Non-invasive nerve stimulation system and method for collaborative stimulation of deep brain region and deep brain region

Abstract

The invention relates to a non-invasive nerve stimulation system and method for collaborative stimulation of deep and shallow brain regions. The non-invasive nerve stimulation system for collaborative stimulation of deep and shallow brain regions comprises a time interference stimulation device used for obtaining a brain electric field simulation result; the phase stimulation device is used for generating a low-frequency electrical stimulation signal and a high-frequency electrical stimulation signal based on the brain electric field simulation result; the electroencephalogram acquisition device is used for recording oscillation signals of the brain in real time; the electroencephalogram feedback device is connected with the phase stimulation device and the electroencephalogram acquisition module and is used for judging whether a target oscillation state is reached or not based on the brain oscillation signal recorded by the electroencephalogram acquisition module; if yes, the phase stimulation device is controlled to stop stimulation on the superficial layer brain area and the deep layer brain area of the brain. The phase difference between the low-frequency electric field for stimulating the superficial brain region and the envelope electric field for stimulating the deep brain region can be fixed, and the blank that non-invasive same-frequency phase difference stimulation between the deep brain region and the shallow brain region cannot be achieved in the prior art is filled.

Description

Technical Field

[0001] This application relates to the technical field of medical devices, and particularly to a non-invasive nerve stimulation system and method for coordinated stimulation of deep and shallow brain regions. Background Art

[0002] Existing non-invasive nerve regulation technologies, such as transcranial alternating current stimulation (tACS), Transcranial Magnetic Stimulation (TMS), and Transcranial Direct Current Stimulation (tDCS), etc., have been widely used in cognitive dysfunction and cognitive impairment in diseases such as Alzheimer's disease (AD), traumatic brain injury (TBI), and stroke. However, existing non-invasive nerve regulation technologies cannot achieve non-invasive co-frequency phase difference stimulation between deep and shallow brain regions. Summary of the Invention

[0003] Based on this, it is necessary to provide a non-invasive nerve stimulation system and method for coordinated stimulation of deep and shallow brain regions to address the problems in the related technologies.

[0004] To achieve the above object, in a first aspect, this application provides a non-invasive nerve stimulation system for coordinated stimulation of deep and shallow brain regions. The non-invasive nerve stimulation system for coordinated stimulation of deep and shallow brain regions includes:

[0005] A time interference stimulation device for simulating a brain electric field to obtain a brain electric field simulation result;

[0006] A phase stimulation device for generating a low-frequency electric stimulation signal and a high-frequency electric stimulation signal at least based on the brain electric field simulation result, and stimulating the superficial brain region of the brain based on the low-frequency electric stimulation signal, and stimulating the deep brain region of the brain based on the high-frequency electric stimulation signal; the envelope electric field generated by the interference of the high-frequency electric stimulation signals has a phase difference from the low-frequency electric stimulation signal;

[0007] An electroencephalogram acquisition device for real-time recording of the oscillation signal of the brain during the process of the phase stimulation device stimulating the superficial brain region and the deep brain region of the brain;

[0008] An electroencephalogram feedback device, which is connected to both the phase stimulation device and the electroencephalogram acquisition module, is used to determine whether the target oscillation state is reached based on the oscillation signals of the brain recorded by the electroencephalogram acquisition module; if so, it controls the phase stimulation device to stop stimulating the superficial brain region and the deep brain region of the brain.

[0009] In some embodiments, the time interference stimulation device includes:

[0010] A head model generation module, which is used to construct a three-dimensional head model based on magnetic resonance imaging data;

[0011] A segmentation module, which is used to automatically segment the three-dimensional head model to generate an initial tetrahedral mesh;

[0012] A correction module, which is used to correct the lesion area of the three-dimensional head model;

[0013] A simulation module, which is used to perform the brain electric field simulation to obtain the brain electric field simulation result, and the brain electric field simulation result includes an envelope electric field;

[0014] A visualization module, which is used to visually display the electric field distribution of the envelope electric field or the generated interactive 3D rendering.

