CN114910501B - A method for detecting pH value of living body using N-acetylaspartic acid molecular magnetic resonance signal for non-diagnostic purpose - Google Patents
A method for detecting pH value of living body using N-acetylaspartic acid molecular magnetic resonance signal for non-diagnostic purpose Download PDFInfo
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- 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 119
- 238000000034 method Methods 0.000 title claims abstract description 42
- 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 29
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims abstract description 18
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract 18
- 238000001228 spectrum Methods 0.000 claims description 28
- 238000001208 nuclear magnetic resonance pulse sequence Methods 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 16
- 238000005516 engineering process Methods 0.000 claims description 14
- 230000009471 action Effects 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 12
- 238000010168 coupling process Methods 0.000 claims description 10
- 238000005859 coupling reaction Methods 0.000 claims description 10
- 230000008878 coupling Effects 0.000 claims description 7
- 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 2
- 238000012546 transfer Methods 0.000 claims description 2
- 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 1
- 238000001727 in vivo Methods 0.000 claims 1
- 210000000056 organ Anatomy 0.000 abstract description 10
- 238000005259 measurement Methods 0.000 abstract description 6
- 230000035945 sensitivity Effects 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 70
- 210000004556 brain Anatomy 0.000 description 20
- 238000002474 experimental method Methods 0.000 description 9
- 238000010586 diagram Methods 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 241000219095 Vitis Species 0.000 description 6
- 235000009754 Vitis X bourquina Nutrition 0.000 description 6
- 235000012333 Vitis X labruscana Nutrition 0.000 description 6
- 235000014787 Vitis vinifera Nutrition 0.000 description 6
- 229920006395 saturated elastomer Polymers 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-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 4
- 235000013922 glutamic acid Nutrition 0.000 description 4
- 239000004220 glutamic acid Substances 0.000 description 4
- 238000003825 pressing Methods 0.000 description 4
- 238000004611 spectroscopical analysis Methods 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000000691 measurement method Methods 0.000 description 3
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 2
- 238000002595 magnetic resonance imaging Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 208000001889 Acid-Base Imbalance Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- 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 living organism by utilizing N-acetyl aspartic acid (N-ACETYL ASPARTIC ACID, NAA) molecular magnetic resonance signals. According to the method, the selective and accurate observation of NAA molecular methylene 1 H magnetic resonance signals is realized by preparing a nuclear spin singlet state of a 3-spin system consisting of NAA molecular methylene and 1 H on methine. Since NAA molecular methylene 1 H magnetic resonance signals are sensitive to the environmental pH value, the accurate measurement of the pH value of a living organism can be realized through the obtained NAA molecular methylene 1 H magnetic resonance signals. The method can rapidly, noninvasively and radiationless measure the pH value of the living body organ of the human body, 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 utilizing N-acetylaspartic acid (N-ACETYL ASPARTIC ACID, NAA) molecular magnetic resonance signals for non-diagnosis.
Background
The normal human body environment often has a certain acidity and alkalinity. The occurrence of an acid-base imbalance in the human environment (i.e., a meta-acid or meta-base as compared to normal) means that the human health condition is changed. By observing the acid-base nature of the body environment, it is possible to realize early diagnosis of diseases and help to judge the treatment effect in the treatment process of some diseases.
The magnetic resonance signals of many biochemical molecules in the human body have obvious pH value dependence. If the magnetic resonance signals of the biochemical molecules affected by the pH value in the living body can be accurately observed, the connection between the pH value and the magnetic resonance signals of the biochemical molecules is established, and the magnetic resonance living body observation of the pH value of the environment where the biochemical molecules are located can be realized. N-acetyl aspartic acid (N-ACETYL ASPARTIC ACID, NAA) is a common biochemical molecule, widely existing in biological brains, and is an important index for assessing neuronal activity and brain cell metabolic activity. The NAA has a methylene chemical group in its chemical structure, and the magnetic resonance signal (chemical shift and J coupling) of the group has a clear dependence on pH. Therefore, if the chemical shift and J coupling of NAA molecule methylene 1 H signal in living body can be accurately observed, the living body magnetic resonance observation of human pH value can be realized.
