z directions, g 1 Being gradient pulses, 90 x ,180 y ,180 y Respectively the pulse and phase used for the layer selection pulse.
Fig. 4 is a schematic diagram of the phase and power variation of the pulse sequence of "optimal control pulse one" according to the present invention. Fig. 4a is a schematic diagram of the phase change of the pulse sequence of the "optimal control pulse one", and fig. 4b is a schematic diagram of the power change of the pulse sequence of the "optimal control pulse one".
Fig. 5 is a schematic diagram of the phase and power variation of the pulse sequence of the "optimal control pulse two" according to the present invention. Fig. 5a is a schematic diagram of the phase change of the pulse sequence of the "second optimal control pulse", and fig. 5b is a schematic diagram of the power change of the pulse sequence of the "second optimal control pulse".
FIG. 6 shows an embodiment of the present invention, a magnetic resonance imaging method for human brain 1 A weighted map and a selected region magnetic resonance spectrum. FIG. 6a isNormal human brain routine T 1 And (4) weighting the graph. The boxes in the figure represent the regions observed by the magnetic resonance spectrum. FIG. 6b shows the result of using the pulse of FIG. 3 to select the region indicated by the block of FIG. 6a 1 H magnetic resonance spectroscopy.
FIG. 7 shows NAA molecules at different pH values 1 H magnetic resonance spectroscopy. The top grey line is the magnetic resonance signal measured by normal human brain using the pulse of the invention, and the grey frame is the NAA molecular methylene group signal.
FIG. 8 is a flow chart illustrating the main steps of the embodiment of the present invention.
FIG. 9 is a conventional T of a sample of a water film of an embodiment of the present invention (a concentrated solution comprising 1.2% NAA, 0.4% glutamic acid, 1.2% glutamine) 1 Weighted graph, conventional MRS magnetic resonance spectrum and magnetic resonance spectrum obtained using the figure 3 pulse. Wherein FIG. 9a is a conventional T of water film sample 1 And (4) weighting the graph. The boxes in the figure represent the regions observed by the magnetic resonance spectrum. Fig. 9b is a magnetic resonance spectrum obtained by selecting the region indicated by the box of fig. 9a by a conventional Magnetic Resonance Spectroscopy (MRS), and fig. 9c is a magnetic resonance spectrum obtained by using the pulse of fig. 3 for the region indicated by the box of fig. 9 a.
Fig. 10 shows a magnetic resonance spectrum obtained by using the pulse of fig. 3 for different subjects in example 3 of the present invention. Figure 10a is a magnetic resonance spectrogram obtained using the pulse of figure 3 for a normal 25 year old female; figure 10b shows a magnetic resonance spectrum obtained using the pulses of figure 3 for a normal 24 year old male; figure 10c shows a magnetic resonance spectrum obtained using the pulse of figure 3 for a normal 25 year old male, with signals in the grey box for the methylene group of the NAA molecule.
Detailed Description
The invention is described in further detail in connection with the following specific examples and the accompanying drawings. The procedures, conditions, experimental methods and the like for carrying out the present invention are general knowledge and common general knowledge in the art except for the contents specifically mentioned below, and the present invention is not particularly limited.
The main step flow of the embodiment is shown in fig. 8:
1. using conventional T 1 Weighting sequences (or similar pulses providing a magnetic resonance image of the living subject)Rush sequence) to locate the position of a living organ (e.g., the human brain) in a magnetic field and select a region of the living organ to be tested.
2. Applying the pulse shown in figure 3 to obtain NAA molecular methylene of the region to be measured in the living body 1 And H signal.
3. Subjecting the obtained NAA molecules in living body to methylene 1 H signal and NAA molecular methylene group under different pH values 1 And H signal comparison is carried out to obtain the pH value of the observed area in the living body.
In practice, localized in vivo magnetic resonance images are provided, which may be obtained using various types of conventional pulse sequences. The invention is not limited to the optimized pulse methods described in figures 3, 4, and 5 for the preparation and detection of 3 spin singlet.
Example 1
The experiments were tested: a normal 25 year old female.
The measuring instrument: the Siemens 3T prism nuclear magnetic resonance spectrometer uses a detection coil which is a Siemens 64-channel head coil.
The measuring method comprises the following steps: the pulse sequence shown in fig. 3.
The experimental procedure was as follows:
1. using conventional T 1 The weighted sequence positions the position of the human brain in the magnetic field and selects the area of the living body organ to be detected. The magnetic resonance image of the human brain and the selected region are shown in fig. 6 a.