[0015] In some embodiments, the phase stimulation device includes:

[0016] A parameter input module, which is used to set the stimulation parameters of the electrical stimulation signal based on the brain electric field simulation result;

[0017] A voltage-controlled waveform generation module, which is connected to the parameter input module and is used to generate a plurality of voltage waveform signals corresponding to the low-frequency electrical stimulation signal and the high-frequency electrical stimulation signal based on the stimulation parameters;

[0018] A Howland constant current source, which is connected to the voltage-controlled waveform generation module and is used to generate the low-frequency electrical stimulation signal and the high-frequency electrical stimulation signal based on the voltage waveform signal;

[0019] An electrical stimulation signal output module, which is connected to the Howland constant current source and is used to stimulate the superficial brain region of the brain based on the low-frequency electrical stimulation signal and stimulate the deep brain region of the brain based on the high-frequency electrical stimulation signal.

[0020] In some embodiments, the electrical stimulation signal output device includes:

[0021] An electrical stimulation signal output unit, connected to the Howland constant current source, includes a first channel and a plurality of second channels; the first channel is used to output the low-frequency electrical stimulation signal, and the plurality of second channels are used to output the high-frequency electrical stimulation signal;

[0022] An electrode unit includes several pairs of first electrodes and multiple pairs of second electrodes; the first electrodes are connected to the first channel and are used to stimulate the superficial brain regions of the brain based on the low-frequency electrical stimulation signal; the second electrodes are connected to the second channel and are used to electrically stimulate the deep brain regions of the brain based on the high-frequency electrical stimulation signal.

[0023] In some embodiments, the electroencephalogram acquisition device includes:

[0024] A multi-channel data acquisition module, connected to a plurality of acquisition electrodes on the head, is used to collect the oscillation signals of the brain in real time;

[0025] An electroencephalogram signal recording device, connected to the multi-channel data acquisition module, is used to record the oscillation signals of the brain collected in real time;

[0026] A filter, connected to the electroencephalogram signal recording device, is used to preprocess the recorded oscillation signals of the brain to obtain the finally feedback oscillation signals.

[0027] In some embodiments, the electroencephalogram feedback device includes:

[0028] A Hilbert transform module, connected to the electroencephalogram acquisition device, is used to perform Hilbert transform on the oscillation signals of the brain to obtain an instantaneous phase signal;

[0029] A comparison and judgment module, connected to the Hilbert transform module, is used to compare the instantaneous phase signal with a target phase to judge whether the oscillation signals of the brain reach a target oscillation state;

[0030] A feedback control module, connected to both the comparison and judgment module and the phase stimulation device, is used to generate a feedback control signal when the oscillation signals of the brain reach the target oscillation state, and control the phase stimulation device to stop stimulating the superficial and deep brain regions of the brain based on the feedback control signal.

[0031] In some embodiments, the non-invasive nerve stimulation system for coordinated stimulation of superficial and deep brain regions further includes:

[0032] A power management device is at least connected to the time interference stimulation device, the phase stimulation device, the electroencephalogram acquisition device, and the electroencephalogram feedback device, and is at least used to supply power to the time interference stimulation device, the phase stimulation device, the electroencephalogram acquisition device, and the electroencephalogram feedback device.

[0033] In some embodiments, the power management device includes:

[0034] A power input module, which is compatible with AC and DC power supply modes, is used to convert DC power into AC power, and perform clutter removal, noise elimination, and voltage spike elimination processing on the converted AC power;

[0035] A voltage conversion module is connected to the power input module, the time interference stimulation device, the phase stimulation device, the electroencephalogram acquisition device, and the electroencephalogram feedback device, and is used to convert the input voltage obtained by the power input module into different voltages required by the time interference stimulation device, the phase stimulation device, the electroencephalogram acquisition device, and the electroencephalogram feedback device;

[0036] A power management module is used to monitor, protect, and optimize the power supply;

[0037] An energy management device is connected to the voltage conversion module, the time interference stimulation device, the phase stimulation device, the electroencephalogram acquisition device, and the electroencephalogram feedback device, and is used to perform power distribution and monitoring;

[0038] A safety isolator is connected to the power input module and the phase stimulation device, and is used to detect the real-time voltage of the power input module and perform a safety isolation action when the real-time voltage is abnormal;

[0039] A heat dissipation device is located on the surface of the power input module.

