Enhanced non-invasive deep brain electrical stimulation system and method based on time interference

Abstract

The invention provides an enhanced non-invasive deep brain electrical stimulation system and method based on time interference. The system comprises an enhanced sawtooth wave stimulation waveform; a stimulation circuit supporting the enhanced sawtooth waveform; a finite element simulation subsystem to guide the stimulation pattern. Compared with the traditional time interference based on sine waves, the time interference based on sawtooth waves generates a steeper envelope, so that the stimulation intensity is enhanced. The sawtooth wave spectrum component is more complex and contains more high-frequency components, and a specific constant current source stimulator is needed to ensure that the high-frequency components output constant current without distortion. The system also includes a simulation subsystem that determines stimulation parameters using a corrected finite element method and a stimulation subsystem that stimulates in accordance with the parameters. Compared with traditional sine waves, the non-invasive deep brain electrical stimulation based on sawtooth wave time interference is provided, the stimulation intensity is improved, and a more effective method is provided for non-invasive regulation and control of the brain and intervention of diseases.

Description

Technical Field

[0001] The embodiments of the present invention relate to the field of medical device technology, and in particular to an enhanced non-invasive deep brain electrical stimulation system and method based on time interference. Background Art

[0002] Central nervous system regulation technology using electric current has been widely used to regulate deep brain regions to explore brain function and treat brain diseases. Deep brain regions and brain function are closely related to brain diseases. For example, the hippocampus of the brain is mainly related to human learning and memory, and the subthalamic nucleus and globus pallidus are the main targets for the treatment of Parkinson's disease.

[0003] Traditional deep brain stimulation is mainly divided into two categories: non-invasive and invasive. The main non-invasive type is transcranial electrical stimulation, such as transcranial direct current stimulation and transcranial alternating current stimulation, while the main invasive type is implanted deep brain stimulation. Transcranial electrical stimulation can stimulate the deep brain, but it will also strongly stimulate the surface of the brain outside the target area. This non-ideal stimulation outside the target area will have negative effects and affect its stimulation effect. Implanted deep brain stimulation can accurately stimulate deep brain areas by implanting electrodes in the brain, but the implanted electrodes and craniotomy limit its wider clinical application.

[0004] In 2017, Nir Grossman et al. proposed a non-invasive deep brain electrical stimulation technology based on time interference, which can selectively stimulate deep brain areas without stimulating the surface of the brain. The non-invasive deep brain electrical stimulation technology based on time interference transmits two high-frequency stimulation currents (frequencies of f1 and f2) into the brain through scalp electrodes, because the frequencies of these two currents are too high to effectively activate neurons. The two currents overlap and interfere in the deep brain area, generating an amplitude modulated current whose envelope frequency (Δf = |f1-f2|) is low enough to effectively activate neurons.

[0005] The aforementioned non-invasive deep brain electrical stimulation based on sinusoidal wave time interference can pioneer the non-invasive and selective stimulation of deep brain areas, but it still has two defects: weak stimulation intensity and low stimulation accuracy. To effectively stimulate the deep brain areas of the brain to achieve the purpose of disease intervention, it is necessary to enhance the stimulation intensity. The existing methods all use multiple frequencies or multiple electrode pairs, which have certain technical limitations. For example, when using 4 pairs of electrodes to transmit 4 stimulation currents of different frequencies (such as 2000, 2002, 6000, 6002Hz), 2000 and 2002Hz interfere with each other to produce a 2Hz envelope, and 6000 and 6002Hz interfere to produce a 2Hz envelope. In theory, the overlap of two 2Hz stimulation points can increase the stimulation intensity. However, the frequency multiples of these currents can also interfere with each other, producing stimulations of other frequencies and interfering with the original 2H stimulation. For example, the triple frequency of 2002 (that is, 6006Hz) will interfere with 6000Hz to produce a 6Hz envelope, generating stimuli of other frequencies and interfering with the original stimuli.

[0006] Therefore, effective and practical methods to enhance the intensity of non-invasive deep brain stimulation based on time interference have not yet been studied. How to effectively improve the accuracy and intensity of the stimulation current has become a technical problem that needs to be solved urgently. Summary of the invention

[0007] In view of this, an embodiment of the present invention provides an enhanced non-invasive deep brain electrical stimulation system and method based on time interference to at least partially solve the above problems.

[0008] According to a first aspect of an embodiment of the present invention, there is provided an enhanced non-invasive deep brain electrical stimulation method based on time interference.

[0009] A sawtooth wave stimulation waveform is used, the spectrum of which is complex and contains high-frequency components. After the two stimulation waveforms interfere, a steep envelope is formed, thereby enhancing the stimulation effect.

[0010] A constant current source stimulator supports a high-frequency stimulation waveform with more complex frequency components including high-frequency components. The constant current source stimulator includes a signal generator to ensure anti-phase drive, a constant current source circuit to ensure constant current output, and a second-stage constant current source composed of transistors to ensure that the high-frequency components of the output current are not distorted.