2. The pulse sequence shown in fig. 3 is applied. In the experimental process, the 'saturation pulse' for pressing the water signal consists of 4 Gaussian pulses with the pulse width of 250ms and the power of 35 Hz; "optimal control pulse one" is obtained by the optimal control pulse technique based on the numerical GRAPE method, with an action time of 40ms, consisting of 1000 independent pulses of 40 μ s, the phase and power of which are shown in fig. 4a and 4 b. The RF center of the "optimal control pulse one" is 2.66ppm, and the total power is 100 Hz. The "decoupling pulses" use continuous wave decoupling where the radio frequency center is 2.66ppm, the power is 400Hz, and the application time is 1 ms; the power of the gradient pulse is 2Gauss/cm, and the action time is 2 ms; the optimized control pulse II is obtained by an optimized control pulse technology based on a numerical calculation GRAPE method, and the action time is 40ms, consisting of 1000 individual pulses of 40 mus, the phase and power of these pulses being shown in figures 5a and 5 b. The radio frequency center of the second optimized control pulse is 2.66ppm, and the total power is 100 Hz. The magnetic resonance spectrum pulse module comprises a 90-degree and two 180-degree sine pulses, and the pulse time is 1ms, 2ms and 2ms respectively. The power of these pulses was 250 Hz. In the experimental process, the power and the radio frequency center of the pulse can be controlled by fine adjustment to optimize the methylene of the NAA molecule 1 And H signal.
3. Then the obtained NAA molecules of the human brain are methylene 1 The H signal was compared with the previously obtained methylene signal of the NAA molecule at different pH values (see FIG. 7) to obtain a pH value of about 7.4 in the observed region of the brain in vivo (see FIG. 6).
Example 2
The experiments were tested: 35mL of a neutral mixed aqueous solution of 0.4% of glutamic acid, 1.2% of glutamine and 1.2% of NAA in solute mass fraction.
The measuring instrument: the Siemens 3T prism nuclear magnetic resonance spectrometer uses a detection coil which is a Siemens 64-channel head coil.
The determination method comprises the following steps: the pulse sequence shown in fig. 3.
The experimental procedure was as follows:
1. using conventional T 1 And the weighting sequence positions the position of the water film sample in the magnetic field and selects the area of the water film sample to be detected. The water film magnetic resonance image and the selected region are shown in figure 9 a.
2. The pulse sequence shown in fig. 3 is applied. In the experimental process, a 'saturation pulse' for pressing the water signal consists of 4 Gaussian pulses with the pulse width of 250ms and the power of 35 Hz; "optimal control pulse one" is obtained by the optimal control pulse technique based on the numerical GRAPE method, with an action time of 40ms, consisting of 1000 independent pulses of 40 μ s, the phase and power of which are shown in fig. 4a and 4 b. The RF center of the "optimal control pulse one" is 2.66ppm, and the total power is 100 Hz. The "decoupling pulses" use continuous wave decoupling where the radio frequency center is 2.66ppm, the power is 400Hz, and the application time is 1 ms; the power of the gradient pulse is 2Gauss/cm, and the action time is 2 ms; "optimized control pulse two" is calculated by a GRAPE square based on numerical valuesThe optimized control pulse technology of the method obtains the action time of 40ms and consists of 1000 independent pulses of 40 mus, and the phases and the powers of the pulses are shown in figures 5a and 5 b. The radio frequency center of the second optimized control pulse is 2.66ppm, and the total power is 100 Hz. The magnetic resonance spectrum pulse module comprises a 90-degree and two 180-degree sine pulses, and the pulse time is 1ms, 2ms and 2ms respectively. The power of these pulses was 250 Hz. In the experimental process, the power and the radio frequency center of the pulse can be controlled by fine adjustment to optimize the methylene of the NAA molecule 1 And H signal.
3. The conclusion of the conventional MRS experiment is shown in FIG. 9b, where the signal at 2.1ppm is the methyl group of the NAA molecule, and at 2.2 and 2.3ppm is the glutamic acid and glutamine signals, where the glutamine signal overlaps with the methylene signal of the NAA molecule; FIG. 9c shows the magnetic resonance spectrum obtained by using the pulse of FIG. 3 to select the region indicated by the box of FIG. 9a, in which both glutamate and glutamine signals are greatly suppressed, and only the signal of the methylene group of the NAA molecule is retained. Subjecting the obtained water film sample NAA molecule methylene 1 And (4) comparing the H signal with the previously obtained methylene signal of the NAA molecule at different pH values to obtain the pH value of the observed area (see figure 9a) in the water film sample.
Example 3
The experiments were tested: normal 25 year old female, normal 24 year old male, normal 25 year old male
The measuring instrument: the Siemens 3T prism nuclear magnetic resonance spectrometer uses a detection coil which is a Siemens 64-channel head coil.
The determination method comprises the following steps: the pulse sequence shown in fig. 3.
The experimental procedure was as follows:
1. using conventional T 1 And the weighted sequences are used for positioning the positions of the brains of different human living bodies in the magnetic field and selecting the brain area of the living body of the sample to be detected. The in vivo brain magnetic resonance image and selected region are shown in figure 6 a.