[0040] In some embodiments, the non-invasive nerve stimulation system for coordinated stimulation of deep and shallow brain regions further includes:

[0041] A comprehensive oscilloscope display is connected to the phase stimulation device and the electroencephalogram acquisition device, and is used to display the current stimulation parameters, the low-frequency electrical stimulation signal, the high-frequency electrical stimulation signal, and the oscillation signal of the brain.

[0042] In a second aspect, the present application further provides a non-invasive nerve stimulation method for coordinated stimulation of deep and shallow brain regions, and the non-invasive nerve stimulation method for coordinated stimulation of deep and shallow brain regions includes:

[0043] Perform brain electric field simulation to obtain a brain electric field simulation result;

[0044] Generate a low-frequency electrical stimulation signal and a high-frequency electrical stimulation signal based on the simulated results of the brain electric field, stimulate the superficial brain regions of the brain based on the low-frequency electrical stimulation signal, and stimulate the deep brain regions of the brain based on the high-frequency electrical stimulation signal; the envelope electric field generated by the interference of the high-frequency electrical stimulation signal has a phase difference from the low-frequency electrical stimulation signal;

[0045] During the process of the phase stimulation device stimulating the superficial brain regions and deep brain regions of the brain, record the oscillation signals of the brain in real time;

[0046] Based on the oscillation signals of the brain recorded by the electroencephalogram acquisition module, determine whether the target oscillation state is reached; if so, control the phase stimulation device to stop stimulating the superficial brain regions and deep brain regions of the brain.

[0047] In the above non-invasive nerve stimulation system and method for coordinated stimulation of superficial and deep brain regions, by generating a low-frequency electrical stimulation signal for stimulating the superficial brain regions of the brain and a high-frequency electrical stimulation signal for stimulating the deep brain regions of the brain, it is possible to fix the phase difference between the low-frequency electric field stimulating the superficial brain regions and the envelope electric field stimulating the deep brain regions, thus solving the problem that the prior art cannot achieve non-invasive co-frequency phase difference stimulation between superficial and deep brain regions. Description of the Drawings

[0048] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the traditional technologies, the following will briefly introduce the drawings required for use in the description of the embodiments or the traditional technologies. Obviously, the following drawings are only some embodiments of the present application. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative efforts.

[0049] Figure 1 It is a structural block diagram of a non-invasive nerve stimulation system for coordinated stimulation of superficial and deep brain regions provided in an embodiment of the present application;

[0050] Figure 2 It is a flowchart of a non-invasive nerve stimulation method for coordinated stimulation of superficial and deep brain regions provided in another embodiment of the present application;

[0051] Figure 3 It is a schematic diagram of the power of each frequency band (δ, θ, α, β, slow γ, fast γ) before and after non-invasive nerve stimulation for coordinated stimulation of superficial and deep brain regions via the present application;

[0052] Figure 4 It is a time-frequency diagram before and after non-invasive nerve stimulation for coordinated stimulation of superficial and deep brain regions via the present application.

[0053] Description of the reference numerals: 10, time interference stimulation device; 20, phase stimulation device; 30, electroencephalogram acquisition device; 40, electroencephalogram feedback device. Detailed implementation manners

[0054] In order to make the objectives, technical solutions and advantages of the present application clearer and more understandable, the present application will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.

[0055] Non-invasive neuromodulation techniques, such as transcranial alternating current stimulation (tACS), Transcranial Magnetic Stimulation (TMS), and Transcranial Direct Current Stimulation (tDCS), etc., have been widely used in cognitive dysfunction and cognitive impairment in diseases such as Alzheimer's disease (AD), traumatic brain injury (TBI), and stroke. However, the current non-invasive neuromodulation techniques have the following key limitations:

[0056] 1) Limitations of single brain region stimulation:

[0057] Traditional tACS techniques are mostly limited to static stimulation of single brain regions or dual targets, lacking the ability to regulate the dynamic cooperative activities across brain regions. For example, cognitive impairment after stroke is mostly caused by the disruption of brain network synchrony, but the existing techniques cannot dynamically adjust the neural oscillation phase relationship between multiple brain regions and it is difficult to restore network synchrony.

