WO2022171038A1 - Method for detecting ph value of living body with an n-acetylaspartic acid molecular magnetic resonance signal for non-diagnostic purpose - Google Patents

Method for detecting ph value of living body with an n-acetylaspartic acid molecular magnetic resonance signal for non-diagnostic purpose Download PDF

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WO2022171038A1
WO2022171038A1 PCT/CN2022/075149 CN2022075149W WO2022171038A1 WO 2022171038 A1 WO2022171038 A1 WO 2022171038A1 CN 2022075149 W CN2022075149 W CN 2022075149W WO 2022171038 A1 WO2022171038 A1 WO 2022171038A1
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magnetic resonance
methylene
pulse
naa
resonance signal
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Chinese (zh)
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姚叶锋
辛家祥
魏达秀
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华东师范大学
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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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  • the invention belongs to the technical field of magnetic resonance, in particular to a non-diagnostic method for detecting the pH value of a living body by utilizing N-acetyl aspartic acid (NAA) molecular magnetic resonance signals.
  • NAA N-acetyl aspartic acid
  • the normal human body environment often has a certain acidity and alkalinity.
  • an acid-base imbalance in the body's internal environment ie, it is more acidic or more alkaline than normal
  • the magnetic resonance signals of many biochemical molecules in the human body have obvious pH value dependence. If the biochemical molecular magnetic resonance signals affected by pH value in living organisms can be accurately observed, and the connection between pH value and biochemical molecular magnetic resonance signals can be established, the magnetic resonance in vivo observation of the pH value of the environment where the biochemical molecules are located can be realized.
  • N-acetyl aspartic acid (NAA) is a common biochemical molecule that exists widely in biological brains and is an important indicator for evaluating neuronal activity and brain cell metabolic activity.
  • a methylene chemical group exists in the chemical structure of NAA, and the magnetic resonance signal (chemical shift and J-coupling) of this group is significantly pH-dependent. Therefore, if the chemical shift and J coupling of the methylene 1 H signal of NAA molecules in vivo can be accurately observed, it will be possible to realize the in vivo magnetic resonance observation of human pH.
  • MRS magnetic resonance spectroscopy
  • the present invention proposes a non-diagnostic method for detecting the pH value of a living body by using NAA molecular magnetic resonance signals.
  • the method of the present invention cannot directly obtain the diagnosis result of the disease.
  • the present invention accurately observes the methylene 1 H signal of the NAA molecule in the living human brain, and based on the magnetic resonance signal of the methylene 1 H signal and the magnetic resonance signal of the NAA molecule at different pH values.
  • the observation of the pH value of the NAA-containing brain region in the human brain was achieved.
  • the method is fast, non-invasive, and can be applied to living organisms, and the measurement results have good stability and sensitivity.
  • the present invention is directed to the 3-spin system composed of NAA molecular methylene and methine 1 H.
  • the magnetic resonance signal of the nuclear spin system has good sensitivity to the acidity and alkalinity of its surrounding environment.
  • the invention prepares the nuclear spin single state of the 3-spin system composed of the NAA molecular methylene group and methine 1 H by designing a new pulse sequence, and utilizes the characteristic that the nuclear spin single state is not affected by the gradient field and evolves, The selective and precise observation of the methylene 1H magnetic resonance signal of the NAA molecule was achieved. Using the corresponding relationship between the obtained methylene 1 H magnetic resonance signal of NAA molecule and the acidity and alkalinity of the surrounding environment, the accurate measurement of the pH of the environment where the biochemical molecules in living organisms are located is realized.
  • the present invention provides a non-diagnostic method for measuring the pH value of living organisms by using N-acetyl aspartic acid (NAA) molecular magnetic resonance signals.
  • NAA N-acetyl aspartic acid
  • Step i Using a pulse sequence to prepare a 3-spin system nuclear spin singlet composed of 1 H on the methylene and methine groups of NAA molecules; the nuclear spin singlet obtained by the preparation is R x S x +R y S y +In ;
  • Step ii Utilizing the feature that the nuclear spin singlet is not affected by the pulse gradient field, the selective observation of the methylene 1 H magnetic resonance signal of the NAA molecule is realized;
  • Step iii compare the measured methylene 1 H magnetic resonance signal of the NAA molecule in the actual biological body with the magnetic resonance signal of the NAA molecule at different pH values, and determine the pH value of the surrounding environment of the NAA molecule;
  • the magnetic resonance signal includes the J-coupling value, the 1 H chemical shifts of the two methylene groups ( ⁇ R , ⁇ S ), and the difference between the two methylene groups and the methyl 1 H chemical shifts of the NAA molecule ( ⁇ R and One or more of ⁇ S ) etc.
  • the pulse sequence shown in FIG. 3 is used to prepare the spin singlet of the 3 - spin system of the NAA molecule.
  • R and S see Figure 1
  • a spin system composed of one 1 H spin of methine (labeled I, see Figure 1), which is transformed from the thermal equilibrium state R z +S z +I z to the state R x S x +R y S y +In , where n ⁇ ⁇ x,y,z ⁇ .
  • the pulse gradient field is used to eliminate or suppress other signals except the singlet signal of the methylene 1 H nuclear spin of the NAA molecule, so as to realize the selective observation of the methylene 1 H magnetic resonance signal of the NAA molecule.
  • the intensity, time, application times and position of the pulsed gradient field were adjusted to optimize the selective observation of the methylene 1 H magnetic resonance signal of NAA molecules.
  • the methylene 1 H magnetic resonance signal is obtained through accurate observation of the methylene 1 H magnetic resonance signal of the actual biological NAA molecule, including: J coupling value, two 1 H magnetic resonance signals on the methylene group.
  • the measurement of the pH value of the surrounding environment of the NAA molecule is achieved.
  • the present invention also includes the following basic steps: (1) Locating the to-be-observed area of the living organism by traditional magnetic resonance imaging technology. (2) If necessary, acquire the MRS spectrum of the area to be measured by traditional magnetic resonance spectroscopy (MRS) technology.
  • MRS magnetic resonance spectroscopy
  • the present invention designs a pulse sequence as shown in FIG. 3 for the coupling characteristics of the 3-spin system composed of 1 H on the methylene group and the methine group in the NAA molecule.
  • the pulse sequence is functionally mainly composed of the "Singleton Preparation and Selection” module and the "Magnetic Resonance Spectroscopy” module.
  • the present invention designs NAA based on the characteristics of the 3-spin system composed of methylene and methine 1 H in the NAA molecule, using the optimal control pulse technology based on numerical calculation. Preparation of molecular singlet pulses.
  • the main idea of the optimized control pulse technology is: 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.
  • Figure 4 shows the phase and power of the preparation pulse for the nuclear spin singlet of the 3-spin system composed of methine 1 H.
  • the preparation pulse the preparation of the nuclear spin singlet of the NAA molecule methylene 1 H can be realized, and the nuclear spin singlet obtained by the preparation is R x S x +R y S y + In; Selection of methylene 1 H signal of NAA molecule;
  • the present invention design a combination of radio frequency pulse and gradient pulse, which realizes the detection of the NAA molecule subgroup at a specific spatial position. Selective observation of methyl 1 H signal.
  • the pH value of the observed specific spatial position can be obtained by comparing the methylene 1 H magnetic resonance signal of the measured NAA molecule in the actual biological body with the 1 H magnetic resonance signal of the NAA molecule at different pH values.
  • the "single state preparation and selection" module in the pulse sequence shown in Fig. 3 is mainly composed of "saturation pulse”, “optimized control pulse 1", “decoupling pulse”, “gradient pulse” and “optimized control pulse 2”. :
  • “Saturation pulse” It is mainly used to suppress the signal of water in living tissue. According to the needs of system detection, “saturation pulse” can be used or not;
  • Optimized Control Pulse One a spin system composed of two 1 H spins (marked as R and S) of the methylene group of the NAA molecule and one 1 H spin (marked as I) of the methine group , from the thermal equilibrium state S z +R z +I z to the state R x S x +R y S y +In (n ⁇ ⁇ x,y,z ⁇ ), so as to realize the conversion of NAA molecules methylene and methine Preparation of singlet nuclear spins in a system composed of 1 H-based spins.
  • the present invention designs "optimized control pulse 1" by using the optimal control pulse technology based on numerical calculation.
  • Figure 4 shows an example of an optimized control pulse for preparing a singlet of methylene 1 H nuclear spins in NAA molecules, wherein Figure 4a is the phase of an optimized control pulse, and Figure 4b is the power of the corresponding pulse.
  • Decoupling pulse used to preserve the nuclear spin singlet of the NAA molecule, while eliminating the magnetic resonance signal of a part of the non-nuclear spin singlet in the analyte. In natural abundance samples, conventional homonuclear decoupling pulses can be used for this purpose.
  • Gdient pulse used to further eliminate signals other than nuclear spin singlet in the analyte.