[0011] A simulation subsystem using a calibrated finite element simulation method is used to simulate and calibrate the stimulation intensity and accuracy of the stimulation pattern.

[0012] In one implementation, the two stimulation waveforms are specifically two different high-frequency sawtooth waves. If two high-frequency sawtooth wave stimuli are applied to the surface of the brain, the neurons in the brain of the subject to be tested cannot be effectively and periodically activated because the stimulation frequency is too high. However, the two different high-frequency sawtooth waves overlap and interfere in the deep area of ​​the brain of the subject to be tested, and an amplitude modulated electric field with a low-frequency envelope will be generated. The amplitude modulated electric field with a low-frequency envelope can effectively and periodically activate the neurons in the brain of the subject to be tested.

[0013] In one implementation, the constant current source stimulator includes a microcontroller, a signal generator, a first-stage constant current source module based on an operational amplifier, a second-stage constant current source module based on a transistor, a high-voltage power supply, and a low-voltage power supply.

[0014] In one implementation, the stimulator is specifically a constant current source stimulator that supports a sawtooth waveform with more complex frequency components and containing higher high-frequency components, including a microcontroller, a signal generator, a first-stage constant current source module based on an operational amplifier, a second-stage constant current source module based on a transistor, a high-voltage power supply, and a low-voltage power supply.

[0015] In one implementation, the transistor-based second-stage constant current source module is composed of an operational amplifier ADA4098-1, a transistor MJD122, and a transistor MJD127.

[0016] In one implementation, the microcontroller includes a first microcontroller and a second microcontroller, and the signal generator includes a first signal generator and a second signal generator.

[0017] In one implementation, a low voltage source powers a first microcontroller, a signal generator, and a stimulation signal detection module based on a second microcontroller, and a high voltage source powers a first-stage constant current source module based on an operational amplifier and a second-stage constant current source module based on a transistor.

[0018] In one implementation, the stimulation signal detection module includes a first stimulation signal detection module, a second stimulation signal detection module, a third stimulation signal detection module, and a fourth stimulation signal detection module;

[0019] The first stimulation signal detection module, the second stimulation signal detection module, the third stimulation signal detection module and the fourth stimulation signal detection module respectively transmit the detected stimulation signal parameters to the second microcontroller.

[0020] According to a second aspect of an embodiment of the present invention, there is provided a stimulation system, comprising:

[0021] A simulation subsystem, for simulating the stimulation amplitude, electrode site, and stimulation site of each channel using a calibrated finite element method, and determining stimulation parameters and stimulation electrode attachment locations;

[0022] The stimulation subsystem is used to connect the stimulation electrode to the specified position of the subject to be detected according to the stimulation amplitude, electrode site, and stimulation site of each channel obtained by simulation, connect the stimulation electrode and the stimulator, set the stimulation parameters determined by simulation on the stimulator, start the stimulation, generate an amplitude modulated electric field with a low-frequency envelope through the interference of two sawtooth waveforms, stimulate the deep brain area of ​​the subject to be detected through the stimulation current generated by the amplitude modulated electric field, detect the stimulation current information in real time, continue the stimulation before the set stimulation time is reached, and stop the stimulation after the set stimulation time is reached. Compared with the traditional sine wave waveform, the sawtooth wave waveform has a more complex spectrum and contains more high-frequency components.

[0023] In one implementation, the stimulation subsystem is specifically used for: writing stimulation parameters determined by simulation of the simulation subsystem to the first microcontroller through a parameter setting button; issuing instructions to the first signal generator and the second signal generator respectively through the first microcontroller, and the first signal generator and the second signal generator respectively generate sawtooth waveforms of corresponding frequencies, and output them in an anti-phase manner; the sawtooth waveforms generated by the first signal generator and the second signal generator are respectively converted into constant current signals through a first-stage constant current source module based on an operational amplifier; the constant current signal is then converted into a constant current signal that ensures that the high-frequency component is not distorted through a second-stage constant current source module based on a transistor; the constant current signal that ensures that the high-frequency component is not distorted is respectively converted into a constant current signal through the first stimulation signal. A first stimulation signal detection module, a second stimulation signal detection module, a third stimulation signal detection module and a fourth stimulation signal detection module are connected to the head of the subject to be detected; wherein, the constant current signal that ensures that the high-frequency component is not distorted after passing through the first stimulation signal detection module and the second stimulation signal detection module constitutes the stimulation current of the first channel, and the constant current signal that ensures that the high-frequency component is not distorted after passing through the third stimulation signal detection module and the fourth stimulation signal detection module constitutes the stimulation current of the second channel. The stimulation currents of the first channel and the second channel overlap and interfere in the deep brain of the subject to be detected, generating an amplitude modulated electric field with a low-frequency envelope, and the stimulation current generated by the amplitude modulated electric field stimulates the deep brain area of ​​the subject to be detected, thereby realizing enhanced non-invasive deep brain electrical stimulation based on time interference.