[0058] 2) Insufficient deep brain region stimulation:

[0059] Due to the significant attenuation of the electric field with the skull impedance in traditional tACS (the electric field intensity in deep brain regions is only 0.1 - 0.2 V / m), it is unable to effectively activate deep targets (such as the hippocampus). Although TMS can penetrate deep tissues, it has poor focusing and cannot accurately control the stimulation parameters.

[0060] 3) Simplification of phase regulation:

[0061] The current non-invasive neuromodulation techniques mostly adopt synchronous stimulation schemes with fixed phase differences (such as 0° or 180°), and cannot simulate the physiological phase lag between brain regions in the natural cognitive process (such as the 21° phase difference of the θ-band information from the hippocampus to the medial prefrontal cortex). This single regulation limits the restoration effect of neural activity coordination.

[0062] In one embodiment, refer to Figure 1 , the present application provides a non-invasive nerve stimulation system for coordinated stimulation of shallow and deep brain regions. The non-invasive nerve stimulation system for coordinated stimulation of shallow and deep brain regions may include: a temporal interference stimulation device 10, a phase stimulation device 20, an electroencephalogram acquisition device 30, and an electroencephalogram feedback device 40; wherein, the temporal interference stimulation device 10 is used for simulating the brain electric field to obtain a brain electric field simulation result; the phase stimulation device 20 is used to generate a low-frequency electric stimulation signal and a high-frequency electric stimulation signal at least based on the brain electric field simulation result, and stimulate the shallow brain region of the brain based on the low-frequency electric stimulation signal, and stimulate the deep brain region of the brain based on the high-frequency electric stimulation signal; the envelope electric field signal generated by the interference of the high-frequency electric stimulation signals has a phase difference from the low-frequency electric stimulation signal; the electroencephalogram acquisition device 30 is used to record the oscillation signal of the brain in real time during the process of the phase stimulation device stimulating the shallow brain region and the deep brain region of the brain; the electroencephalogram feedback device 40 is connected to both the phase stimulation device and the electroencephalogram acquisition module, and is used to judge whether the target oscillation state is reached based on the oscillation signal of the brain recorded by the electroencephalogram acquisition module; if so, control the phase stimulation device to stop stimulating the shallow brain region and the deep brain region of the brain.

[0063] In the non-invasive nerve stimulation system for coordinated stimulation of shallow and deep brain regions of the present application, by generating a low-frequency electric stimulation signal for stimulating the shallow brain region of the brain and a high-frequency electric stimulation signal for stimulating the deep brain region of the brain, it is possible to fix the phase difference between the low-frequency electric field stimulating the shallow brain region and the envelope electric field stimulating the deep brain region, thereby solving the problem that the prior art cannot achieve non-invasive co-frequency phase difference stimulation between shallow and deep brain regions.

[0064] As an example, the temporal interference stimulation (TIS) device 10 may include: a head model generation module (not shown), a segmentation module (not shown), a correction module (not shown), a simulation module (not shown), and a visualization module (not shown); wherein, the head model generation module is used to construct a three-dimensional head model based on magnetic resonance imaging data; the segmentation module is used to automatically segment the three-dimensional head model to generate an initial tetrahedral mesh; the correction module is used to correct the lesion area of the three-dimensional head model; the simulation module is used to perform the brain electric field simulation to obtain the brain electric field simulation result, and the brain electric field simulation result includes an envelope electric field; the visualization module is used to visually display the electric field distribution of the envelope electric field or the generated interactive 3D rendering.

[0065] As an example, the phase stimulation device 20 may include: a parameter input module (not shown), a voltage-controlled waveform generation module (not shown), a Howland constant current source (not shown), and an electrical stimulation signal output module; wherein, the parameter input module is configured to set the stimulation parameters of the electrical stimulation signal based on the brain electric field simulation result; the voltage-controlled waveform generation module is connected to the parameter input module and is configured to generate a plurality of voltage waveform signals corresponding to the low-frequency electrical stimulation signal and the high-frequency electrical stimulation signal based on the stimulation parameters; the Howland constant current source is connected to the voltage-controlled waveform generation module and is configured to generate the low-frequency electrical stimulation signal and the high-frequency electrical stimulation signal based on the voltage waveform signals; the electrical stimulation signal output module is connected to the Howland constant current source and is configured to stimulate the superficial brain region of the brain based on the low-frequency electrical stimulation signal and stimulate the deep brain region of the brain based on the high-frequency electrical stimulation signal.