  • Optimized control pulse two used to convert the 1 H nuclear spin singlet signals of the methylene and methine groups of NAA molecules to a thermal equilibrium state.
  • the present invention designs "optimized control pulse II" by using the numerical calculation-based optimal control pulse technology.
  • Figure 5 shows an example of an optimized control pulse for converting the nuclear spin singlet signals of the methylene and methine groups of NAA molecules to a thermal equilibrium state, wherein Figure 5a is the phase of an optimized control pulse, and Figure 5b is the corresponding pulse. power.
  • the "magnetic resonance spectroscopy" module in the pulse sequence in Fig. 3 is mainly composed of radio frequency gradient pulses and layer-selective pulses, and the purpose is to realize the selective observation of the methylene 1 H signal of NAA molecules in specific spatial positions.
  • the location of the living organism in the magnetic field can be localized using conventional T 1 -weighted sequences. This part of knowledge is known knowledge in the field, and will not be described in detail in the present invention.
  • a conventional T1 - weighted sequence (or similar pulse sequence capable of providing in vivo magnetic resonance images) is first used to locate the position of the living organ in the magnetic field, and select the area of the living organ to be measured. Then, the pulse shown in FIG. 3 was applied to the living organ. 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 signals of the methylene and methine groups of NAA molecules, and the pulse is controlled by optimization based on numerical calculation. The pulse technique is obtained, the action time is 40ms, and it consists of 1000 independent pulses of 40 ⁇ s.
  • the phase and power of each pulse are shown in Figures 4a and 4b; the "decoupling pulse” is used to preserve the singlet state of the NAA molecule.
  • the present invention uses continuous wave decoupling pulses. 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. The pulse is used to suppress other signals except the NAA spin singlet signal; "Optimized control" Pulse two” was used to convert the nuclear spin singlet signals of the methylene and methine groups of NAA molecules to thermal equilibrium. The pulse has a total time of 40ms and consists of 1000 individual pulses of 40 ⁇ s. The phase and power of each pulse are shown in Figures 5a and 5b.
  • magnetic Resonance Spectroscopy the selection of voxels in living organs is achieved by a pulse combination of one 90-degree and two 180-degree sincs.
  • the 1 H spectrum shown in Fig. 6b can be obtained.
  • This signal is the 1 H magnetic resonance signal of the methylene group of the NAA molecule.
  • the present invention is based on the magnetic resonance technology, and has a significant feature and innovation point that is different from other magnetic resonance spectroscopy technologies in the past: that is, the accurate detection of the methylene 1 H signal of the NAA molecule in the brain of the human body is realized. observed, and based on the resulting methylene 1 H signal of NAA molecules in the living human brain, the measurement of brain pH was achieved.
  • the method of the invention can quickly, non-invasively and non-radiatively measure the pH value of the living organs of the human body, has good accuracy, sensitivity and stability, has important application value in biology, medicine and the like, and is a new and original technology .
  • Figure 1 is a schematic diagram of the molecular structure of NAA of the present invention. Among them, R, S identify two 1 H protons of methylene on the NAA molecule, and I identify one 1 H proton of methine.
  • FIG. 2 is a specific implementation flow of the present invention. Specifically, it includes: (1) preparing the nuclear spin singlet of the 3-spin system composed of 1 H on the methylene and methine groups in the NAA molecule through a suitable pulse sequence; (2) realizing the nuclear spin singlet based on the prepared nuclear spin singlet Selective observation of the methylene 1 H signal of NAA molecules; (3) by comparing the methylene 1 H magnetic resonance signals of the NAA molecules measured in actual living organisms with the magnetic resonance signals of NAA molecules at different pH values , the pH value of the surrounding environment of NAA molecules in the observation space can be obtained.
  • FIG. 3 is a schematic diagram of a pulse sequence for accurately observing the methylene 1 H signal of NAA molecules in a living body according to the present invention.
  • 1 H represents the hydrogen channel
  • G x , G y and G z represent the pulse gradient channels in the x, y, and z directions, respectively
  • g 1 is the gradient pulse
  • 90 x , 180 y , and 180 y are used for the layer-selective pulse, respectively. pulse and phase.
  • FIG. 4 is a schematic diagram of the pulse sequence phase and power variation of the “optimized control pulse 1” of the present invention.
  • Fig. 4a is a schematic diagram of the phase change of the pulse sequence of "optimized control pulse 1”
  • Fig. 4b is a schematic diagram of the pulse sequence power change of "optimized control pulse 1”.
  • FIG. 5 is a schematic diagram of the pulse sequence phase and power changes of the “optimized control pulse 2” of the present invention.
  • Fig. 5a is a schematic diagram of the phase change of the pulse sequence of the "optimized control pulse 2”
  • Fig. 5b is a schematic diagram of the pulse sequence power change of the "optimized control pulse 2”.
  • FIG. 6 is a T1 - weighted image of a human brain magnetic resonance imaging and a magnetic resonance spectrogram of a selected region according to an embodiment of the present invention.
  • Figure 6a is a conventional T1 - weighted map of a normal human brain. The box in the figure represents the region observed by the magnetic resonance spectrum.
  • Fig. 6b is a 1 H magnetic resonance spectrum obtained by using the pulses of Fig. 3 to select the region shown in the box of Fig. 6a.
  • Figure 7 shows the 1 H magnetic resonance spectra of NAA molecules at different pH values.
  • the top gray line is the magnetic resonance signal measured by the normal human brain using the pulses of the present invention, and the gray box is the methylene group signal of the NAA molecule.
  • FIG. 8 is a schematic flow chart of main steps in an embodiment of the present invention.
  • FIG. 9 is a conventional T1 - weighted diagram of a water film sample (including a concentrated solution of 1.2% NAA, 0.4% glutamic acid, and 1.2% glutamine) according to an embodiment of the present invention, a conventional MRS magnetic resonance spectrum diagram and a pulse obtained by using FIG. 3 Magnetic resonance spectroscopy.
  • Figure 9a is a conventional T1 - weighted map of the water film sample. The box in the figure represents the region observed by the magnetic resonance spectrum.
  • Fig. 9b is a magnetic resonance spectrum obtained by conventional magnetic resonance spectroscopy (MRS) by selecting the region shown in the box of Fig. 9a
  • Fig. 9c is a magnetic resonance spectrum obtained by using the pulse of Fig. 3 to the region shown in the box of Fig. 9a.
  • FIG. 10 is a magnetic resonance spectrogram obtained by using the pulse of FIG. 3 for different subjects in Example 3 of the present invention.
  • Figure 10a is for a normal 25-year-old female, using the pulse of Figure 3 to obtain a magnetic resonance spectrogram
  • Figure 10b is for a normal 24-year-old male, using the pulse of Figure 3 to obtain a magnetic resonance spectrogram
  • Figure 10c is for a normal 25-year-old male, using Figure 3
  • the magnetic resonance spectrum was obtained by the pulse, and the methylene group signal of the NAA molecule is in the gray box.
  • T1 - weighted sequence or a similar pulse sequence that can provide a living magnetic resonance image
  • a living organ eg, human brain
  • localized in vivo magnetic resonance images are provided, which can be obtained with various conventional pulse sequences.
  • the present invention is not limited to the optimized pulse method described in Figs.
  • Measuring instrument Siemens 3T Prisma nuclear magnetic resonance instrument, and the detection coil used is a Siemens 64-channel head coil.
  • the "saturation pulse” used to suppress the water signal consists of four Gaussian pulses with a pulse width of 250ms and a power of 35Hz; The time is 40 ms and consists of 1000 individual pulses of 40 ⁇ s, the phase and power of these pulses are shown in Figures 4a and 4b.
  • the RF center of "Optimized Control Pulse One" 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 “gradient pulse” power is 2Gauss/cm, and the action time is 2ms; “Optimized control pulse 2” is based on numerical value The optimal control pulse technique for calculating the GRAPE method was obtained, with an action time of 40 ms, consisting of 1000 individual pulses of 40 ⁇ s, the phase and power of these pulses are shown in Figures 5a and 5b.
  • the RF center of "Optimized Control Pulse II" 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 all 250 Hz.
  • the power of the control pulse and the radio frequency center can be optimized by fine-tuning to optimize the methylene 1 H signal of the NAA molecule.
  • Measuring instrument Siemens 3T Prisma nuclear magnetic resonance instrument, and the detection coil used is a Siemens 64-channel head coil.
  • 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 time is 40 ms and consists of 1000 individual pulses of 40 ⁇ s, the phase and power of these pulses are shown in Figures 4a and 4b.
  • the RF center of "Optimized Control Pulse One" 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 "gradient pulse” power is 2Gauss/cm, and the action time is 2ms;
  • the optimized control pulse technique for calculating the GRAPE method was obtained, with an action time of 40 ms, consisting of 1000 individual pulses of 40 ⁇ s, the phase and power of these pulses are shown in Figures 5a and 5b.