[0024] In one implementation, the corrected finite element method in the simulation subsystem specifically corrects a finite element algorithm based on sinusoidal wave time interference, which is used to simulate the intensity and accuracy of TI stimulation. In time interference stimulation using a sawtooth waveform, the stimulation intensity is the smaller value of the current of two frequencies.

[0025] The beneficial effects of the solution of the present invention are:

[0026] Compared with traditional sinusoidal wave time interference, the non-invasive deep brain electrical stimulation based on sawtooth wave time interference of the present invention has a higher stimulation intensity, thereby improving the effectiveness of neural regulation, and providing a more effective method for regulating the brain and intervening in diseases through non-invasive deep brain electrical stimulation technology. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the embodiments of the present invention. For ordinary technicians in this field, other drawings can also be obtained based on these drawings.

[0028] Figure 1 A schematic diagram of an amplitude modulated electric field having a low frequency envelope is formed for the present invention;

[0029] Figure 2 It is a schematic diagram comparing the stimulation intensity of the temporal interference waveform based on a sawtooth wave and the temporal interference waveform based on a sine wave according to the present invention;

[0030] Figure 3 It is a waveform analysis diagram of the sine wave and sawtooth wave time interference of the present invention;

[0031] Figure 4 It is a structural framework diagram of the stimulator of the present invention;

[0032] Figure 5 It is a schematic diagram of the spectrum comparison of the sine wave and the sawtooth wave of the present invention;

[0033] Figure 6 The circuit diagram of the second-stage constant current source module based on transistor of the present invention;

[0034] Figure 7 It is a schematic diagram of the working process of the present invention. DETAILED DESCRIPTION

[0035] In order to have a clearer understanding of the technical features, purposes and effects of the embodiments of the present invention, the specific implementation of the embodiments of the present invention is now described with reference to the accompanying drawings.

[0036] In this document, “exemplary” means “serving as an example, instance or illustration”, and any illustration or implementation described in this document as “exemplary” should not be construed as a more preferred or more advantageous technical solution.

[0037] In order to simplify the drawings, only the parts related to the present invention are schematically shown in each figure, and they do not represent the actual structure of the product. In addition, in order to simplify the drawings and facilitate understanding, in some figures, only one or more of the parts with the same structure or function are schematically drawn, or only one or more of them are marked.

[0038] In order to enable those skilled in the art to better understand the technical solutions in the embodiments of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in the field based on the embodiments in the embodiments of the present invention should fall within the scope of protection of the embodiments of the present invention.

[0039] See also Figure 1-Figure 6 The present invention provides an enhanced non-invasive deep brain electrical stimulation method based on time interference.

[0040] A sawtooth wave stimulation waveform is used, the spectrum of which is complex and contains high-frequency components. After the two stimulation waveforms interfere, a steep envelope is formed, thereby enhancing the stimulation effect.

[0041] A constant current source stimulator supports a high-frequency stimulation waveform with more complex frequency components including high-frequency components. The constant current source stimulator includes a signal generator to ensure anti-phase drive, a constant current source circuit to ensure constant current output, and a second-stage constant current source composed of transistors to ensure that the high-frequency components of the output current are not distorted.

[0042] A simulation subsystem using a calibrated finite element simulation method is used to simulate and calibrate the stimulation intensity and accuracy of the stimulation pattern.

[0043] Specifically, the two stimulation waveforms are two different high-frequency sawtooth waves. If two high-frequency sawtooth wave stimuli are applied to the surface of the brain, the neurons in the brain of the subject to be tested cannot be effectively and periodically activated because the stimulation frequency is too high. However, the two different high-frequency sawtooth waves overlap and interfere in the deep area of ​​the brain of the subject to be tested, which will produce an amplitude modulated electric field with a low-frequency envelope. The amplitude modulated electric field with a low-frequency envelope can effectively and periodically activate the neurons in the brain of the subject to be tested.

[0044] Optionally, the constant current source stimulator includes a microcontroller, a signal generator, a first-stage constant current source module based on an operational amplifier, a second-stage constant current source module based on a transistor, a high-voltage power supply and a low-voltage power supply.

[0045] Optionally, the transistor-based second-stage constant current source module is composed of an operational amplifier ADA4098-1, a transistor MJD122, and a transistor MJD127.

[0046] Optionally, the microcontroller includes a first microcontroller and a second microcontroller, and the signal generator includes a first signal generator and a second signal generator.

[0047] Optionally, the low voltage source powers the first microcontroller, the signal generator and the stimulation signal detection module based on the second microcontroller, and the high voltage source powers the first-stage constant current source module based on the operational amplifier and the second-stage constant current source module based on the transistor.

[0048] Optionally, the stimulation signal detection module includes a first stimulation signal detection module, a second stimulation signal detection module, a third stimulation signal detection module and a fourth stimulation signal detection module;

[0049] The first stimulation signal detection module, the second stimulation signal detection module, the third stimulation signal detection module and the fourth stimulation signal detection module respectively transmit the detected stimulation signal parameters to the second microcontroller.

