A time-interference based enhanced non-invasive deep brain stimulation system and method

Abstract

The application provides an enhanced non-invasive deep brain stimulation system and method based on time interference, which comprises: an enhanced sawtooth wave stimulation waveform; a stimulation circuit supporting the enhanced sawtooth waveform; and a finite element simulation subsystem for guiding the stimulation mode. Compared with the traditional sine wave time interference, the sawtooth wave time interference generates a steeper envelope, thereby enhancing the stimulation intensity. The sawtooth wave spectrum has more complex components and contains more high-frequency components, and a specific constant-current source stimulator is required to ensure that the high-frequency component output constant current is not distorted. The system further comprises a simulation subsystem for determining stimulation parameters using a corrected finite element method and a stimulation subsystem for stimulating according to the parameters. Compared with the traditional sine wave, the application provides a non-invasive deep brain stimulation based on sawtooth wave time interference, improves the stimulation intensity, and provides a more effective method for non-invasively regulating the brain and intervening in 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 technologies using electrical currents have been widely used to manipulate deep brain regions to investigate brain function and treat brain diseases. Deep brain regions, brain function, and brain disease are closely linked. For example, the hippocampus is primarily associated with learning and memory, while the subthalamic nucleus and globus pallidus are primary targets for Parkinson's disease treatment.

[0003] Traditional deep brain stimulation is mainly divided into two categories: non-invasive and invasive. The non-invasive ones are mainly transcranial electrical stimulation, such as transcranial direct current stimulation and transcranial alternating current stimulation, while the invasive ones are mainly implantable deep brain stimulation. Transcranial electrical stimulation can stimulate the deep brain, but it can 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. Implantable 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 noninvasive deep brain stimulation technique based on temporal interferometry, which can selectively and noninvasively stimulate deep brain regions without stimulating the surface. This technique, based on temporal interferometry, delivers two high-frequency stimulation currents (at frequencies f1 and f2) to the brain via scalp electrodes. Because these two currents are too high in frequency to effectively activate neurons, these two currents overlap and interfere in the deep brain regions, generating an amplitude-modulated current whose envelope frequency (Δf = |f1-f2|) is sufficiently low 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 intervening in diseases, 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 stimulation of other frequencies and interfering with the original stimulation.

[0006] Therefore, effective and practical methods to enhance the intensity of time-interference-based non-invasive deep brain stimulation 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, a method for enhanced non-invasive deep brain electrical stimulation based on time interference is provided.

[0009] A sawtooth stimulation waveform is used. The spectrum of the sawtooth stimulation waveform 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 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.

[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 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 the first microcontroller, the signal generator, and the stimulation signal detection module based on the second microcontroller, and a 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.

[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 sites, and stimulation locations of each channel using a calibrated finite element method to determine stimulation parameters and stimulation electrode attachment locations;

[0022] The stimulation subsystem is used to connect the stimulation electrodes to the specified positions of the subject to be detected based on the stimulation amplitude, electrode site, and stimulation site of each channel obtained by simulation, connect the stimulation electrodes 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 by 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 the 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 the first-stage constant current source module based on the 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 the transistor; the constant current signal that ensures that the high-frequency component is not distorted is respectively converted into a constant current signal that ensures that the high-frequency component is not distorted through the first stimulation signal 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 and passes 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 and passes 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 deep in the 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.

[0024] In one implementation, 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 current of the 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 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 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 following briefly introduces the drawings required for use in the embodiments or the description of the prior art. 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 with a low-frequency envelope formed in the present invention;

[0029] Figure 2 Schematic diagram comparing the stimulation intensity of a sawtooth-based temporal interferometry waveform and a sine-wave-based temporal interferometry waveform according to the present invention;

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

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

[0032] Figure 5 Schematic diagram of the comparison of the spectrum of the sine wave and the sawtooth wave of the present invention;

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

[0034] Figure 7 Schematic diagram of the workflow 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, specific implementation methods of the embodiments of the present invention are 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 interpreted as a more preferred or more advantageous technical solution.