However, classical living magnetic resonance techniques (e.g., magnetic resonance spectroscopy, MRS) generally only observe the 1 H signal of NAA molecule methyl groups in living organisms, and no 1 H signal of NAA molecule methylene groups. In particular, the J-coupling value, chemical shift of the methylene group of NAA molecules, and the difference in the chemical shift of the methylene group from the methyl signal of NAA molecules, are often not available. Based on the classical living body magnetic resonance technology, the measurement of the pH value of a living body cannot be realized by precisely observing NAA molecule methylene 1 H signals.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides a method for detecting the pH value of a living body by using NAA molecular magnetic resonance signals for non-diagnosis purposes, and the method can not directly obtain the diagnosis result of diseases. By utilizing the method, the NAA molecule methylene 1 H signal in the living human brain is accurately observed, and the magnetic resonance signals based on the methylene 1 H signal and the magnetic resonance signals of NAA molecules under different pH values are compared, so that the observation of the pH value of a brain region containing NAA in the human brain is realized. Experiments prove that the method is rapid, noninvasive and applicable to living organisms, and meanwhile, the measurement result has good stability and sensitivity.
The invention aims at a 3-spin system consisting of NAA molecules of methylene and methine 1 H. The magnetic resonance signal of the nuclear spin system has good sensitivity to the acid-base nature of the surrounding environment. When the pH value is changed, the chemical shift and J coupling of the methylene molecule are changed. According to the invention, a novel pulse sequence is designed to prepare a nuclear spin singlet state of a 3-spin system consisting of NAA molecular methylene and methine 1 H, and the characteristic that the nuclear spin singlet state is not evolved under the action of a gradient field is utilized to realize the selective and accurate observation of NAA molecular methylene 1 H magnetic resonance signals. The obtained correspondence between NAA molecular methylene 1 H magnetic resonance signal and the pH value of the surrounding environment is utilized to realize the accurate measurement of the pH value of the environment where the biochemical molecules in the living organism are located.
The invention provides a method for measuring the pH value of a living organism by utilizing N-acetyl aspartic acid (N-ACETYL ASPARTIC ACID, NAA) molecular magnetic resonance signals for non-diagnostic purposes, wherein the flow of the method is shown in figure 2, and the method specifically comprises the following steps:
Step i, preparing a nuclear spin singlet state of a 3-spin system formed by NAA molecule methylene and 1 H on methine by using a pulse sequence, wherein the nuclear spin singlet state obtained by the preparation is R xSx+RySy+In;
Step ii, utilizing the characteristic that nuclear spin singlet is not influenced by a pulse gradient field to realize the selective observation of NAA molecular methylene 1 H magnetic resonance signals;
Step iii, comparing the measured NAA molecule methylene 1 H magnetic resonance signals in the actual living organism with the magnetic resonance signals of NAA molecules under different pH values to determine the pH value of the surrounding environment of the NAA molecules;
The magnetic resonance signal comprises one or more of a J coupling value, two methylene 1 H chemical shifts (omega R、ωS), and differences (delta omega R and delta omega S) between the two methylene and NAA molecule methyl 1 H chemical shifts.
In the step I, the NAA molecule 3 spin system spin state is prepared by using the pulse sequence shown in FIG. 3, wherein the preparation step comprises the step of converting a spin system consisting of 2 1 H spins (marked as R and S, see FIG. 1) of methylene and 1 1 H spins (marked as I, see FIG. 1) of methine from a thermal equilibrium state R z+Sz+Iz to a state R xSx+RySy+In, wherein n is { x, y, z }.
In the step ii, other signals except the NAA molecule methylene 1 H nuclear spin singlet signal are eliminated or suppressed by using a pulse gradient field, so that the selective observation of the NAA molecule methylene 1 H magnetic resonance signal is realized. The intensity, time, application times and position of the pulse gradient field are adjusted, so that the optimization of the selective observation of NAA molecular methylene 1 H magnetic resonance signals is realized.