2. The pulse sequence shown in fig. 3 is applied. In the experimental process, the 'saturation pulse' for pressing the water signal consists of 4 Gaussian pulses with the pulse width of 250ms and the power of 35 Hz; "optimal control pulse one" is optimized by the GRAPE method based on numerical calculationThe pulsing technique results in an action time of 40ms, consisting of 1000 individual pulses of 40 mus, the phase and power of which are shown in figures 4a and 4 b. The RF center of the "optimal control pulse one" is 2.66ppm, and the total power is 100 Hz. The "decoupling pulses" use continuous wave decoupling where the radio frequency center is 2.66ppm, the power is 400Hz, and the application time is 1 ms; the power of the gradient pulse is 2Gauss/cm, and the action time is 2 ms; "optimal control pulse two" is obtained by the optimal control pulse technique based on the numerical GRAPE method, with an action time of 40ms, consisting of 1000 independent pulses of 40 μ s, the phase and power of which are shown in fig. 5a and 5 b. The radio frequency center of the second optimized control pulse is 2.66ppm, and the total power is 100 Hz. The magnetic resonance spectrum pulse module comprises a 90-degree and two 180-degree sinc pulses, and the pulse time is 1ms, 2ms and 2ms respectively. The power of these pulses was 250 Hz. In the experimental process, the power and the radio frequency center of the pulse can be controlled by fine adjustment to optimize the methylene of the NAA molecule 1 The H signal.
3. Figure 10a is a magnetic resonance spectrum obtained by the pulse of figure 3 from a normal 25 year old female; figure 10b shows a magnetic resonance spectrum obtained by the pulse of figure 3 for a normal 24 year old male; figure 10c is a magnetic resonance spectrum of the pulse acquisition of figure 3 for a normal 25 year old male. As can be seen from the figure, the position and peak shape of the NAA molecule methylene signal of the normal brain are completely the same, so that the pH value of the normal brain is neutral and is about 7.4.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that may occur to those skilled in the art may be incorporated into the invention without departing from the spirit and scope of the inventive concept, and the scope of the appended claims is intended to be protected.
Claims (7)
1. A method for measuring pH of a living organism using a magnetic resonance signal of a molecule N-acetyl aspartic acid for non-diagnostic purposes, the method comprising:
step i: preparation of N-acetyl aspartic acid molecule on methylene and methine by pulse sequence 1 H constitutes 3 spin system nuclear spin singlet; the nuclear spin singlet state obtained by the preparation is R x S x +R y S y +I n ；
Step ii: utilizes the characteristic that nuclear spin singlet state is not influenced by pulse gradient field to realize methylene of N-acetyl aspartic acid molecule 1 Selective observation of H magnetic resonance signals;
step iii: measuring the measured N-acetyl aspartic acid molecular methylene in the actual living organism 1 And comparing the H magnetic resonance signal with the magnetic resonance signal of the N-acetyl aspartic acid molecule under different pH values to determine the pH value of the environment around the N-acetyl aspartic acid molecule.
2. The method of claim 1, wherein the N-acetyl aspartic acid molecule spin singlet state in step i is prepared by the steps of: 2 of the methylene groups which will be labelled R, S 1 H spin, and 1 of methine labeled I 1 3 spin coupling system consisting of H spins and consisting of thermal equilibrium state R z +S z +I z Conversion to state R x S x +R y S y +I n Where n ∈ { x, y, z }.
3. The method of claim 1, wherein in step ii, the methylene groups of the N-acetyl aspartic acid molecules are eliminated or suppressed by using a pulse gradient field 1 Signals except H nuclear spin singlet signals realize methylene of N-acetyl aspartic acid molecules 1 Selective observation of H magnetic resonance signals; the strength, time, application times and position of the pulse gradient field are adjusted to realize the methylene of the N-acetyl aspartic acid molecule 1 Optimization of the selective observation of H magnetic resonance signals.
4. The method of claim 1 or 2, wherein the pulse sequence comprises: a single-state preparation and selection module and a magnetic resonance spectrum module; wherein,
the singlet preparation and selection module comprises: saturation pulse, optimization control pulse I, decoupling pulse, gradient pulse and optimization control pulse II; the magnetic resonance spectroscopy module includes: radio frequency gradient pulses and slice selection pulses.
5. The method of claim 1, wherein in step iii, the biological sample is treated by methylene of the actual living organism's N-acetyl aspartic acid molecule 1 Accurately observing H magnetic resonance signals to obtain N-acetyl aspartic acid molecular methylene 1 H magnetic resonance signals; by reacting the methylene group 1 H magnetic resonance signal and N-acetyl aspartic acid molecule under different pH values 1 And H magnetic resonance signals are compared to realize the measurement of the pH value of the environment around the N-acetyl aspartic acid molecules.
6. The method of claim 5, wherein said N-acetyl aspartic acid molecule 1 H magnetic resonance signals include J coupling value and on methylene 1 H chemical shift, methylene on 1 H and N-acetyl aspartic acid molecule methyl 1 One or more of H signal chemical shift difference.
7. Use of a method according to any one of claims 1 to 6 for in vivo pH detection of a living organism for non-diagnostic purposes.
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| PCT/CN2022/075149 WO2022171038A1 (en) | 2021-02-10 | 2022-01-30 | Method for detecting ph value of living body with an n-acetylaspartic acid molecular magnetic resonance signal for non-diagnostic purpose |
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