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

[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 accompanying 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 them. All other embodiments obtained by those skilled in the art 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 Figures 1-6 The present invention provides an enhanced non-invasive deep brain electrical stimulation method based on time interference.

[0040] A sawtooth stimulation waveform is used. The spectrum of the sawtooth stimulation waveform 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 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.

[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, 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.

[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 stimulation system, comprising:

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

[0052] The stimulation subsystem is used to connect the stimulation electrodes to the specified positions of the subject to be detected based on the stimulation amplitude, electrode site, and stimulation site of each channel obtained by simulation, connect the stimulation electrodes 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 by 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 to: write stimulation parameters determined by simulation of the simulation subsystem to the first microcontroller through the parameter setting button; send instructions to the first signal generator and the second signal generator simultaneously 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 the first-stage constant current source module based on the 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 the 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 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. 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 to 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 containing 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 a transistor 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 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 the 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 case of sine wave time interference stimulation, the stimulation intensity is twice the smaller value of the two frequency currents, while in the case of sawtooth wave time interference stimulation, the stimulation intensity is the smaller value of the two frequency currents (not twice). For details, 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 solution 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. However, because the stimulation frequency is too high, it cannot effectively and periodically activate neurons. However, the two different high-frequency sawtooth waves overlap and interfere deep in the brain, generating 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 and periodically activate neurons.

[0060] See also Figure 2 , based on Neuron Environment simulations of neuronal membrane potential polarization amplitudes under sine-wave and sawtooth-wave temporal interferometric stimulation (waiting for model and software). (A) Subthreshold neuronal membrane potential induced by sine-wave temporal interferometric stimulation (80 V / m). The black line represents the neuronal membrane potential, the blue line represents the waveform of the sine-wave temporal interferometric stimulation, the red asterisk "*" represents the minimum neuronal membrane potential within a cycle, and the red circle "O" represents the maximum neuronal membrane potential within a cycle. (B) Same as (A) but using sawtooth-wave temporal interferometric stimulation (80 V / m). (C) The difference between the maximum (i.e., amplitude represented by "O") and minimum (i.e., amplitude represented by "*") fluctuations in the subthreshold neuronal membrane potential within a cycle induced by sine-wave temporal interferometric stimulation is significantly smaller than that induced by sawtooth-wave temporal interferometric stimulation (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. 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 enhanced non-invasive deep brain stimulation based on time interferometry using a calibrated finite element method. Finite element algorithms have been widely used to simulate the intensity and accuracy of non-invasive deep brain stimulation based on time interferometry. When using a stimulation method based on sawtooth wave time interferometry, the calculation of the stimulation electric field is different from that of a sine wave.

[0063] Specifically, in temporal interferometric stimulation using a sine wave, the stimulation intensity is twice the smaller of the two current frequencies, while in temporal interferometric stimulation using a sawtooth wave, the stimulation intensity is the smaller of the two current frequencies (not twice). This corrected finite element algorithm enables more accurate simulation of stimulation intensity and precision, providing more precise reference information for scientific research and clinical applications.

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

[0065] The low voltage source (5V) powers microcontroller 1, i.e., the first microcontroller, and the signal generator. The low voltage source (5V) also powers stimulation signal detection modules 1, 2, 3, and 4, 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, based on microcontroller 2, i.e., the second microcontroller. A high voltage source (±50V) powers the first-stage constant current source modules 1, 2, 3, and 4, which are based on operational amplifiers. The high voltage source also powers the second-stage constant current source modules 1, 2, 3, and 4, which are based on transistors.

[0066] Its working logic sequence is: the parameter setting button writes the stimulation signal parameters (such as amplitude and frequency) to the microcontroller 1, and the microcontroller 1 simultaneously sends instructions to the signal generators 1 and 2, namely the first signal generator and the second signal generator, respectively. 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 respectively 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 by 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 human / animal through stimulation signal detection modules 1, 2, 3, and 4, respectively. The currents passing through stimulation signal detection modules 1 and 2 constitute the stimulation current of the first channel (as shown by the blue arrow line), and the currents passing through stimulation signal detection modules 3 and 4 constitute the stimulation current of the second channel (as shown by the black arrow line). The stimulation currents of the two channels overlap and interfere in the deep part of the brain (as shown by the red oval area), 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, and 4 respectively transmit the detected stimulation signal parameters to the microcontroller 2, thereby being able to monitor the actual stimulation parameters in real time and ensure the accuracy of the stimulation current.