  • the RF center of "Optimized Control Pulse II" 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 all 250Hz.
  • the power of the control pulse and the radio frequency center can be optimized by fine-tuning to optimize the methylene 1 H signal of the NAA molecule.
  • Measuring instrument Siemens 3T Prisma nuclear magnetic resonance instrument, and the detection coil used is a Siemens 64-channel head coil.
  • 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 time is 40 ms and consists of 1000 individual pulses of 40 ⁇ s, the phase and power of these pulses are shown in Figures 4a and 4b.
  • the RF center of "Optimized Control Pulse One" 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 “gradient pulse” power is 2Gauss/cm, and the action time is 2ms; “Optimized control pulse 2” is based on numerical value The optimal control pulse technique for calculating the GRAPE method was obtained, with an action time of 40 ms, consisting of 1000 individual pulses of 40 ⁇ s, the phase and power of these pulses are shown in Figures 5a and 5b.
  • the RF center of "Optimized Control Pulse II" 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 all 250 Hz.
  • the power of the control pulse and the radio frequency center can be optimized by fine-tuning to optimize the methylene 1 H signal of the NAA molecule.
  • Figure 10a is a normal 25-year-old woman's magnetic resonance spectrum obtained by the pulse of Figure 3;
  • Figure 10b is a normal 24-year-old man's Figure 3 pulse obtained by the magnetic resonance spectrum;
  • Figure 10c is a normal 25-year-old male obtained by the pulse of Figure 3. It can be seen from the figure that the methylene signal position and peak shape of NAA molecules in the normal human brain are exactly the same. Therefore, the pH value of the normal human brain is neutral, about 7.4.

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Abstract

A method for detecting a pH value of a biological living body with an N-acetylaspartic acid (NAA) molecular magnetic resonance signal. The method realizes selective accurate observation of an NAA molecular methylene 1H magnetic resonance signal by preparing the nuclear spin singlet state of a 3-spin system composed of the NAA molecular methylene group and a secondary methyl group 1H. Since the NAA molecular methylene 1H magnetic resonance signal is sensitive to the environment pH value, the obtained NAA molecular methylene 1H magnetic resonance signal can realize accurate measurement of the pH value of the biological living body. The pH value of a living organ of a human body can be measured quickly and noninvasively without radiation, has good accuracy and sensitivity, and has an important application value in the aspects of biology, medicine and the like.

Description

一种非诊断目的的利用N-乙酰天门冬氨酸分子磁共振信号检测活体pH值的方法A method for detecting pH value of living body using N-acetylaspartate molecular magnetic resonance signals for non-diagnostic purposes
本申请要求申请日为2021年02月10日、申请号为202110183425.0、发明名称为“一种非诊断目的的利用N-乙酰天门冬氨酸分子磁共振信号检测活体pH值的方法”的中国发明专利申请的优先权。This application requires a Chinese invention with an application date of February 10, 2021, an application number of 202110183425.0, and the title of the invention as "a non-diagnostic method for detecting the pH value of a living body using N-acetylaspartate molecular magnetic resonance signals" Priority for patent applications.
技术领域technical field
本发明属于磁共振技术领域，具体涉及一种非诊断目的的利用N-乙酰天门冬氨酸(N-acetyl aspartic acid,NAA)分子磁共振信号检测活体pH值的方法。The invention belongs to the technical field of magnetic resonance, in particular to a non-diagnostic method for detecting the pH value of a living body by utilizing N-acetyl aspartic acid (NAA) molecular magnetic resonance signals.
背景技术Background technique
正常人体内环境常常具有一定的酸碱性。当人体内环境出现酸碱失衡(即，与正常相比偏酸或偏碱)意味着人体健康状况发生了变化。通过对身体环境的酸碱性观测，不仅有可能实现对疾病的早期诊断，同时有助于一些疾病治疗过程中治疗效果的判断。The normal human body environment often has a certain acidity and alkalinity. When there is an acid-base imbalance in the body's internal environment (ie, it is more acidic or more alkaline than normal), it means that the health of the body has changed. Through the observation of the acidity and alkalinity of the body environment, it is not only possible to realize the early diagnosis of diseases, but also help to judge the therapeutic effect in the treatment of some diseases.
人体内很多生化分子的磁共振信号具有明显的pH值依赖性。如果能精准观测到生物活体内受pH值影响的生化分子磁共振信号，建立pH值与生化分子磁共振信号之间的联系，就可以实现生化分子所在环境pH值的磁共振活体观测。N-乙酰天门冬氨酸(N-acetyl aspartic acid,NAA)是一种常见的生化分子，广泛存在于生物大脑中，是评估神经元活动和脑细胞代谢活动的一个重要指标。NAA的化学结构中存在一个亚甲基化学基团，该基团的磁共振信号(化学位移和J耦合)对pH值有明显的依赖性。因此，如果能够精准观测活体内NAA分子亚甲基 1H信号的化学位移和J耦合，就将有可能实现对人体pH值的活体磁共振观测。 The magnetic resonance signals of many biochemical molecules in the human body have obvious pH value dependence. If the biochemical molecular magnetic resonance signals affected by pH value in living organisms can be accurately observed, and the connection between pH value and biochemical molecular magnetic resonance signals can be established, the magnetic resonance in vivo observation of the pH value of the environment where the biochemical molecules are located can be realized. N-acetyl aspartic acid (NAA) is a common biochemical molecule that exists widely in biological brains and is an important indicator for evaluating neuronal activity and brain cell metabolic activity. A methylene chemical group exists in the chemical structure of NAA, and the magnetic resonance signal (chemical shift and J-coupling) of this group is significantly pH-dependent. Therefore, if the chemical shift and J coupling of the methylene 1 H signal of NAA molecules in vivo can be accurately observed, it will be possible to realize the in vivo magnetic resonance observation of human pH.
然而，经典活体磁共振技术(如，磁共振波谱，MRS)通常只能观测到生物活体中NAA分子甲基的 1H信号，无法观测到NAA分子亚甲基的 1H信号。特别是，常常无法获得NAA分子亚甲基的J耦合值、化学位移，以及亚甲基与NAA分子甲基信号化学位移的差值。基于经典活体磁共振技术无法通过精准观测NAA分子亚甲基 1H信号实现对生物活体pH值的测量。 However, classical in vivo magnetic resonance techniques (eg, magnetic resonance spectroscopy, MRS) can usually only observe the 1 H signal of the methyl group of NAA molecules in living organisms, but cannot observe the 1 H signal of the methylene group of the NAA molecule. In particular, J-coupling values, chemical shifts, and the difference in chemical shifts of the methylene and methyl signals of NAA molecules are often not available. Based on classical in vivo magnetic resonance technology, it is impossible to measure the pH value of living organisms by accurately observing the methylene 1 H signal of NAA molecules.
发明内容SUMMARY OF THE INVENTION
为了解决现有技术存在的不足，本发明提出了一种非诊断目的的利用NAA分子磁共振信号检测活体pH值的方法，本发明方法无法直接获得疾病的诊断结果。利用该方法，本发明对活体人脑中NAA分子亚甲基 1H信号进行了精准观测，并基于所述亚甲基 1H信号的磁共振信号和不同pH值下NAA分子的磁共振信号进行对比，实现了对人脑中含NAA脑区pH值的观测。实验证明该方法具有快速、无创、可以应用于生物活体，同时测量结果具有良好的稳定性和灵敏度。 In order to solve the deficiencies of the prior art, the present invention proposes a non-diagnostic method for detecting the pH value of a living body by using NAA molecular magnetic resonance signals. The method of the present invention cannot directly obtain the diagnosis result of the disease. Using this method, the present invention accurately observes the methylene 1 H signal of the NAA molecule in the living human brain, and based on the magnetic resonance signal of the methylene 1 H signal and the magnetic resonance signal of the NAA molecule at different pH values. In contrast, the observation of the pH value of the NAA-containing brain region in the human brain was achieved. Experiments show that the method is fast, non-invasive, and can be applied to living organisms, and the measurement results have good stability and sensitivity.
本发明中所针对的是NAA分子亚甲基和次甲基 1H组成的3自旋体系。该核自旋体系的 磁共振信号对其周围环境的酸碱性具有良好的灵敏度。当pH值发生变化时，亚甲基分子的化学位移和J耦合都会发生变化。本发明通过设计新型脉冲序列，制备了NAA分子亚甲基和次甲基 1H组成的3自旋体系的核自旋单态，利用核自旋单态不受梯度场作用而演化的特点，实现了对NAA分子亚甲基 1H磁共振信号的选择性精准观测。利用所获得的NAA分子亚甲基 1H磁共振信号与周围环境酸碱性的对应关系，实现对生物活体中生化分子所在环境pH的精确测量。 The present invention is directed to the 3-spin system composed of NAA molecular methylene and methine 1 H. The magnetic resonance signal of the nuclear spin system has good sensitivity to the acidity and alkalinity of its surrounding environment. When the pH is changed, both the chemical shift and J-coupling of the methylene molecule change. The invention prepares the nuclear spin single state of the 3-spin system composed of the NAA molecular methylene group and methine 1 H by designing a new pulse sequence, and utilizes the characteristic that the nuclear spin single state is not affected by the gradient field and evolves, The selective and precise observation of the methylene 1H magnetic resonance signal of the NAA molecule was achieved. Using the corresponding relationship between the obtained methylene 1 H magnetic resonance signal of NAA molecule and the acidity and alkalinity of the surrounding environment, the accurate measurement of the pH of the environment where the biochemical molecules in living organisms are located is realized.