In the step iii, the methylene 1 H magnetic resonance signal is obtained through the accurate observation of the methylene 1 H magnetic resonance signal of the actual living organism NAA molecule, wherein the magnetic resonance signal comprises J coupling value, chemical shifts omega R and omega S of two 1 H on the methylene, and the difference value between the chemical shifts of the two 1 H and the NAA molecule methyl signal, namely delta omega R, delta omega S and the like. The measurement of the pH value of the environment around the NAA molecule is realized by comparing the methylene 1 H magnetic resonance signal with the 1 H magnetic resonance signal of the NAA molecule at different pH values.
In addition, the invention also comprises the following basic steps of (1) positioning the region to be observed of the living organism by the traditional magnetic resonance imaging technology. (2) If necessary, the MRS spectra of the region to be measured are acquired by conventional Magnetic Resonance Spectroscopy (MRS) techniques.
Specifically, the invention designs a pulse sequence shown in figure 3 aiming at the coupling characteristic of a 3-spin system consisting of methylene and methylene on the NAA molecule and 1 H. The pulse sequence is functionally mainly composed of a 'single-state preparation and selection' module and a 'magnetic resonance spectrum' module.
In the 'single-state preparation and selection' module, the invention designs NAA molecular single-state preparation pulse by utilizing the numerical calculation-based optimal control pulse technology aiming at the characteristic of a 3-spin system consisting of methylene and methine 1 H in NAA molecules. The main idea of the optimized control pulse technology is that the whole optimized control pulse is divided into a plurality of small pulses, the transfer efficiency from an initial state to a target state is improved by continuously changing the phase and the power of each small pulse, and the phase and the power of the preparation pulse of a nuclear spin single state of a 3-spin system consisting of methylene and methine 1 H in NAA molecules are shown as figure 4. The preparation pulse can realize the preparation of NAA molecule methylene 1 H nuclear spin singlet, wherein the nuclear spin singlet obtained by the preparation is R xSx+RySy+In, and further realizes the selection of NAA molecule methylene 1 H signals;
in the magnetic resonance spectrum module, on the basis of selecting NAA molecule methylene 1 H signals based on the preamble, the invention designs the combination of radio frequency pulse and gradient pulse, and realizes the selective observation of NAA molecule methylene 1 H signals at specific space positions.
And comparing the measured NAA molecular methylene 1 H magnetic resonance signal in the actual living organism with the NAA molecular 1 H magnetic resonance signal under different pH values to obtain the pH value of the observed specific spatial position.
Further, the "singlet preparation and selection" module in the pulse sequence of fig. 3 may mainly consist of "saturation pulse", "optimal control pulse one", "decoupling pulse", "gradient pulse" and "optimal control pulse two":
The saturation pulse is mainly used for pressing the signal of water in living tissue, and can be used or not used according to the system detection requirement;
"optimized control pulse one" is used for converting a spin system consisting of 2 1 H spins (labeled R and S) of NAA molecular methylene and 1 1 H spins (labeled I) of methine from a thermal equilibrium state S z+Rz+Iz to a state R xSx+RySy+In (n.epsilon. { x, y, z }) so as to realize nuclear spin singlet preparation of the spin system consisting of NAA molecular methylene and methine 1 H. The invention designs an 'optimal control pulse I' by utilizing an optimal control pulse technology based on numerical calculation. Fig. 4 shows an example of an optimized control pulse for preparing the nuclear spin singlet state of the NAA molecule methylene 1 H, wherein fig. 4a is the phase of an optimized control pulse and fig. 4b is the power of the corresponding pulse.
The decoupling pulse is used for preserving the nuclear spin singles of NAA molecules and simultaneously eliminating a part of magnetic resonance signals of non-nuclear spin singles in the object to be detected. In natural abundance samples, this can be achieved with conventional homonuclear decoupling pulses.
The gradient pulse is used for further eliminating other signals except nuclear spin singles in the object to be detected.