[0050] See also Figure 7 The present invention also provides a deep brain electrical stimulation system, comprising:

[0051] A simulation subsystem, for simulating the stimulation amplitude, electrode site, and stimulation site of each channel using a calibrated finite element method, and determining stimulation parameters and stimulation electrode attachment locations;

[0052] The stimulation subsystem is used to connect the stimulation electrode to the specified position of the subject to be detected according to the stimulation amplitude, electrode site, and stimulation site of each channel obtained by simulation, connect the stimulation electrode and the stimulator, set the stimulation parameters determined by simulation on the stimulator, start the stimulation, generate an amplitude modulated electric field with a low-frequency envelope through the interference of two sawtooth waveforms, stimulate the deep brain area of ​​the subject to be detected through the stimulation current generated by the amplitude modulated electric field, detect the stimulation current information in real time, continue the stimulation before the set stimulation time is reached, and stop the stimulation after the set stimulation time is reached. Compared with the traditional sine wave waveform, the sawtooth wave waveform has a more complex spectrum and contains more high-frequency components.

[0053] Optionally, the stimulation subsystem is specifically used for: writing stimulation parameters determined by simulation of the simulation subsystem to the first microcontroller through a parameter setting button; issuing instructions to the first signal generator and the second signal generator respectively through the first microcontroller, and the first signal generator and the second signal generator respectively generate sawtooth waveforms of corresponding frequencies, and output them in an anti-phase manner; the sawtooth waveforms generated by the first signal generator and the second signal generator are respectively converted into constant current signals through a first-stage constant current source module based on an operational amplifier; the constant current signal is then converted into a constant current signal that ensures that the high-frequency component is not distorted through a second-stage constant current source module based on a transistor; the constant current signal that ensures that the high-frequency component is not distorted is respectively passed through the first stimulation signal detection module. The first stimulation signal detection module, the second stimulation signal detection module, the third stimulation signal detection module and the fourth stimulation signal detection module are connected to the head of the subject to be detected; wherein, the constant current signal that ensures that the high-frequency component is not distorted after passing through the first stimulation signal detection module and the second stimulation signal detection module constitutes the stimulation current of the first channel, and the constant current signal that ensures that the high-frequency component is not distorted after passing through the third stimulation signal detection module and the fourth stimulation signal detection module constitutes the stimulation current of the second channel. The stimulation currents of the first channel and the second channel overlap and interfere in the deep brain of the subject to be detected, generating an amplitude modulated electric field with a low-frequency envelope, and the stimulation current generated by the amplitude modulated electric field stimulates the deep brain area of ​​the subject to be detected, thereby realizing enhanced non-invasive deep brain electrical stimulation based on time interference.

[0054] It can be seen that compared with the traditional non-invasive deep brain electrical stimulation method based on sinusoidal wave time interference, the present invention uses a stimulation waveform with a more complex spectrum and high-frequency components: a sawtooth wave. After the two stimulation waveforms interfere, a steeper envelope is formed, thereby enhancing the stimulation effect. The stimulator that supports this high-frequency stimulation waveform with more complex frequency components, i.e., containing higher-frequency components, includes a signal generator to ensure anti-phase drive, a constant current source circuit, i.e., a first-stage constant current source module based on an operational amplifier to ensure constant current output, and a second-stage constant current source composed of transistors, i.e., a second-stage constant current source module based on transistors to ensure that the high-frequency components of the output current are not distorted.

[0055] Optionally, the corrected finite element method in the simulation subsystem specifically corrects a finite element algorithm based on sinusoidal time interference, which is used to simulate the intensity and accuracy of TI stimulation. In time interference stimulation using a sawtooth waveform, the stimulation intensity is the smaller value of the currents of two frequencies.

[0056] It can be seen that the finite element algorithm has been widely used to simulate the intensity and accuracy of TI stimulation. When the stimulation method based on sawtooth wave time interference is used, the calculation of the stimulation electric field is different from that of sine wave. Specifically, in the time interference stimulation using sine wave, the stimulation intensity is twice the smaller value of the current of the two frequencies, while in the time interference stimulation using sawtooth wave, the stimulation intensity is the smaller value of the current of the two frequencies (not twice), see Figure 3 .

[0057] The corrected finite element algorithm can simulate stimulation intensity and accuracy more accurately, providing more accurate reference information for scientific research experiments and clinical applications.

[0058] Specifically, the scheme of the present invention is further described according to the following examples:

[0059] See also Figure 1 The present invention applies two high-frequency sawtooth wave stimuli (f1 and f2, such as 2000 and 2002 Hz) to the surface of the brain, but the stimulation frequency is too high to effectively activate neurons periodically. However, two different high-frequency sawtooth waves overlap and interfere in the deep part of the brain, and generate an amplitude-modulated electric field with a low-frequency envelope (envelope frequency Δf = |f1-f2|, such as |2000-2002| = 2 Hz). This amplitude-modulated electric field with a low-frequency envelope can effectively activate neurons periodically.