本发明提供了一种非诊断目的的利用N-乙酰天门冬氨酸(N-acetyl aspartic acid,NAA)分子磁共振信号测量生物活体pH值的方法，所述方法流程如图2所示，具体包括：The present invention provides a non-diagnostic method for measuring the pH value of living organisms by using N-acetyl aspartic acid (NAA) molecular magnetic resonance signals. include:
步骤i：利用脉冲序列制备NAA分子亚甲基和次甲基上 1H构成的3自旋体系核自旋单态；所述制备获得的核自旋单态为R xS x+R yS y+I n； Step i: Using a pulse sequence to prepare a 3-spin system nuclear spin singlet composed of 1 H on the methylene and methine groups of NAA molecules; the nuclear spin singlet obtained by the preparation is R x S x +R y S y +In ;
步骤ii：利用核自旋单态不受脉冲梯度场影响的特点，实现对NAA分子亚甲基 1H磁共振信号的选择性观测； Step ii: Utilizing the feature that the nuclear spin singlet is not affected by the pulse gradient field, the selective observation of the methylene 1 H magnetic resonance signal of the NAA molecule is realized;
步骤iii：将测得的实际生物活体中的NAA分子亚甲基 1H磁共振信号与不同pH值下NAA分子的磁共振信号进行对比，确定NAA分子周围环境的pH值； Step iii: compare the measured methylene 1 H magnetic resonance signal of the NAA molecule in the actual biological body with the magnetic resonance signal of the NAA molecule at different pH values, and determine the pH value of the surrounding environment of the NAA molecule;
所述磁共振信号包括J耦合值、两个亚甲基 1H化学位移(ω R、ω S)，以及这两个亚甲基与NAA分子甲基 1H化学位移的差值(Δω R和Δω S)等中的一种或几种。 The magnetic resonance signal includes the J-coupling value, the 1 H chemical shifts of the two methylene groups (ω R , ω S ), and the difference between the two methylene groups and the methyl 1 H chemical shifts of the NAA molecule (Δω R and One or more of Δω S ) etc.
所述步骤i中，利用图3所示的脉冲序列，对所述NAA分子3自旋体系自旋单态进行制备，所述制备步骤包括：将亚甲基的2个 1H自旋(标记为R和S，见图1)和次甲基的1个 1H自旋(标记为I，见图1)组成的自旋体系，由热平衡态R z+S z+I z转化至状态R xS x+R yS y+I n，其中n∈{x,y,z}。 In the step i, the pulse sequence shown in FIG. 3 is used to prepare the spin singlet of the 3 - spin system of the NAA molecule. is R and S, see Figure 1) and a spin system composed of one 1 H spin of methine (labeled I, see Figure 1), which is transformed from the thermal equilibrium state R z +S z +I z to the state R x S x +R y S y +In , where n∈ { x,y,z}.
所述步骤ii中，利用脉冲梯度场消除或压制除NAA分子亚甲基 1H核自旋单态信号以外的其他信号，实现对NAA分子亚甲基 1H磁共振信号的选择性观测。调整脉冲梯度场的强度、时间、施加次数和位置，实现对NAA分子亚甲基 1H磁共振信号选择性观测的优化。 In the step ii, the pulse gradient field is used to eliminate or suppress other signals except the singlet signal of the methylene 1 H nuclear spin of the NAA molecule, so as to realize the selective observation of the methylene 1 H magnetic resonance signal of the NAA molecule. The intensity, time, application times and position of the pulsed gradient field were adjusted to optimize the selective observation of the methylene 1 H magnetic resonance signal of NAA molecules.
所述步骤iii中，通过对实际生物活体NAA分子亚甲基 1H磁共振信号的精准观测，获得亚甲基 1H磁共振信号，包括：J耦合值、亚甲基上两个 1H的化学位移ω R和ω S，以及这两个 1H与NAA分子甲基信号化学位移的差值，即Δω R和Δω S等。通过将所述亚甲基 1H磁共振信号与不同pH值下NAA分子的 1H磁共振信号进行对比，实现对NAA分子周围环境pH值的测量。 In the step iii, the methylene 1 H magnetic resonance signal is obtained through accurate observation of the methylene 1 H magnetic resonance signal of the actual biological NAA molecule, including: J coupling value, two 1 H magnetic resonance signals on the methylene group. The chemical shifts ω R and ω S , and the difference between the chemical shifts of these two 1 H and NAA molecule methyl signals, ie Δω R and Δω S , etc. By comparing the methylene 1 H magnetic resonance signal with the 1 H magnetic resonance signal of the NAA molecule at different pH values, the measurement of the pH value of the surrounding environment of the NAA molecule is achieved.
此外，本发明中还包括以下基础步骤：(1)通过传统磁共振成像技术定位生物活体的待观测区。(2)如有需要，通过传统磁共振波谱(MRS)技术采集待测区的MRS谱图。In addition, the present invention also includes the following basic steps: (1) Locating the to-be-observed area of the living organism by traditional magnetic resonance imaging technology. (2) If necessary, acquire the MRS spectrum of the area to be measured by traditional magnetic resonance spectroscopy (MRS) technology.
具体地，本发明针对NAA分子中亚甲基和次甲基上 1H组成的3自旋体系的耦合特征， 设计了如图3所示的脉冲序列。该脉冲序列在功能上主要由“单态制备和选择”模块和“磁共振波谱”模块组成。 Specifically, the present invention designs a pulse sequence as shown in FIG. 3 for the coupling characteristics of the 3-spin system composed of 1 H on the methylene group and the methine group in the NAA molecule. The pulse sequence is functionally mainly composed of the "Singleton Preparation and Selection" module and the "Magnetic Resonance Spectroscopy" module.
在所述“单态制备和选择”模块中，本发明针对NAA分子中亚甲基和次甲基 1H组成的3自旋体系的特点，利用基于数值计算的优化控制脉冲技术，设计了NAA分子单态的制备脉冲。所述优化控制脉冲技术的主要思路为：将整个优化控制脉冲分成若干个小脉冲，通过不断改变各个小脉冲的相位和功率，提高初始态到目标态的转移效率，对于NAA分子中亚甲基和次甲基 1H组成的3自旋体系核自旋单态的制备脉冲，其相位和功率如图4所示。通过该制备脉冲，可以实现NAA分子亚甲基 1H核自旋单态的制备，所述制备获得的核自旋单态为R xS x+R yS y+I n；并进而实现对NAA分子亚甲基 1H信号的选择； In the "single state preparation and selection" module, the present invention designs NAA based on the characteristics of the 3-spin system composed of methylene and methine 1 H in the NAA molecule, using the optimal control pulse technology based on numerical calculation. Preparation of molecular singlet pulses. The main idea of the optimized control pulse technology is: 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. Figure 4 shows the phase and power of the preparation pulse for the nuclear spin singlet of the 3-spin system composed of methine 1 H. Through the preparation pulse, the preparation of the nuclear spin singlet of the NAA molecule methylene 1 H can be realized, and the nuclear spin singlet obtained by the preparation is R x S x +R y S y + In; Selection of methylene 1 H signal of NAA molecule;
在所述“磁共振波谱”模块中，在基于前序对NAA分子亚甲基 1H信号选择的基础上，本发明设计了射频脉冲和梯度脉冲的组合，实现了对特定空间位置NAA分子亚甲基 1H信号的选择性观测。 In the "magnetic resonance spectroscopy" module, on the basis of selecting the methylene 1 H signal of the NAA molecule based on the pre-sequence, the present invention designs a combination of radio frequency pulse and gradient pulse, which realizes the detection of the NAA molecule subgroup at a specific spatial position. Selective observation of methyl 1 H signal.
将测得的实际生物活体中的NAA分子亚甲基 1H磁共振信号与不同pH值下NAA分子的 1H磁共振信号进行对比，即可获得所观测特定空间位置的pH值。 The pH value of the observed specific spatial position can be obtained by comparing the methylene 1 H magnetic resonance signal of the measured NAA molecule in the actual biological body with the 1 H magnetic resonance signal of the NAA molecule at different pH values.