"Optimal control pulse two" is used to convert the 1 H nuclear spin singlet signals of the NAA molecules methylene and methine 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 nuclear spin singlet signals of the NAA molecules methylene and methine 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 mainly consists of radio frequency gradient pulses and layer selection pulses, in order to achieve selective observation of NAA molecule methylene 1 H signals in specific spatial positions. To enable selection of NAA molecule methylene 1 H signals in specific spatial locations, the location of a living organism in a magnetic field can be located using conventional T 1 weighting sequences. This part of knowledge is well known in the art and the present invention will not be described in more detail.
In some embodiments, the location of the living organ in the magnetic field is first located using a conventional T 1 weighted sequence (or similar pulse sequence that can provide images of the living organism), and the region of the living organ to be measured is selected. Then, the pulse shown in fig. 3 is applied to the living organ. Wherein, the water signal in the human body is suppressed by applying a 'saturation pulse', the 'optimal control pulse one' is used for preparing nuclear spin singlet signals of NAA molecules methylene and methine, the pulse is obtained by an optimal control pulse technology based on numerical calculation, the action time is 40ms, the pulse consists of 1000 independent pulses of 40 mu s, the phase and the power of each pulse are shown in figures 4a and 4b, the 'decoupling pulse' is used for preserving the singlet state of NAA molecules, and in some specific embodiments, the invention uses continuous wave decoupling pulses. Wherein the power of the decoupling pulse is 400Hz, the time is 1ms, the strength of the gradient pulse is 2Gauss/cm, the acting time is 2ms, the pulse is used for suppressing other signals except NAA spin Shan Tai signals, and the optimal control pulse II is used for converting the nuclear spin singlet signals of NAA molecules methylene and methine into a thermal equilibrium state. The total time of the pulse is 40ms, consisting of 1000 individual pulses of 40 mus. The phase and power of each pulse is shown in figures 5a and 5b.
In the "magnetic resonance spectroscopy" module, selection of voxels in the living organ is achieved by a combination of pulses of one 90 degrees and two 180 degrees sinc.
Under the above conditions, the pulse shown in fig. 3 was applied to a human body, and 1 H spectrum shown in fig. 6b was obtained. In this spectrum, a distinct 7-fold peak with J-coupling characteristics appears between 2.2ppm and 3.0 ppm. The signal is 1 H magnetic resonance signal of NAA molecule methylene. The pH value of the corresponding position of the relevant human living organ can be obtained by comparing the 1 H magnetic resonance signal of NAA molecular methylene in the spectrogram with the 1 H magnetic resonance signal of NAA molecular methylene under different pH values.
The invention has the advantages that the invention is based on the magnetic resonance technology, has a remarkable characteristic and innovation point different from the prior other magnetic resonance spectrum technologies, namely, the invention realizes the accurate observation of NAA molecule methylene 1 H signals in the living brain of the human body, and the measurement of the pH value of the brain is realized based on the obtained NAA molecule methylene 1 H signals in the living brain of the human body. The method can rapidly, noninvasively and nonradiative measure the pH value of the living body organ of the human body, 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 according to the invention. Wherein R, S identifies two 1 H protons of the methylene group on the NAA molecule and I identifies one 1 H proton of the methine group.
FIG. 2 shows a flow chart of the present invention. The method comprises the steps of (1) preparing nuclear spin singles of a 3-spin system composed of methylene and 1 H on methylene in NAA molecules through a proper pulse sequence, (2) realizing selective observation of NAA molecule methylene 1 H signals based on the prepared nuclear spin singles, and (3) comparing measured NAA molecule methylene 1 H magnetic resonance signals in an actual living organism with magnetic resonance signals of NAA molecules at different pH values to obtain the pH value of the environment around NAA molecules in an observation space.
FIG. 3 is a schematic diagram of a pulse sequence for precisely observing NAA molecule methylene 1 H signals in a living body according to the present invention. Wherein 1 H represents a hydrogen channel, G x,Gy and G z respectively represent pulse gradient channels in x, y and z directions, G 1 is a gradient pulse, and 90 x,180y,180y is a pulse and a phase used for layer selection pulse respectively.