[0060] See also Figure 2 , based on Neuron Environment simulation based on sine wave and sawtooth wave time interference stimulation, the amplitude of neuronal membrane potential polarization (waiting for model and software) (A) Subthreshold neuronal cell membrane potential induced by sine wave time interference stimulation (80V / m). The black line represents the neuronal cell membrane potential, the blue represents the waveform based on sine wave time interference stimulation, the red asterisk "*" represents the minimum value of neuronal cell membrane potential in one cycle, and the red circle "O" represents the maximum value of neuronal cell membrane potential in one cycle. (B) Same as Figure (A) but based on sawtooth wave time interference stimulation (80V / m). (C) The difference between the maximum value (i.e., the amplitude represented by "O") and the minimum value (i.e., the amplitude represented by "*") of the subthreshold neuronal cell membrane potential fluctuation induced by sine wave time interference stimulation in one cycle is much smaller than that of sawtooth wave time interference (p<0.005, paired T test, N=14).

[0061] It can be seen that the effectiveness of the solution of the present invention has been verified by simulation of a neuron model based on Hodgkin–Huxley, and the results show that the stimulation intensity of the time interference waveform based on the sawtooth wave is significantly higher than that of the sine wave stimulation waveform.

[0062] See also Figure 3The present invention simulates the stimulation intensity and accuracy of the enhanced non-invasive deep brain electrical stimulation based on time interference through a corrected finite element method. Finite element algorithms have been widely used to simulate the intensity and accuracy of non-invasive deep brain electrical stimulation based on time interference. When a stimulation method based on sawtooth wave time interference is used, the calculation of the stimulation electric field is different from that of a sine wave.

[0063] Specifically, in the case of temporal interferometric stimulation using a sine wave, the stimulation intensity is twice the smaller value of the currents of the two frequencies, while in the case of temporal interferometric stimulation using a sawtooth wave, the stimulation intensity is the smaller value of the currents of the two frequencies (not twice). The corrected finite element algorithm can simulate the stimulation intensity and accuracy more accurately, providing more accurate reference information for scientific research experiments and clinical applications.

[0064] Place the stimulator in Figure 4 Connect the stimulation electrodes as shown. Figure 4 As shown, it is connected to the head of a subject to be detected, such as a human body or an animal.

[0065] The low voltage source (5V) supplies power to the microcontroller 1, i.e., the first microcontroller and the signal generator. The low voltage source (5V) also supplies power to the stimulation signal detection modules 1, 2, 3, 4 based on the microcontroller 2, i.e., the second microcontroller, i.e., the first stimulation signal detection module, the second stimulation signal detection module, the third stimulation signal detection module, and the fourth stimulation signal detection module. The high voltage source (±50V) supplies power to the first-stage constant current source modules 1, 2, 3, 4 based on the operational amplifier. The high voltage source also supplies power to the second-stage constant current source modules 1, 2, 3, 4 based on the transistor.

[0066] The working logic sequence is: the parameter setting button writes the stimulation signal parameters (such as amplitude and frequency) to the microcontroller 1, the microcontroller 1 sends instructions to the signal generators 1 and 2, namely the first signal generator and the second signal generator, respectively, and the signal generators 1 and 2 respectively generate sawtooth waveforms of corresponding frequencies (such as f1 and f2), and output them in an anti-phase manner to prevent crosstalk between the two frequency channels.

[0067] The sawtooth waveforms generated by signal generators 1 and 2, i.e., the first signal generator and the second signal generator, are converted into constant current signals through the first-stage constant current source module based on an operational amplifier. The constant current signal is then converted into a constant current signal that ensures that the high-frequency component is not distorted through the second-stage constant current source module based on a transistor. The constant current signal that ensures that the high-frequency component is not distorted is connected to the head of a person / animal through stimulation signal detection modules 1, 2, 3, and 4, respectively, wherein the current passing through the stimulation signal detection modules 1 and 2 constitutes the stimulation current of the first channel (such as the blue arrow line), and the current passing through the stimulation signal detection modules 3 and 4 constitutes the stimulation current of the second channel (such as the black arrow line). The stimulation currents of the two channels overlap and interfere in the deep part of the brain (such as the red ellipse), generating a stimulation current with a low-frequency envelope, stimulating the deep brain area, and realizing enhanced non-invasive deep brain electrical stimulation based on time interference.

[0068] The aforementioned stimulation signal detection modules 1, 2, 3, 4 respectively transmit the detected stimulation signal parameters to the microcontroller 2, so as to monitor the actual stimulation parameters in real time and ensure the accuracy of the stimulation current.

[0069] See also Figure 5 Compared with traditional sine wave-based time-interference non-invasive deep brain stimulation, the sawtooth wave frequency component of this stimulator is more complex and contains more high-frequency components.

[0070] See also Figure 6 The present invention adds a second-level constant current source circuit based on a transistor, i.e., a second-level constant current source module based on a transistor, after the first-level constant current source circuit based on an operational amplifier, i.e., the first-level constant current source module based on an operational amplifier. The second-level constant current source circuit based on a transistor is composed of an operational amplifier ADA4098-1, a transistor MJD122, and a transistor MJD127. Its main function is to enhance the current output stability of the constant current source circuit when a high-frequency signal is generated.