进一步地，所述图3脉冲序列中“单态制备和选择”模块主要可由“饱和脉冲”、“优化控制脉冲一”、“去耦脉冲”、“梯度脉冲”和“优化控制脉冲二”组成：Further, the "single state preparation and selection" module in the pulse sequence shown in Fig. 3 is mainly composed of "saturation pulse", "optimized control pulse 1", "decoupling pulse", "gradient pulse" and "optimized control pulse 2". :
“饱和脉冲”：主要用于压制活体组织内水的信号，可根据体系检测需要，使用或不使用“饱和脉冲”；"Saturation pulse": It is mainly used to suppress the signal of water in living tissue. According to the needs of system detection, "saturation pulse" can be used or not;
“优化控制脉冲一”：用于将NAA分子亚甲基的2个 1H自旋(标记为R和S)和次甲基的1个 1H自旋(标记为I)组成的自旋体系，由热平衡态S z+R z+I z转化至状态R xS x+R yS y+I n(n∈{x,y,z})，从而实现对NAA分子亚甲基和次甲基 1H组成自旋体系的核自旋单态制备。本发明利用基于数值计算的优化控制脉冲技术设计了“优化控制脉冲一”。图4展示了一个用于制备NAA分子亚甲基 1H核自旋单态的优化控制脉冲实例，其中图4a为一个优化控制脉冲的相位，图4b为相应的脉冲的功率。 "Optimized Control Pulse One": a spin system composed of two 1 H spins (marked as R and S) of the methylene group of the NAA molecule and one 1 H spin (marked as I) of the methine group , from the thermal equilibrium state S z +R z +I z to the state R x S x +R y S y +In (n∈ { x,y,z}), so as to realize the conversion of NAA molecules methylene and methine Preparation of singlet nuclear spins in a system composed of 1 H-based spins. The present invention designs "optimized control pulse 1" by using the optimal control pulse technology based on numerical calculation. Figure 4 shows an example of an optimized control pulse for preparing a singlet of methylene 1 H nuclear spins in NAA molecules, wherein Figure 4a is the phase of an optimized control pulse, and Figure 4b is the power of the corresponding pulse.
“去耦脉冲”：用于保存NAA分子的核自旋单态，同时消除待测物中一部分非核自旋单态的磁共振信号。在天然丰度样品中，可用常规同核去耦脉冲实现该目的。"Decoupling pulse": used to preserve the nuclear spin singlet of the NAA molecule, while eliminating the magnetic resonance signal of a part of the non-nuclear spin singlet in the analyte. In natural abundance samples, conventional homonuclear decoupling pulses can be used for this purpose.
“梯度脉冲”：用于进一步消除待测物中除核自旋单态之外的其他信号。"Gradient pulse": used to further eliminate signals other than nuclear spin singlet in the analyte.
“优化控制脉冲二”：用于将NAA分子亚甲基和次甲基的 1H核自旋单态信号转化至热平衡态。本发明利用基于数值计算的优化控制脉冲技术设计了“优化控制脉冲二”。图5展示了一个将NAA分子亚甲基和次甲基的核自旋单态信号转化至热平衡态的优化控制脉冲实例，其中图5a为一个优化控制脉冲的相位，图5b为相应的脉冲的功率。 "Optimized control pulse two": used to convert the 1 H nuclear spin singlet signals of the methylene and methine groups of NAA molecules to a thermal equilibrium state. The present invention designs "optimized control pulse II" by using the numerical calculation-based optimal control pulse technology. Figure 5 shows an example of an optimized control pulse for converting the nuclear spin singlet signals of the methylene and methine groups of NAA molecules to a thermal equilibrium state, wherein Figure 5a is the phase of an optimized control pulse, and Figure 5b is the corresponding pulse. power.
图3脉冲序列中“磁共振波谱”模块主要由射频梯度脉冲和选层脉冲组成，目的是为实现对特定空间位置中NAA分子亚甲基 1H信号的选择性观测。为了实现对特定空间位置中NAA分子亚甲基 1H信号的选择，可利用常规T 1加权序列对生物活体在磁场中的位置进行定位。这部分知识为领域内公知知识，本发明不作更多赘述。 The "magnetic resonance spectroscopy" module in the pulse sequence in Fig. 3 is mainly composed of radio frequency gradient pulses and layer-selective pulses, and the purpose is to realize the selective observation of the methylene 1 H signal of NAA molecules in specific spatial positions. In order to achieve the selection of the methylene 1 H signal of the NAA molecule in a specific spatial location, the location of the living organism in the magnetic field can be localized using conventional T 1 -weighted sequences. This part of knowledge is known knowledge in the field, and will not be described in detail in the present invention.
在一些具体实施例中，首先利用常规T 1加权序列(或类似可提供活体磁共振图像的脉冲序列)对活体器官在磁场中的位置进行定位，并选择待测的活体器官区域。然后，对所述活体器官实施图3所示脉冲。其中，施加“饱和脉冲”压制人体内的水信号；“优化控制脉冲一”用于制备NAA分子亚甲基和次甲基的核自旋单态信号，该脉冲是通过基于数值计算的优化控制脉冲技术得到，作用时间为40ms，由1000个40μs独立脉冲组成，各脉冲的相位和功率见图4a和4b；“去耦脉冲”用于保存NAA分子的单态，在一些具体实施例中，本发明使用了连续波去耦脉冲。其中，去耦脉冲的功率为400Hz，时间为1ms；“梯度脉冲”的强度为2Gauss/cm，作用时间为2ms，该脉冲用于压制除NAA自旋单态信号外的其他信号；“优化控制脉冲二”用于将NAA分子亚甲基和次甲基的核自旋单态信号转化至热平衡态。该脉冲总时间为40ms，由1000个40μs的独立脉冲组成。各脉冲的相位和功率见图5a和5b。 In some embodiments, a conventional T1 - weighted sequence (or similar pulse sequence capable of providing in vivo magnetic resonance images) is first used to locate the position of the living organ in the magnetic field, and select the area of the living organ to be measured. Then, the pulse shown in FIG. 3 was applied to the living organ. 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 signals of the methylene and methine groups of NAA molecules, and the pulse is controlled by optimization based on numerical calculation. The pulse technique is obtained, the action time is 40ms, and it consists of 1000 independent pulses of 40μs. The phase and power of each pulse are shown in Figures 4a and 4b; the "decoupling pulse" is used to preserve the singlet state of the NAA molecule. In some specific embodiments, The present invention uses continuous wave decoupling pulses. 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. The pulse is used to suppress other signals except the NAA spin singlet signal; "Optimized control" Pulse two" was used to convert the nuclear spin singlet signals of the methylene and methine groups of NAA molecules to thermal equilibrium. The pulse has a total time of 40ms and consists of 1000 individual pulses of 40μs. The phase and power of each pulse are shown in Figures 5a and 5b.
在“磁共振波谱”模块中，由一个90度和两个180度的sinc的脉冲组合实现了对活体器官中的体素进行选择。In the "Magnetic Resonance Spectroscopy" module, the selection of voxels in living organs is achieved by a pulse combination of one 90-degree and two 180-degree sincs.
在上述条件下，将图3所示脉冲应用于人体，可获得图6b所示的 1H谱图。在该谱图中，2.2ppm到3.0ppm之间出现的明显的具有J耦合特征的7重峰。该信号为NAA分子亚甲基的 1H磁共振信号。通过将谱图中NAA分子亚甲基的 1H磁共振信号和不同pH值下NAA分子亚甲基的 1H磁共振信号进行对比，即可得到相关人体活体器官对应位置的pH值。 Under the above conditions, applying the pulse shown in Fig. 3 to the human body, the 1 H spectrum shown in Fig. 6b can be obtained. In this spectrum, a distinct septet with J-coupling characteristics appears between 2.2 ppm and 3.0 ppm. This signal is the 1 H magnetic resonance signal of the methylene group of the NAA molecule. By comparing the 1 H magnetic resonance signal of the methylene group of the NAA molecule in the spectrum with the 1 H magnetic resonance signal of the methylene group of the NAA molecule at different pH values, the pH value of the corresponding position of the relevant human living organ can be obtained.
本发明的有益效果在于：本发明基于磁共振技术，具有区别于以往其他磁共振波谱技术的一个显著特点和创新点：即，实现了对人体活体大脑中NAA分子亚甲基 1H信号的精准观测，并且基于所得到的人体活体大脑中NAA分子亚甲基 1H信号实现了对大脑pH值的测量。本发明方法能够快速、无创、无辐射地测量人体活体器官的pH值，具有良好的精确性、灵敏度和稳定性，在生物学，医学等方面具有重要的应用价值，是一种新的独创技术。 The beneficial effects of the present invention are as follows: the present invention is based on the magnetic resonance technology, and has a significant feature and innovation point that is different from other magnetic resonance spectroscopy technologies in the past: that is, the accurate detection of the methylene 1 H signal of the NAA molecule in the brain of the human body is realized. observed, and based on the resulting methylene 1 H signal of NAA molecules in the living human brain, the measurement of brain pH was achieved. The method of the invention can quickly, non-invasively and non-radiatively measure the pH value of the living organs of the human body, has good accuracy, sensitivity and stability, has important application value in biology, medicine and the like, and is a new and original technology .