Fig. 4 is a schematic diagram of pulse sequence phase and power variation of "optimize control pulse one" according to the present invention. Fig. 4a is a schematic diagram of pulse sequence phase variation of "optimizing control pulse one", and fig. 4b is a schematic diagram of pulse sequence power variation of "optimizing control pulse one".
Fig. 5 is a schematic diagram of pulse sequence phase and power variation of "optimize control pulse two" according to the present invention. Fig. 5a is a schematic diagram of pulse sequence phase variation of "optimizing control pulse two", and fig. 5b is a schematic diagram of pulse sequence power variation of "optimizing control pulse two".
Fig. 6 is a weighted image of a human brain magnetic resonance imaging T 1 and a magnetic resonance spectrogram of a selected region according to an embodiment of the present invention. Fig. 6a is a conventional T 1 weighted graph of a normal human brain. The square box in the figure shows the region of the magnetic resonance spectrum observed. Figure 6b is a 1 H magnetic resonance spectrum obtained using the pulses of figure 3 to select the region indicated by the box of figure 6 a.
Figure 7 is a 1 H magnetic resonance spectrum of NAA molecules at different pH values. The top grey line is the magnetic resonance signal measured by the normal human brain using the pulse of the invention, and the grey frame is NAA molecular methylene group signal.
FIG. 8 is a schematic flow chart of main steps of the embodiment of the invention.
Fig. 9 is a conventional T 1 weighted graph of a water film sample (including a concentrated solution of 1.2% naa, 0.4% glutamic acid, 1.2% glutamine), a conventional MRS magnetic resonance spectrum and a magnetic resonance spectrum obtained using the pulse of fig. 3, according to an embodiment of the present invention. Wherein fig. 9a is a conventional T 1 weighted graph of a water film sample. The square box in the figure shows the region of the magnetic resonance spectrum observed. Fig. 9b is a magnetic resonance spectrum obtained by conventional Magnetic Resonance Spectroscopy (MRS) selecting the region shown in the box of fig. 9a, and fig. 9c is a magnetic resonance spectrum obtained by using the pulse of fig. 3 for the region shown in the box of fig. 9 a.
Fig. 10 is a magnetic resonance spectrum obtained by using the pulse of fig. 3 for different subjects in embodiment 3 of the present invention. Fig. 10a shows a magnetic resonance spectrum obtained by using the pulse of fig. 3 for a normal 25 year old female, fig. 10b shows a magnetic resonance spectrum obtained by using the pulse of fig. 3 for a normal 24 year old male, and fig. 10c shows a magnetic resonance spectrum obtained by using the pulse of fig. 3 for a normal 25 year old male, with NAA molecular methylene group signals in gray boxes.
Detailed Description
The invention will be described in further detail with reference to the following specific examples and drawings. The procedures, conditions, experimental methods, etc. for carrying out the present invention are common knowledge and common knowledge in the art, except for the following specific references, and the present invention is not particularly limited.
The main step flow of the embodiment is shown in fig. 8:
1. The location of a living organ (e.g., human brain) in a magnetic field is located using a conventional T 1 weighted sequence (or similar pulse sequence that provides a living magnetic resonance image) and a region of the living organ to be measured is selected.
2. The pulses shown in FIG. 3 are applied to obtain NAA molecule methylene 1 H signals of the region to be detected in the living body.
3. And comparing the NAA molecular methylene 1 H signal with NAA molecular methylene 1 H signal at different pH values to obtain the pH value of the observed area in the living body.
In the implementation process, the positioned living body magnetic resonance image is provided and can be obtained by various conventional pulse sequences. The invention is applicable to the preparation of the singlet state of 3 spins and detection pulses and is not limited to the optimized pulse method described in fig. 3,4, 5.
Example 1
The experiment was tested on a normal 25 year old female.