[0071] Among them, the positive power supply in the high-voltage power supply is respectively connected to the positive voltage terminal (port 6) of the operational amplifier ADA4098-1 and the collector (port 2) of the transistor MJD122, and the negative power supply is respectively connected to the negative voltage terminal (port 2) of the amplifier ADA4098-1 and the emitter (port 3) of the transistor MJD127.

[0072] The input of the previous constant current source (i.e., the first constant current source module based on the operational amplifier) ​​is connected to the negative input terminal (port 4) of the operational amplifier ADA4098-1 through resistor R1, and the positive input terminal (port 3) of the operational amplifier ADA4098-1 is grounded through resistor R3. The output terminal (port 2) of the operational amplifier ADA4098-1 is connected to the base of transistor MJD122 and transistor MJD127 (port 1), respectively, and is also connected to the left side of resistor R4. The emitter (port 3) of transistor MJD122 and the collector (port 2) of transistor MJD127 are simultaneously connected to the right side of resistor R4, and then connected to the left side of resistor R5 as the constant current source output. The constant current source output is then grounded through resistors R2 and R3.

[0073] The operational amplifier ADA4098-1, transistor MJD122, and transistor MJD127 selected in the present invention have a higher frequency and higher voltage operating range, so when the sawtooth current is output, the high-frequency component in the sawtooth waveform is guaranteed not to be distorted, thereby ensuring the accuracy of the stimulation current and the accuracy of the stimulation intensity.

[0074] See also Figure 7 The present invention first uses a calibrated finite element method to simulate the stimulation amplitude, electrode site, and stimulation point of each channel to determine the stimulation parameters and the attachment position of the stimulation electrode; then, according to the stimulation amplitude, electrode site, and stimulation point of each channel obtained by simulation, the stimulation electrode is connected to the specified position of the object to be detected, the stimulation electrode and the stimulator are connected, and the stimulation parameters determined by simulation are set on the stimulator to start stimulation; the stimulation current information is detected in real time, the stimulation is continued before the set stimulation time is reached, and the stimulation is stopped after the set stimulation time is reached.

[0075] The present invention uses specific stimulation parameters, such as (applying 2000Hz 1.5mA sawtooth wave stimulation to the lower pair of electrodes and 2002Hz 1.5mA sawtooth wave stimulation to the other pair of electrodes), to conduct human or animal experiments, regulate specific brain areas, observe the real-time effects and after-effects of the stimulation through specific observation methods (such as neurophysiological EEG, local field potential, functional magnetic resonance imaging, and behavior), and achieve intervention in brain function or treatment of brain diseases through long-term repetitive stimulation.

[0076] Compared to traditional non-invasive deep brain stimulation based on time interference, such as based on a sine wave waveform, the present invention uses a stimulation waveform with a more complex spectrum containing more high-frequency components: a sawtooth waveform, thereby significantly improving the intensity of non-invasive deep brain stimulation based on time interference, and providing a more effective method for using non-invasive deep brain stimulation to intervene in brain function and treat brain diseases. Because the stimulation waveform contains more high-frequency components, a specially designed stimulation circuit is required to ensure that the high-frequency components in the stimulation waveform are not distorted. Because the time interference process of the stimulation waveform is different from the traditional time interference method, the finite element simulation method needs to be corrected when performing finite element simulation (in order to simulate the stimulation intensity and accuracy).

[0077] The present invention enhances the stimulation intensity of traditional non-invasive deep brain electrical stimulation based on time interference, and provides technical support for more effective neural regulation.

[0078] Deep Brain Stimulation System

[0079] It should be noted that the present invention may also be a method, an apparatus and / or a computer program product. The computer program product may include a computer-readable storage medium carrying computer-readable program instructions for causing a processor to implement various aspects of the present invention.

[0080] Computer readable storage medium can be a tangible device that can hold and store instructions used by an instruction execution device. Computer readable storage medium can be, for example, but not limited to, an electrical storage device, a magnetic storage device, an optical storage device, an electromagnetic storage device, a semiconductor storage device, or any suitable combination thereof. More specific examples (non-exhaustive list) of computer readable storage medium include: a portable computer disk, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or flash memory), a static random access memory (SRAM), a portable compact disk read-only memory (CD-ROM), a digital versatile disk (DVD), a memory stick, a floppy disk, a mechanical encoding device, for example, a punch card or a convex structure in a groove on which instructions are stored, and any suitable combination thereof. The computer readable storage medium used here is not interpreted as a transient signal itself, such as a radio wave or other freely propagating electromagnetic wave, an electromagnetic wave propagated by a waveguide or other transmission medium (for example, a light pulse by an optical fiber cable), or an electrical signal transmitted by a wire.