附图说明Description of drawings
图1为本发明NAA分子结构示意图。其中，R，S标识了NAA分子上亚甲基的两个 1H质子，I标识了次甲基的一个 1H质子。 Figure 1 is a schematic diagram of the molecular structure of NAA of the present invention. Among them, R, S identify two 1 H protons of methylene on the NAA molecule, and I identify one 1 H proton of methine.
图2为本发明具体实施流程。具体包括：(1)通过合适脉冲序列制备NAA分子中亚甲基和次甲基上 1H组成的3自旋体系的核自旋单态；(2)基于所制备的核自旋单态实现对NAA分子亚甲基 1H信号的选择性观测；(3)通过将测得的实际生物活体中的NAA分子亚甲基 1H 磁共振信号与不同pH值下NAA分子的磁共振信号进行对比，即可获得观测空间NAA分子周围环境的pH值。 FIG. 2 is a specific implementation flow of the present invention. Specifically, it includes: (1) preparing the nuclear spin singlet of the 3-spin system composed of 1 H on the methylene and methine groups in the NAA molecule through a suitable pulse sequence; (2) realizing the nuclear spin singlet based on the prepared nuclear spin singlet Selective observation of the methylene 1 H signal of NAA molecules; (3) by comparing the methylene 1 H magnetic resonance signals of the NAA molecules measured in actual living organisms with the magnetic resonance signals of NAA molecules at different pH values , the pH value of the surrounding environment of NAA molecules in the observation space can be obtained.
图3为本发明用于精准观测活体中NAA分子亚甲基 1H信号的脉冲序列示意图。其中， 1H表示氢通道，G x,G y和G z分别表示x，y，z方向的脉冲梯度通道，g 1为梯度脉冲，90 x,180 y,180 y分别为选层脉冲所用的脉冲和相位。 FIG. 3 is a schematic diagram of a pulse sequence for accurately observing the methylene 1 H signal of NAA molecules in a living body according to the present invention. Among them, 1 H represents the hydrogen channel, G x , G y and G z represent the pulse gradient channels in the x, y, and z directions, respectively, g 1 is the gradient pulse, and 90 x , 180 y , and 180 y are used for the layer-selective pulse, respectively. pulse and phase.
图4为本发明“优化控制脉冲一”的脉冲序列相位和功率变化示意图。图4a为“优化控制脉冲一”的脉冲序列相位变化示意图，图4b为“优化控制脉冲一”的脉冲序列功率变化示意图。FIG. 4 is a schematic diagram of the pulse sequence phase and power variation of the “optimized control pulse 1” of the present invention. Fig. 4a is a schematic diagram of the phase change of the pulse sequence of "optimized control pulse 1", and Fig. 4b is a schematic diagram of the pulse sequence power change of "optimized control pulse 1".
图5为本发明“优化控制脉冲二”的脉冲序列相位和功率变化示意图。图5a为“优化控制脉冲二”的脉冲序列相位变化示意图，图5b为“优化控制脉冲二”的脉冲序列功率变化示意图。FIG. 5 is a schematic diagram of the pulse sequence phase and power changes of the “optimized control pulse 2” of the present invention. Fig. 5a is a schematic diagram of the phase change of the pulse sequence of the "optimized control pulse 2", and Fig. 5b is a schematic diagram of the pulse sequence power change of the "optimized control pulse 2".
图6为本发明实施例人脑磁共振成像T 1加权图和选定区域磁共振波谱图。图6a为正常人大脑的常规T 1加权图。图中方框表示了磁共振波谱所观测的区域。图6b为利用图3脉冲选取图6a方框所示区域所获得的 1H磁共振波谱。 FIG. 6 is a T1 - weighted image of a human brain magnetic resonance imaging and a magnetic resonance spectrogram of a selected region according to an embodiment of the present invention. Figure 6a is a conventional T1 - weighted map of a normal human brain. The box in the figure represents the region observed by the magnetic resonance spectrum. Fig. 6b is a 1 H magnetic resonance spectrum obtained by using the pulses of Fig. 3 to select the region shown in the box of Fig. 6a.
图7为在不同pH值下NAA分子的 1H磁共振波谱。顶部灰色线为正常人脑利用本发明所述脉冲所测得磁共振信号，灰色框内为NAA分子亚甲基基团信号。 Figure 7 shows the 1 H magnetic resonance spectra of NAA molecules at different pH values. The top gray line is the magnetic resonance signal measured by the normal human brain using the pulses of the present invention, and the gray box is the methylene group signal of the NAA molecule.
图8为本发明实施方式的主要步骤流程示意图。FIG. 8 is a schematic flow chart of main steps in an embodiment of the present invention.
图9为本发明实施例水膜样品(包括1.2％NAA、0.4％谷氨酸、1.2％谷氨酰胺的浓溶液)的常规T 1加权图，常规MRS磁共振波谱图和利用图3脉冲获得磁共振波谱图。其中，图9a为水膜样品的常规T 1加权图。图中方框表示了磁共振波谱所观测的区域。图9b为常规磁共振波谱技术(MRS)选取图9a方框所示区域所获得的磁共振波谱图，图9c为利用图3脉冲对图9a方框所示区域所获得的磁共振波谱图。 FIG. 9 is a conventional T1 - weighted diagram of a water film sample (including a concentrated solution of 1.2% NAA, 0.4% glutamic acid, and 1.2% glutamine) according to an embodiment of the present invention, a conventional MRS magnetic resonance spectrum diagram and a pulse obtained by using FIG. 3 Magnetic resonance spectroscopy. Among them, Figure 9a is a conventional T1 - weighted map of the water film sample. The box in the figure represents the region observed by the magnetic resonance spectrum. Fig. 9b is a magnetic resonance spectrum obtained by conventional magnetic resonance spectroscopy (MRS) by 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 to the region shown in the box of Fig. 9a.
图10为本发明实施例3中，对不同被试者利用图3脉冲获得磁共振波谱图。图10a为针对正常25岁女性，利用图3脉冲获得磁共振波谱图；图10b为针对正常24岁男性，利用图3脉冲获得磁共振波谱图；图10c为针对正常25岁男性，利用图3脉冲获得磁共振波谱图，灰色框内为NAA分子亚甲基基团信号。FIG. 10 is a magnetic resonance spectrogram obtained by using the pulse of FIG. 3 for different subjects in Example 3 of the present invention. Figure 10a is for a normal 25-year-old female, using the pulse of Figure 3 to obtain a magnetic resonance spectrogram; Figure 10b is for a normal 24-year-old male, using the pulse of Figure 3 to obtain a magnetic resonance spectrogram; Figure 10c is for a normal 25-year-old male, using Figure 3 The magnetic resonance spectrum was obtained by the pulse, and the methylene group signal of the NAA molecule is in the gray box.
具体实施方式Detailed ways
结合以下具体实施例和附图，对发明作进一步的详细说明。实施本发明的过程、条件、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。The invention will be further described in detail with reference to the following specific embodiments and accompanying drawings. Except for the content specifically mentioned below, the process, conditions, experimental methods, etc. for implementing the present invention are all common knowledge and common knowledge in the field, and the present invention is not particularly limited.
实施方式的主要步骤流程如图8所示：The main step flow of the implementation is shown in Figure 8:
1、利用常规T 1加权序列(或类似可提供活体磁共振图像的脉冲序列)对活体器官(如，人体大脑)在磁场中的位置进行定位，选择待测活体器官区域。 1. Use a conventional T1 - weighted sequence (or a similar pulse sequence that can provide a living magnetic resonance image) to locate the position of a living organ (eg, human brain) in the magnetic field, and select the area of the living organ to be tested.
2、施加图3所示脉冲，获得活体中待测区域的NAA分子亚甲基 1H信号。 2. Apply the pulse shown in FIG. 3 to obtain the methylene 1 H signal of the NAA molecule in the region to be tested in the living body.
3、将所获得的活体中NAA分子亚甲基 1H信号与不同pH值下NAA分子亚甲基 1H信号比较，得到活体中所观测区域的pH值。 3. Compare the methylene 1 H signal of the obtained NAA molecule in the living body with the methylene 1 H signal of the NAA molecule at different pH values to obtain the pH value of the observed area in the living body.
在实施过程中，提供定位的活体磁共振图像，可用各类常规脉冲序列获得。本发明适用于3自旋的单态的制备和检测脉冲不局限于图3，4，5中描述的优化脉冲方法。During implementation, localized in vivo magnetic resonance images are provided, which can be obtained with various conventional pulse sequences. The present invention is not limited to the optimized pulse method described in Figs.
实施例1Example 1
实验被试：正常25岁女性。Subjects: normal 25-year-old female.