The measuring instrument is a Siemens 3T Prisma nuclear magnetic resonance instrument, and the detection coil is a Siemens 64-channel head coil.
The measurement method is the pulse sequence shown in FIG. 3.
The experimental procedure was as follows:
1. And positioning the position of the human brain in the magnetic field by using a conventional T 1 weighting sequence, and selecting a living organ region to be detected. The human brain magnetic resonance image and the selected region are shown in fig. 6a.
2. The pulse sequence shown in fig. 3 is applied. In the experimental process, the 'saturated pulse' for pressing the water signal consists of 4 Gaussian pulses with the pulse width of 250ms and the power of 35Hz, the 'optimal control pulse I' is obtained by an optimal control pulse technology based on a numerical calculation GRAPE method, the action time is 40ms, and the 'saturated pulse' consists of 1000 independent pulses with the pulse width of 40 mu s, and the phases and the power of the pulses are shown in figures 4a and 4b. The radio frequency center of the optimized control pulse I is 2.66ppm, and the total power is 100Hz. The "decoupling pulse" uses continuous wave decoupling, where the radio frequency center is 2.66ppm, the power is 400Hz, the application time is 1ms, the "gradient pulse" power is 2Gauss/cm, the action time is 2ms, the "optimal control pulse two" is obtained by the optimal control pulse technique based on the numerical calculation GRAPE method, the action time is 40ms, and the pulse is composed of 1000 independent pulses of 40 μs, and the phases and the powers of the pulses are shown in fig. 5a and 5b. The radio frequency center of the optimal control pulse II is 2.66ppm, and the total power is 100Hz. The "magnetic resonance spectrum" pulse module comprises one 90 degree and two 180 degree sine pulses with pulse times of 1ms,2ms and 2ms, respectively. The power of these pulses was 250Hz. In the experimental process, the NAA molecule methylene 1 H signal can be optimized by fine tuning and optimizing the power and the radio frequency center of the control pulse.
3. The NAA molecular methylene 1 H signal obtained from the human brain was then compared with the NAA molecular methylene signal obtained in advance at different pH values (see FIG. 7) to give a pH of about 7.4 in the region observed in the living brain (see FIG. 6).
Example 2
Experiments were carried out with 35mL of a neutral mixed aqueous solution of 0.4% glutamic acid, 1.2% glutamine and 1.2% NAA by mass fraction of solute.
The measuring instrument is a Siemens 3T Prisma nuclear magnetic resonance instrument, and the detection coil is a Siemens 64-channel head coil.
The measurement method is the pulse sequence shown in FIG. 3.
The experimental procedure was as follows:
1. and positioning the position of the water film sample in the magnetic field by using a conventional T 1 weighting sequence, and selecting a water film sample area to be detected. The water film magnetic resonance image and the selected region are shown in fig. 9a.
2. The pulse sequence shown in fig. 3 is applied. In the experimental process, the 'saturated pulse' for pressing the water signal consists of 4 Gaussian pulses with the pulse width of 250ms and the power of 35Hz, the 'optimal control pulse I' is obtained by an optimal control pulse technology based on a numerical calculation GRAPE method, the action time is 40ms, and the 'saturated pulse' consists of 1000 independent pulses with the pulse width of 40 mu s, and the phases and the power of the pulses are shown in figures 4a and 4b. The radio frequency center of the optimized control pulse I is 2.66ppm, and the total power is 100Hz. The "decoupling pulse" uses continuous wave decoupling, where the radio frequency center is 2.66ppm, the power is 400Hz, the application time is 1ms, the "gradient pulse" power is 2Gauss/cm, the action time is 2ms, the "optimal control pulse two" is obtained by the optimal control pulse technique based on the numerical calculation GRAPE method, the action time is 40ms, and the pulse is composed of 1000 independent pulses of 40 μs, and the phases and the powers of the pulses are shown in fig. 5a and 5b. The radio frequency center of the optimal control pulse II is 2.66ppm, and the total power is 100Hz. The "magnetic resonance spectrum" pulse module comprises one 90 degree and two 180 degree sine pulses with pulse times of 1ms,2ms and 2ms, respectively. The power of these pulses was 250Hz. In the experimental process, the NAA molecule methylene 1 H signal can be optimized by fine tuning and optimizing the power and the radio frequency center of the control pulse.