[0081] The computer-readable program instructions described herein can be downloaded from a computer-readable storage medium to each computing / processing device, or downloaded to an external computer or external storage device via a network, such as the Internet, a local area network, a wide area network, and / or a wireless network. The network can include copper transmission cables, optical fiber transmissions, wireless transmissions, routers, firewalls, switches, gateway computers, and / or edge servers. The network adapter card or network interface in each computing / processing device receives the computer-readable program instructions from the network and forwards the computer-readable program instructions for storage in the computer-readable storage medium in each computing / processing device.

[0082] The computer program instructions for performing the operation of the present invention may be assembly instructions, instruction set architecture (ISA) instructions, machine instructions, machine-dependent instructions, microcode, firmware instructions, state setting data, or source code or object code written in any combination of one or more programming languages, including object-oriented programming languages, such as Smalltalk, C++, Python, etc., and conventional procedural programming languages, such as "C" language or similar programming languages. Computer-readable program instructions may be executed entirely on a user's computer, partially on a user's computer, as an independent software package, partially on a user's computer, partially on a remote computer, or entirely on a remote computer or server. In the case of a remote computer, the remote computer may be connected to the user's computer via any type of network, including a local area network (LAN) or a wide area network (WAN), or may be connected to an external computer (e.g., using an Internet service provider to connect via the Internet). In some embodiments, an electronic circuit, such as a programmable logic circuit, a field programmable gate array (FPGA), or a programmable logic array (PLA), may be personalized by utilizing the state information of the computer-readable program instructions, and the electronic circuit may execute the computer-readable program instructions, thereby realizing various aspects of the present invention.

[0083] Various aspects of the present invention are described herein with reference to the flow charts and / or block diagrams of the methods, devices (systems) and computer program products according to embodiments of the present invention. It should be understood that each box of the flow chart and / or block diagram and the combination of each box in the flow chart and / or block diagram can be implemented by computer-readable program instructions.

[0084] These computer-readable program instructions can be provided to a processor of a general-purpose computer, a special-purpose computer, or other programmable data processing device, thereby producing a machine, so that when these instructions are executed by the processor of the computer or other programmable data processing device, a device that implements the functions / actions specified in one or more boxes in the flowchart and / or block diagram is generated. These computer-readable program instructions can also be stored in a computer-readable storage medium, and these instructions cause the computer, programmable data processing device, and / or other equipment to work in a specific manner, so that the computer-readable medium storing the instructions includes a manufactured product, which includes instructions for implementing various aspects of the functions / actions specified in one or more boxes in the flowchart and / or block diagram.

[0085] Computer-readable program instructions may also be loaded onto a computer, other programmable data processing apparatus, or other device so that a series of operating steps are performed on the computer, other programmable data processing apparatus, or other device to produce a computer-implemented process, thereby causing the instructions executed on the computer, other programmable data processing apparatus, or other device to implement the functions / actions specified in one or more boxes in the flowchart and / or block diagram.

[0086] The flow charts and block diagrams in the accompanying drawings show the possible architecture, functions and operations of the systems, methods and computer program products according to multiple embodiments of the present invention. In this regard, each box in the flow chart or block diagram can represent a part of a module, a program segment or an instruction, and a part of the module, a program segment or an instruction contains one or more executable instructions for realizing the specified logical function. In some alternative implementations, the functions marked in the box can also occur in a different order from the order marked in the accompanying drawings. For example, two consecutive boxes can actually be executed substantially in parallel, and they can sometimes be executed in the opposite order, depending on the functions involved. It should also be noted that each box in the block diagram and / or flow chart, and the combination of the boxes in the block diagram and / or flow chart can be implemented by a dedicated hardware-based system that performs the specified function or action, or can be implemented by a combination of dedicated hardware and computer instructions. It is well known to those skilled in the art that it is equivalent to implement it by hardware, implement it by software, and implement it by combining software and hardware.

[0087] Embodiments of the present invention have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments. The selection of terms used herein is intended to best explain the principles of the embodiments, practical applications, or technical improvements in the marketplace, or to enable other persons of ordinary skill in the art to understand the embodiments disclosed herein. The scope of the present invention is defined by the appended claims.

Claims

1. An enhanced non-invasive deep brain electrical stimulation method based on time interference. It is characterized in that A sawtooth wave stimulation waveform is used, the spectrum of which is complex and contains high-frequency components. After the two stimulation waveforms interfere, a steep envelope is formed, thereby enhancing the stimulation effect. It is also characterized in that it supports a constant current source stimulator with a high-frequency stimulation waveform having more complex frequency components and including high-frequency components. The constant current source stimulator includes a signal generator to ensure reverse phase drive, a constant current source circuit to ensure constant current output, and a second-stage constant current source composed of transistors to ensure that the high-frequency components of the output current are not distorted. The invention is also characterized in that a simulation subsystem using a calibrated finite element simulation method is used to simulate and calibrate the stimulation intensity and accuracy of the stimulation pattern.