测定仪器：西门子3T Prisma核磁共振仪，所用探测线圈为西门子64通道头部线圈。Measuring instrument: Siemens 3T Prisma nuclear magnetic resonance instrument, and the detection coil used is a Siemens 64-channel head coil.
测定方法：图3所示脉冲序列。Measurement method: The pulse sequence shown in Figure 3.
实验步骤如下：The experimental steps are as follows:
1.利用常规T 1加权序列对人体大脑在磁场中的位置进行定位，选择待测活体器官区域。人体大脑磁共振图像和选择区域见图6a。 1. Use the conventional T 1 weighted sequence to locate the position of the human brain in the magnetic field, and select the area of the living organ to be tested. The MRI image and selected regions of the human brain are shown in Figure 6a.
2.施加图3所示的脉冲序列。实验过程中，用于压制水信号的“饱和脉冲”由4个脉宽为250ms，功率为35Hz的高斯脉冲组成；“优化控制脉冲一”由基于数值计算GRAPE方法的优化控制脉冲技术得到，作用时间为40ms，由1000个40μs独立脉冲组成，这些脉冲的相位和功率见图4a和4b。“优化控制脉冲一”射频中心为2.66ppm，总功率为100Hz。“去耦脉冲”使用连续波去耦，该处射频中心为2.66ppm，功率为400Hz，施加时间1ms；“梯度脉冲”功率为2Gauss/cm，作用时间2ms；“优化控制脉冲二”由基于数值计算GRAPE方法的优化控制脉冲技术得到，作用时间为40ms，由1000个40μs独立脉冲组成，这些脉冲的相位和功率见图5a和5b。“优化控制脉冲二”射频中心为2.66ppm，总功率为100Hz。“磁共振波谱”脉冲模块，包含一个90度和两个180度sinc脉冲，脉冲时间分别为1ms，2ms和2ms。这些脉冲的功率都为250Hz。实验过程中，可通过微调优化控制脉冲的功率和射频中心优化NAA分子亚甲基 1H信号。 2. Apply the pulse sequence shown in Figure 3. During the experiment, the "saturation pulse" used to suppress the water signal consists of four Gaussian pulses with a pulse width of 250ms and a power of 35Hz; The time is 40 ms and consists of 1000 individual pulses of 40 μs, the phase and power of these pulses are shown in Figures 4a and 4b. The RF center of "Optimized Control Pulse One" 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 "gradient pulse" power is 2Gauss/cm, and the action time is 2ms; "Optimized control pulse 2" is based on numerical value The optimal control pulse technique for calculating the GRAPE method was obtained, with an action time of 40 ms, consisting of 1000 individual pulses of 40 μs, the phase and power of these pulses are shown in Figures 5a and 5b. The RF center of "Optimized Control Pulse II" 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 all 250 Hz. During the experiment, the power of the control pulse and the radio frequency center can be optimized by fine-tuning to optimize the methylene 1 H signal of the NAA molecule.
3.再将所获得的人脑NAA分子亚甲基 1H信号与预先获得的、不同pH值下NAA分子亚甲基信号比较(见图7)，得到活体大脑中所观测区域(见图6)的pH值，约为7.4。 3. Then compare the methylene 1 H signal of the obtained human brain NAA molecule with the pre-acquired methylene signal of NAA molecules at different pH values (see Figure 7) to obtain the observed area in the living brain (see Figure 6). ) at a pH of about 7.4.
实施例2Example 2
实验被试：溶质质量分数为0.4％的谷氨酸，1.2％的谷氨酰胺和1.2％的NAA的中性混合水溶液35mL。Experiment subjects: 35 mL of a neutral mixed aqueous solution with a solute mass fraction of 0.4% glutamic acid, 1.2% glutamine and 1.2% NAA.
测定仪器：西门子3T Prisma核磁共振仪，所用探测线圈为西门子64通道头部线圈。Measuring instrument: Siemens 3T Prisma nuclear magnetic resonance instrument, and the detection coil used is a Siemens 64-channel head coil.
测定方法：图3所示脉冲序列。Measurement method: The pulse sequence shown in Figure 3.
实验步骤如下：The experimental steps are as follows:
1.利用常规T 1加权序列对水膜样品在磁场中的位置进行定位，选择待测水膜样品区域。水膜磁共振图像和选择区域见图9a。 1. Use the conventional T 1 weighted sequence to locate the position of the water film sample in the magnetic field, and select the area of the water film sample to be measured. The water film magnetic resonance image and selected area are shown in Figure 9a.
2.施加图3所示的脉冲序列。实验过程中，用于压制水信号的“饱和脉冲”由4个脉宽为250ms，功率为35Hz的高斯脉冲组成；“优化控制脉冲一”由基于数值计算GRAPE方法的优化控制脉冲技术得到，作用时间为40ms，由1000个40μs独立脉冲组成，这些脉冲的相位和功率见图4a和4b。“优化控制脉冲一”射频中心为2.66ppm，总功率为100Hz。“去耦脉冲”使用连续波去耦，该处射频中心为2.66ppm，功率为400Hz，施加时间1ms；“梯度脉冲”功率为2Gauss/cm，作用时间2ms；“优化控制脉冲二”由基于数值计算GRAPE方法的优化控制脉冲技术得到，作用时间为40ms，由1000个40μs独立脉冲组成，这些脉冲的相位和功率见图5a和5b。“优化控制脉冲二”射频中心为2.66ppm，总功率为100Hz。“磁共振波谱”脉冲模块，包含一个90度和两个180度sinc脉冲，脉冲时间分别为1ms，2ms和2ms。这些脉冲的功率都为250Hz。实验过程中，可通过微调优化控制脉冲的功率和射频中心优化NAA分子亚甲基 1H信号。 2. Apply the pulse sequence shown in 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 time is 40 ms and consists of 1000 individual pulses of 40 μs, the phase and power of these pulses are shown in Figures 4a and 4b. The RF center of "Optimized Control Pulse One" 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 "gradient pulse" power is 2Gauss/cm, and the action time is 2ms; The optimized control pulse technique for calculating the GRAPE method was obtained, with an action time of 40 ms, consisting of 1000 individual pulses of 40 μs, the phase and power of these pulses are shown in Figures 5a and 5b. The RF center of "Optimized Control Pulse II" 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 all 250Hz. During the experiment, the power of the control pulse and the radio frequency center can be optimized by fine-tuning to optimize the methylene 1 H signal of the NAA molecule.
3.常规MRS实验结论如图9b所示，其中2.1ppm处为NAA分子甲基的信号，处于2.2和2.3ppm处为谷氨酸和谷氨酰胺信号，其中谷氨酰胺信号与NAA分子的亚甲基信号有重叠；图9c为利用图3脉冲选取图9a方框所示区域所获得的磁共振波谱，可以看到，谷氨酸和谷氨酰胺信号均受到了大幅度的压制，只保留NAA分子亚甲基的信号。将所获得的水膜样品NAA分子亚甲基 1H信号与预先获得的、不同pH值下NAA分子亚甲基信号比较，即可获得水膜样品中所观测区域(见图9a)的pH值。 3. The conclusion of the conventional MRS experiment is shown in Figure 9b, where 2.1 ppm is the signal of the methyl group of the NAA molecule, and at 2.2 and 2.3 ppm is the glutamate and glutamine signals, wherein the glutamine signal is related to the sub-group of the NAA molecule. The methyl signals overlap; Figure 9c is the magnetic resonance spectrum obtained by using the pulse of Figure 3 to select the area shown in the box of Figure 9a. It can be seen that the glutamate and glutamine signals are greatly suppressed, and only the remaining The signal of the methylene group of the NAA molecule. The pH value of the observed area in the water film sample (see Figure 9a) can be obtained by comparing the obtained NAA molecular methylene 1 H signal with the pre-obtained NAA molecular methylene signal at different pH values. .
实施例3Example 3
实验被试：正常25岁女性，正常24岁男性，正常25岁男性Subjects: normal 25-year-old female, normal 24-year-old male, normal 25-year-old male
测定仪器：西门子3T Prisma核磁共振仪，所用探测线圈为西门子64通道头部线圈。Measuring instrument: Siemens 3T Prisma nuclear magnetic resonance instrument, and the detection coil used is a Siemens 64-channel head coil.
测定方法：图3所示脉冲序列。Measurement method: The pulse sequence shown in Figure 3.
实验步骤如下：The experimental steps are as follows:
1.利用常规T 1加权序列对不同人活体大脑在磁场中的位置进行定位，选择待测样品活体大脑区域。活体大脑磁共振图像和选择区域见图6a。 1. Use conventional T1 - weighted sequences to locate the positions of different human living brains in the magnetic field, and select the living brain regions of the samples to be tested. In vivo brain magnetic resonance images and selected regions are shown in Figure 6a.