[0069] See also Figure 5 Compared with the 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-stage transistor-based constant current source circuit, also known as a second-stage transistor-based constant current source module, to the first-stage operational amplifier-based constant current source circuit. The second-stage transistor-based constant current source circuit consists of an operational amplifier ADA4098-1, a transistor MJD122, and a transistor MJD127. Its primary function is to enhance the current output stability of the constant current source circuit when operating with high-frequency signals.

[0071] Among them, the positive power supply in the high-voltage power supply is 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 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 upper 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 a resistor R1, and the positive input terminal (port 3) of the operational amplifier ADA4098-1 is grounded through a resistor R3. The output terminal (port 2) of the operational amplifier ADA4098-1 is connected to the base (port 1) of the transistor MJD122 and the transistor MJD127, respectively, and also connected to the left side of a resistor R4. The emitter (port 3) of the transistor MJD122 and the collector (port 2) of the transistor MJD127 are simultaneously connected to the right side of the resistor R4 and then to the left side of a resistor R5 as the constant current source output. The constant current source output is then grounded through the resistor R2 and the resistor R3.

[0073] The operational amplifier ADA4098-1, the transistor MJD122, and the transistor MJD127 used in the present application have a higher frequency and a higher voltage working range, so that the high frequency component in the sawtooth wave form is not distorted when the sawtooth wave current is output, thereby ensuring the accuracy of the stimulation current and the accuracy of the stimulation intensity.

[0074] Referring to Figure 7 , the present application first uses a corrected finite element method to simulate the stimulation amplitude, electrode site, and stimulation site 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 site of each channel obtained by simulation, the stimulation electrode is connected to the designated position of the body to be detected, the stimulation electrode and the stimulator are connected, and the stimulation parameters determined by simulation are set on the stimulator, and the stimulation is started; 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 application uses specific stimulation parameters, such as (2000Hz 1.5mA sawtooth wave stimulation applied by one pair of electrodes, and 2002Hz 1.5mA sawtooth wave stimulation applied by another pair of electrodes), to conduct human or animal experiments, to regulate specific brain regions, to observe the real-time effects and aftereffects of stimulation through specific observation means (such as neuroelectrophysiological electroencephalogram, local field potential, functional magnetic resonance, and behavior), and to achieve the intervention of brain function or the treatment of brain diseases through long-term and repetitive stimulation.

[0076] Compared to traditional non-invasive deep brain stimulation based on time interference, such as a sine wave waveform, the present invention uses a stimulation waveform with a more complex spectrum that contains 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, providing 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 keep and store the instructions used by the 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 disc 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 having instructions stored thereon, and any suitable combination thereof.Computer-readable storage medium used herein is not interpreted as a transient signal itself, such as radio waves or other freely propagating electromagnetic waves, electromagnetic waves propagated by waveguides or other transmission media (for example, light pulses by fiber optic cables), or electrical signals transmitted by wires.

[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, fiber optic transmission, wireless transmission, 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 to be stored in the computer-readable storage medium in each computing / processing device.

[0082] The computer program instructions for performing the operation of the present invention can 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, and conventional procedural programming languages ​​such as "C" language or similar programming languages. The computer readable program instructions can be executed entirely on the user's computer, partially on the user's computer, as an independent software package, partially on the user's computer, partially on a remote computer, or completely on a remote computer or server. In the case of a remote computer, the remote computer can 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 can 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), is personalized by utilizing the state information of the computer readable program instructions, and the electronic circuit can 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 flowcharts and / or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the present invention. It should be understood that each block of the flowcharts and / or block diagrams, and combinations of blocks in the flowcharts and / or block diagrams, 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 is generated that implements the functions / actions specified in one or more blocks in the flowchart and / or block diagram. These computer-readable program instructions can also be stored in a computer-readable storage medium, where these instructions cause the computer, programmable data processing device, and / or other device to operate in a specific manner. Thus, the computer-readable medium storing the instructions comprises an article of manufacture that includes instructions for implementing various aspects of the functions / actions specified in one or more blocks 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 operational 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 blocks in the flowchart and / or block diagram.