3. The conventional MRS experiment results are shown in FIG. 9b, wherein signals of NAA molecular methyl are 2.1ppm, signals of glutamic acid and glutamine are 2.2 and 2.3ppm, the glutamine signals are overlapped with the NAA molecular methylene signals, and FIG. 9c shows magnetic resonance spectra obtained by selecting the area shown in the box of FIG. 9a through the pulse of FIG. 3, wherein the glutamic acid and the glutamine signals are greatly suppressed, and only the NAA molecular methylene signals are reserved. The obtained NAA molecular methylene 1 H signal of the water film sample is compared with the obtained NAA molecular methylene signal under different pH values, so that the pH value of an observed area (see figure 9 a) in the water film sample can be obtained.
Example 3
The experiment is tested by normal 25 years old female, normal 24 years old male and normal 25 years old male
The measuring instrument is a Siemens 3T Prisma nuclear magnetic resonance instrument, and the detection coil is a Siemens 64-channel head coil.
The measurement method is the pulse sequence shown in FIG. 3.
The experimental procedure was as follows:
1. And (3) positioning the positions of different human living brains in the magnetic field by using a conventional T 1 weighted sequence, and selecting a living brain region of a sample to be detected. The living brain magnetic resonance image and the selected region are shown in fig. 6a.
2. The pulse sequence shown in fig. 3 is applied. In the experimental process, the 'saturated pulse' for pressing the water signal consists of 4 Gaussian pulses with the pulse width of 250ms and the power of 35Hz, the 'optimal control pulse I' is obtained by an optimal control pulse technology based on a numerical calculation GRAPE method, the action time is 40ms, and the 'saturated pulse' consists of 1000 independent pulses with the pulse width of 40 mu s, and the phases and the power of the pulses are shown in figures 4a and 4b. The radio frequency center of the optimized control pulse I is 2.66ppm, and the total power is 100Hz. The "decoupling pulse" uses continuous wave decoupling, where the radio frequency center is 2.66ppm, the power is 400Hz, the application time is 1ms, the "gradient pulse" power is 2Gauss/cm, the action time is 2ms, the "optimal control pulse two" is obtained by the optimal control pulse technique based on the numerical calculation GRAPE method, the action time is 40ms, and the pulse is composed of 1000 independent pulses of 40 μs, and the phases and the powers of the pulses are shown in fig. 5a and 5b. The radio frequency center of the optimal control pulse II is 2.66ppm, and the total power is 100Hz. The "magnetic resonance spectrum" pulse module comprises one 90 degree and two 180 degree sine pulses with pulse times of 1ms,2ms and 2ms, respectively. The power of these pulses was 250Hz. In the experimental process, the NAA molecule methylene 1 H signal can be optimized by fine tuning and optimizing the power and the radio frequency center of the control pulse.
3. Fig. 10a is a magnetic resonance spectrum obtained by the pulse of fig. 3 for a normal 25 year old female, fig. 10b is a magnetic resonance spectrum obtained by the pulse of fig. 3 for a normal 24 year old male, and fig. 10c is a magnetic resonance spectrum obtained by the pulse of fig. 3 for a normal 25 year old male. As can be seen from the figure, the NAA molecule methylene signal position and peak shape of the brain of the normal person are identical, so that the pH value of the brain of the normal person is neutral and is about 7.4.
The protection of the present invention is not limited to the above embodiments. Variations and advantages that would occur to one skilled in the art are included in the invention without departing from the spirit and scope of the inventive concept, and the scope of the invention is defined by the appended claims.