2.施加图3所示的脉冲序列。实验过程中，用于压制水信号的“饱和脉冲”由4个脉宽为250ms，功率为35Hz的高斯脉冲组成；“优化控制脉冲一”由基于数值计算GRAPE方法的优化控制脉冲技术得到，作用时间为40ms，由1000个40μs独立脉冲组成，这些脉冲的 相位和功率见图4a和4b。“优化控制脉冲一”射频中心为2.66ppm，总功率为100Hz。“去耦脉冲”使用连续波去耦，该处射频中心为2.66ppm，功率为400Hz，施加时间1ms；“梯度脉冲”功率为2Gauss/cm，作用时间2ms；“优化控制脉冲二”由基于数值计算GRAPE方法的优化控制脉冲技术得到，作用时间为40ms，由1000个40μs独立脉冲组成，这些脉冲的相位和功率见图5a和5b。“优化控制脉冲二”射频中心为2.66ppm，总功率为100Hz。“磁共振波谱”脉冲模块，包含一个90度和两个180度sinc脉冲，脉冲时间分别为1ms，2ms和2ms。这些脉冲的功率都为250Hz。实验过程中，可通过微调优化控制脉冲的功率和射频中心优化NAA分子亚甲基 1H信号。 2. Apply the pulse sequence shown in 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 time is 40 ms and consists of 1000 individual pulses of 40 μs, the phase and power of these pulses are shown in Figures 4a and 4b. The RF center of "Optimized Control Pulse One" 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 "gradient pulse" power is 2Gauss/cm, and the action time is 2ms; "Optimized control pulse 2" is based on numerical value The optimal control pulse technique for calculating the GRAPE method was obtained, with an action time of 40 ms, consisting of 1000 individual pulses of 40 μs, the phase and power of these pulses are shown in Figures 5a and 5b. The RF center of "Optimized Control Pulse II" 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 all 250 Hz. During the experiment, the power of the control pulse and the radio frequency center can be optimized by fine-tuning to optimize the methylene 1 H signal of the NAA molecule.
3.图10a为正常25岁女性图3脉冲获得磁共振波谱图；图10b为正常24岁男性图3脉冲获得磁共振波谱图；图10c为正常25岁男性图3脉冲获得磁共振波谱图。从图中可以看出，正常人脑部的NAA分子亚甲基信号位置和峰形完全相同，因此，正常人脑部pH值均为中性，约为7.4。3. Figure 10a is a normal 25-year-old woman's magnetic resonance spectrum obtained by the pulse of Figure 3; Figure 10b is a normal 24-year-old man's Figure 3 pulse obtained by the magnetic resonance spectrum; Figure 10c is a normal 25-year-old male obtained by the pulse of Figure 3. It can be seen from the figure that the methylene signal position and peak shape of NAA molecules in the normal human brain are exactly the same. Therefore, the pH value of the normal human brain is neutral, about 7.4.
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。The protection content of the present invention is not limited to the above embodiments. Variations and advantages that can occur to those skilled in the art without departing from the spirit and scope of the inventive concept are included in the present invention, and the appended claims are the scope of protection.

Claims (7)

  1. 一种非诊断目的的利用N-乙酰天门冬氨酸分子磁共振信号测量生物活体pH值的方法，其特征在于，所述方法包括：A method for measuring the pH value of living organisms by utilizing N-acetylaspartate molecular magnetic resonance signals for non-diagnostic purposes, wherein the method comprises:
    步骤i：利用脉冲序列制备N-乙酰天门冬氨酸分子亚甲基和次甲基上 1H构成的3自旋体系核自旋单态；所述制备获得的核自旋单态为R xS x+R yS y+I n； Step i: use a pulse sequence to prepare a 3-spin system nuclear spin singlet composed of 1 H on the N-acetylaspartic acid molecule methylene and methine; the nuclear spin singlet obtained by the preparation is R x S x +R y S y +In ;
    步骤ii：利用核自旋单态不受脉冲梯度场影响的特点，实现对N-乙酰天门冬氨酸分子亚甲基 1H磁共振信号的选择性观测； Step ii: Utilizing the feature that the nuclear spin singlet is not affected by the pulse gradient field, the selective observation of the methylene 1 H magnetic resonance signal of the N-acetylaspartic acid molecule is realized;
    步骤iii：将测得的实际生物活体中的N-乙酰天门冬氨酸分子亚甲基 1H磁共振信号与不同pH值下N-乙酰天门冬氨酸分子的磁共振信号进行对比，确定N-乙酰天门冬氨酸分子周围环境的pH值。 Step iii: Compare the measured methylene 1 H magnetic resonance signal of N-acetylaspartic acid molecule in the actual biological body with the magnetic resonance signal of N-acetylaspartic acid molecule at different pH values to determine N - The pH of the environment surrounding the acetylaspartate molecule.
  2. 如权利要求1所述的方法，其特征在于，所述步骤i中，N-乙酰天门冬氨酸分子自旋单态的制备步骤为：将标记为R、S的亚甲基的2个 1H自旋，和标记为I的次甲基的1个 1H自旋组成的3自旋耦合体系，由热平衡态R z+S z+I z转化至状态R xS x+R yS y+I n，其中n∈{x,y,z}。 The method according to claim 1, wherein, in the step i, the preparation step of the N-acetylaspartic acid molecule spin singlet is: two 1 's of methylene groups marked R and S are The H spin, and a 3-spin coupled system consisting of one 1 H spin of the methine labeled I, transition from the thermal equilibrium state R z +S z +I z to the state R x S x +R y S y +In , where n∈ { x,y,z}.
  3. 如权利要求1所述的方法，其特征在于，所述步骤ii中，利用脉冲梯度场消除或压制除N-乙酰天门冬氨酸分子亚甲基 1H核自旋单态信号以外的信号，实现对N-乙酰天门冬氨酸分子亚甲基 1H磁共振信号的选择性观测；调整脉冲梯度场的强度、时间、施加次数和位置，实现对N-乙酰天门冬氨酸分子亚甲基 1H磁共振信号选择性观测的优化。 The method of claim 1, wherein, in the step ii, signals other than the N-acetylaspartic acid molecule methylene 1 H nuclear spin singlet signal are eliminated or suppressed by using a pulsed gradient field, Achieve selective observation of 1 H magnetic resonance signals of N-acetylaspartate molecular methylene; adjust the intensity, time, application times and position of the pulse gradient field to achieve N-acetylaspartic acid molecular methylene Optimization of selective observation of 1 H magnetic resonance signals.
  4. 如权利要求1或2所述的方法，其特征在于，所述脉冲序列包括：单态制备和选择模块、磁共振波谱模块；其中，The method according to claim 1 or 2, wherein the pulse sequence comprises: a singlet preparation and selection module, a magnetic resonance spectroscopy module; wherein,
    所述单态制备和选择模块包括：饱和脉冲、优化控制脉冲一、去耦脉冲、梯度脉冲和优化控制脉冲二；所述磁共振波谱模块包括：射频梯度脉冲和选层脉冲。The singlet preparation and selection module includes: saturation pulse, optimal control pulse 1, decoupling pulse, gradient pulse and optimal control pulse 2; the magnetic resonance spectrum module includes: radio frequency gradient pulse and slice selection pulse.
  5. 如权利要求1所述的方法，其特征在于，所述步骤iii中，通过对实际生物活体N-乙酰天门冬氨酸分子亚甲基 1H磁共振信号的精准观测，获得N-乙酰天门冬氨酸分子亚甲基 1H磁共振信号；通过将所述亚甲基 1H磁共振信号与不同pH值下N-乙酰天门冬氨酸分子的 1H磁共振信号进行对比，实现对N-乙酰天门冬氨酸分子周围环境pH值的测量。 The method according to claim 1, wherein in the step iii, N-acetylaspartate is obtained by accurately observing the methylene 1 H magnetic resonance signal of the N-acetylaspartic acid molecule in an actual living organism. amino acid molecule methylene 1 H magnetic resonance signal; by comparing the methylene 1 H magnetic resonance signal with the 1 H magnetic resonance signal of N-acetylaspartic acid molecule at different pH values, the realization of N- Measurement of the pH of the environment surrounding the acetylaspartate molecule.
  6. 如权利要求5所述的方法，其特征在于，所述N-乙酰天门冬氨酸分子 1H磁共振信号包括J耦合值、亚甲基上 1H化学位移、亚甲基上 1H与N-乙酰天门冬氨酸分子甲基 1H信号化学位移差值中的一种或几种。 The method of claim 5, wherein the 1 H magnetic resonance signal of the N-acetylaspartic acid molecule comprises J coupling value, 1 H chemical shift on methylene, 1 H and N on methylene - One or more of the chemical shift differences of the methyl 1 H signal of the acetyl aspartate molecule.
  7. 如权利要求1-6之任一项所述方法在非诊断目的的生物活体pH检测中的应用。The application of the method according to any one of claims 1 to 6 in the detection of pH of a biological organism for non-diagnostic purposes.
PCT/CN2022/075149 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 WO2022171038A1 (en)

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