[0086] The flowcharts and block diagrams in the accompanying drawings show the possible implementation 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 flowchart or block diagram can represent a module, program segment or part of an instruction, and the module, program segment or part of the instruction contains one or more executable instructions for implementing the specified logical function. In some alternative implementations, the functions marked in the box can also occur in an order different from that 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 flowchart, and the combination of boxes in the block diagram and / or flowchart, 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 implementation by hardware, implementation by software, and implementation by a combination of software and hardware are all equivalent.

[0087] While various embodiments of the present invention have been described above, the foregoing description is intended to be illustrative, non-exhaustive, and not limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is selected to best explain the principles of the embodiments, their practical applications, or technological improvements in the marketplace, or to enable others skilled 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 stimulation system based on time interference, characterized in that: include: a simulation subsystem for simulating the stimulation amplitude, electrode sites, and stimulation locations of each channel using a calibrated finite element method to determine stimulation parameters and stimulation electrode attachment locations; A stimulation subsystem comprising a constant current source stimulator configured to generate two different high-frequency sawtooth stimulation waveforms, wherein the sawtooth stimulation waveforms have a complex spectrum and contain high-frequency components, and generate an amplitude modulated electric field with a low-frequency envelope by mutual interference of the two sawtooth waveforms; The stimulation subsystem is used to connect the stimulation electrodes to the designated positions of the subject to be detected based on the stimulation amplitude, electrode sites, and stimulation sites of each channel obtained by simulation, connect the stimulation electrodes to a stimulator, set the stimulation parameters determined by simulation on the stimulator, start stimulation, generate an amplitude-modulated electric field with a low-frequency envelope by mutual interference of two sawtooth stimulation waveforms, stimulate the deep brain area of ​​the subject to be detected by the stimulation current generated by the amplitude-modulated electric field, and detect the stimulation current information in real time; the difference in subthreshold neuronal cell membrane potential induced by the time interference stimulation based on the sine wave within one cycle is smaller than that induced by the time interference stimulation based on the sawtooth wave, p < 0.005; 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. The signal generator is used to generate a high-frequency sawtooth wave driven in an anti-phase manner; The first-stage constant current source module based on the operational amplifier is used to convert the voltage signal into a constant current signal; The second-stage constant current source module based on the transistor is used to ensure that the high-frequency components of the output current are not distorted; Among them, the corrected finite element method in the simulation subsystem is a finite element algorithm based on sinusoidal wave 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.

2. The enhanced non-invasive deep brain stimulation system based on time interference according to claim 1, characterized in that: If two high-frequency sawtooth wave stimuli are applied to the surface of the brain, the stimulation frequency is too high to effectively and periodically activate the neurons in the brain of the subject to be tested. However, the two different high-frequency sawtooth waves overlap and interfere in the deep area of ​​the brain of the subject to be tested, generating an amplitude-modulated electric field with a low-frequency envelope.

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

4. The enhanced non-invasive deep brain electrical stimulation system based on time interference according to claim 1, 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.

5. The enhanced non-invasive deep brain stimulation system based on time interference according to claim 4, characterized in that: The low-voltage power supply powers the first microcontroller, the signal generator, and the stimulation signal detection module based on the second microcontroller, and the high-voltage power supply 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.

6. The enhanced non-invasive deep brain electrical stimulation system based on time interference according to claim 5, 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; wherein 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.

7. The enhanced non-invasive deep brain electrical stimulation system based on time interference according to claim 6, characterized in that: The stimulation subsystem is used to: Writing stimulation parameters determined by simulation of the simulation subsystem into the first microcontroller via a parameter setting button; The first microcontroller sends instructions to the first signal generator and the second signal generator simultaneously, so that 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 that 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, and is connected to the head of the subject 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.

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