2. The enhanced non-invasive deep brain electrical stimulation method based on time interference according to claim 1, characterized in that: The two stimulation waveforms are specifically two different high-frequency sawtooth waves. If two high-frequency sawtooth wave stimuli are applied to the surface of the brain, the neurons in the brain of the subject to be tested cannot be effectively and periodically activated because the stimulation frequency is too high. However, the two different high-frequency sawtooth waves overlap and interfere in the deep area of ​​the brain of the subject to be tested, and an amplitude modulated electric field with a low-frequency envelope will be generated. The amplitude modulated electric field with a low-frequency envelope can effectively and periodically activate the neurons in the brain of the subject to be tested.

3. The enhanced non-invasive deep brain electrical stimulation method based on time interference according to claim 1, characterized in that: The constant current source stimulator comprises a microcontroller, a signal generator, a first-level constant current source module based on an operational amplifier, a second-level constant current source module based on a transistor, a high-voltage power supply and a low-voltage power supply.

4. The enhanced non-invasive deep brain electrical stimulation method based on time interference according to claim 3, characterized in that: The transistor-based second-stage constant current source module consists of an operational amplifier ADA4098-1, a transistor MJD122, and a transistor MJD127.

5. The enhanced non-invasive deep brain electrical stimulation method based on time interference according to claim 4, characterized in that: The microcontroller includes a first microcontroller and a second microcontroller, and the signal generator includes a first signal generator and a second signal generator.

6. The enhanced non-invasive deep brain electrical stimulation method based on time interference according to claim 5, characterized in that: The low voltage source powers the first microcontroller, the signal generator and the stimulation signal detection module based on the second microcontroller, and the high voltage source powers the first-stage constant current source module based on the operational amplifier and the second-stage constant current source module based on the transistor.

7. The enhanced non-invasive deep brain electrical stimulation method based on time interference according to claim 6, characterized in that: The stimulation signal detection module includes a first stimulation signal detection module, a second stimulation signal detection module, a third stimulation signal detection module and a fourth stimulation signal detection module; The first stimulation signal detection module, the second stimulation signal detection module, the third stimulation signal detection module and the fourth stimulation signal detection module respectively transmit the detected stimulation signal parameters to the second microcontroller.

8. A stimulation system using the enhanced non-invasive deep brain electrical stimulation method based on time interference as described in any one of claims 1 to 7, characterized in that: include: A simulation subsystem, for simulating the stimulation amplitude, electrode site, and stimulation site of each channel using a calibrated finite element method, and determining stimulation parameters and stimulation electrode attachment locations; The stimulation subsystem is used to connect the stimulation electrode to the specified position of the subject to be detected according to the stimulation amplitude, electrode site, and stimulation site of each channel obtained by simulation, connect the stimulation electrode and the stimulator, set the stimulation parameters determined by simulation on the stimulator, start the stimulation, generate an amplitude modulated electric field with a low-frequency envelope through the interference of two sawtooth waveforms, stimulate the deep brain area of ​​the subject to be detected through the stimulation current generated by the amplitude modulated electric field, detect the stimulation current information in real time, continue the stimulation before the set stimulation time is reached, and stop the stimulation after the set stimulation time is reached. Compared with the traditional sine wave waveform, the sawtooth wave waveform has a more complex spectrum and contains more high-frequency components.

9. The stimulation system according to claim 8, characterized in that The stimulation subsystem is specifically used to: Writing stimulation parameters determined by simulation of the simulation subsystem into the first microcontroller through a parameter setting button; The first microcontroller sends instructions to the first signal generator and the second signal generator at the same time, and the first signal generator and the second signal generator respectively generate sawtooth waveforms of corresponding frequencies and output them in an anti-phase manner; The sawtooth waveforms generated by the first signal generator and the second signal generator are respectively converted into constant current signals through a first-stage constant current source module based on an operational amplifier; The constant current signal is then converted into a constant current signal that ensures that the high-frequency component is not distorted by passing through a second-stage constant current source module based on a transistor; The constant current signal which ensures that the high frequency component is not distorted passes through the first stimulation signal detection module, the second stimulation signal detection module, the third stimulation signal detection module and the fourth stimulation signal detection module respectively, and is connected to the head of the object to be detected; Among them, the constant current signal that ensures that the high-frequency component is not distorted after passing through the first stimulation signal detection module and the second stimulation signal detection module constitutes the stimulation current of the first channel, and the constant current signal that ensures that the high-frequency component is not distorted after passing through the third stimulation signal detection module and the fourth stimulation signal detection module constitutes the stimulation current of the second channel. The stimulation currents of the first channel and the second channel overlap and interfere in the deep brain of the subject to be detected, generating an amplitude modulated electric field with a low-frequency envelope. The stimulation current generated by the amplitude modulated electric field stimulates the deep brain area of ​​the subject to be detected, thereby realizing enhanced non-invasive deep brain electrical stimulation based on time interference.

10. The stimulation system according to claim 8, characterized in that The corrected finite element method in the simulation subsystem specifically corrects the finite element algorithm based on sinusoidal time interference, which is used to simulate the intensity and accuracy of TI stimulation. In the time interference stimulation using a sawtooth waveform, the stimulation intensity is the smaller value of the current of the two frequencies.

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