Claims (5)
1. A method for measuring pH of a living organism using magnetic resonance signals of N-acetyl aspartic acid molecules for non-diagnostic purposes, the method comprising:
Step i, preparing a nuclear spin singlet state of a 3-spin system formed by N-acetyl aspartic acid molecule methylene and 1 H on methine by using a pulse sequence, wherein the nuclear spin singlet state obtained by the preparation is R xSx+RySy+In, the pulse sequence comprises a singlet state preparation and selection module and a magnetic resonance spectrum module,
The single-state preparation and selection module comprises a saturation pulse, an optimized control pulse I, a decoupling pulse, a gradient pulse and an optimized control pulse II, wherein the optimized control pulse I and the optimized control pulse II divide the whole control pulse into a plurality of small pulses, and the phase and the power of each small pulse are continuously changed to improve the transfer efficiency from an initial state to a target state, and the optimized control pulse I and the optimized control pulse II respectively have the action time of 40ms and are composed of 1000 independent pulses of 40 mu s;
the saturation pulse is used for suppressing signals of water in living tissues;
The optimized control pulse I is used for converting a 3-spin coupling system consisting of 2 1 H spins of N-acetyl aspartic acid molecules methylene marked R, S and 1 1 H spins of methine marked I from a thermal equilibrium state R z+Sz+Iz to a state R xSx+RySy+In, wherein N epsilon { x, y, z }, so as to realize nuclear spin singlet preparation of a spin system consisting of N-acetyl aspartic acid molecules methylene and methine 1 H;
the decoupling pulse is used for preserving nuclear spin singles of N-acetyl aspartic acid molecules and simultaneously eliminating magnetic resonance signals of a part of non-nuclear spin singles in an object to be detected, wherein the power of the decoupling pulse is 400Hz, and the time is 1ms;
the gradient pulse is used for further eliminating other signals except nuclear spin singles in the object to be detected, the strength of the gradient pulse is 2Gauss/cm, and the action time is 2ms;
The optimized control pulse II is used for converting 1 H nuclear spin singlet signals of N-acetyl aspartic acid molecules methylene and methine into a thermal equilibrium state, and the pulse is obtained by an optimized control pulse technology based on numerical calculation;
the magnetic resonance spectrum module comprises a radio frequency gradient pulse and a layer selection pulse;
Step ii, utilizing the characteristic that nuclear spin singlet is not influenced by a pulse gradient field to realize the selective observation of N-acetyl aspartic acid molecule methylene 1 H magnetic resonance signals;
And iii, comparing the measured magnetic resonance signals of the methylene 1 H of the N-acetylaspartic acid molecule in the actual living organism with the magnetic resonance signals of the N-acetylaspartic acid molecule under different pH values, and determining the pH value of the surrounding environment of the N-acetylaspartic acid molecule.
2. The method of claim 1, wherein in the step ii, signals except for the nuclear spin singlet signal of the N-acetyl aspartic acid molecule methylene 1 H are eliminated or suppressed by using a pulse gradient field, the selective observation of the magnetic resonance signal of the N-acetyl aspartic acid molecule methylene 1 H is realized, and the intensity, the time, the application times and the position of the pulse gradient field are adjusted, so that the optimization of the selective observation of the magnetic resonance signal of the N-acetyl aspartic acid molecule methylene 1 H is realized.
3. The method according to claim 1, wherein in step iii, the magnetic resonance signal of the methylene 1 H of the N-acetylaspartic acid molecule is obtained by precisely observing the magnetic resonance signal of the methylene 1 H of the N-acetylaspartic acid molecule of an actual living body, and the pH value of the environment surrounding the N-acetylaspartic acid molecule is measured by comparing the magnetic resonance signal of the methylene 1 H with the magnetic resonance signal of 1 H of the N-acetylaspartic acid molecule at different pH values.
4. The method of claim 1, wherein the N-acetyl aspartic acid molecule 1 H magnetic resonance signal comprises one or more of J-coupling value, 1 H chemical shift on methylene, 1 H on methylene, and N-acetyl aspartic acid molecule methyl 1 H signal chemical shift difference.
5. Use of the method according to any one of claims 1-4 for the in vivo pH detection of a organism of non-diagnostic interest.
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