[0066] As an example, the electrical stimulation signal output device may include: an electrical stimulation signal output unit (not shown) and an electrode unit (not shown); wherein, the electrical stimulation signal output unit is connected to the Howland constant current source and includes a first channel and a plurality of second channels; the first channel is configured to output the low-frequency electrical stimulation signal, and the plurality of second channels are configured to output the high-frequency electrical stimulation signal; the electrode unit includes a plurality of pairs of first electrodes and a plurality of pairs of second electrodes; the first electrodes are connected to the first channel and are configured to stimulate the superficial brain region of the brain based on the low-frequency electrical stimulation signal; the second electrodes are connected to the second channels and are configured to electrically stimulate the deep brain region of the brain based on the high-frequency electrical stimulation signal.

[0067] Specifically, the second electrodes and the second channels may be arranged in one-to-one correspondence.

[0068] As an example, the electroencephalogram (EEG) acquisition device may include: a multi-channel data acquisition module (not shown), an electroencephalogram (EEG) signal recording device (not shown), an electroencephalogram signal recording device (not shown), and a filter (not shown); wherein, the multi-channel data acquisition module is connected to a plurality of acquisition electrodes (not shown) on the head and is configured to acquire the oscillation signals of the brain in real time; the electroencephalogram signal recording device is connected to the multi-channel data acquisition module and is configured to record the acquired oscillation signals of the brain in real time; the filter is connected to the electroencephalogram signal recording device and is configured to preprocess the recorded oscillation signals of the brain to obtain the finally feedback oscillation signals.

[0069] As an example, the electroencephalogram feedback device 40 includes: a Hilbert transform module (not shown), a comparison and judgment module (not shown), and a feedback control module (not shown); wherein, the Hilbert transform module is connected to the electroencephalogram acquisition device 30 and is used to perform Hilbert transform on the oscillation signal of the brain to obtain an instantaneous phase signal; the comparison and judgment module is connected to the Hilbert transform module and is used to compare the instantaneous phase signal with a target phase to judge whether the oscillation signal of the brain reaches a target oscillation state; the feedback control module is connected to both the comparison and judgment module and the phase stimulation device 20 and is used to generate a feedback control signal when the oscillation signal of the brain reaches the target oscillation state, and control the phase stimulation device 20 to stop stimulating the superficial brain region and the deep brain region of the brain based on the feedback control signal.

[0070] As an example, the non-invasive nerve stimulation system for collaborative stimulation of the superficial and deep brain regions may further include: a power management device (not shown), and the power management device is connected to at least the time interference stimulation device 10, the phase stimulation device 20, the electroencephalogram acquisition device 30, and the electroencephalogram feedback device 40, and is at least used to supply power to the time interference stimulation device 10, the phase stimulation device 20, the electroencephalogram acquisition device 30, and the electroencephalogram feedback device 40.

[0071] As an example, the power management device includes: a power input module (not shown), a voltage conversion module (not shown), a power management module (not shown), an energy management device (not shown), a safety isolator (not shown), and a heat dissipation device; wherein, the power input module is compatible with AC and DC power supply modes and is used to convert DC power into AC power and perform processing such as removing clutter, eliminating noise, and eliminating voltage spikes on the converted AC power; the voltage conversion module is connected to the power input module, the time interference stimulation device 10, the phase stimulation device 20, the electroencephalogram acquisition device 30, and the electroencephalogram feedback device 40, and is used to convert the input voltage obtained by the power input module into different voltages required by the time interference stimulation device 10, the phase stimulation device 20, the electroencephalogram acquisition device 30, and the electroencephalogram feedback device 40; the power management module is used to monitor, protect, and optimize the power supply; the energy management device is connected to the voltage conversion module, the time interference stimulation device 10, the phase stimulation device 20, the electroencephalogram acquisition device 30, and the electroencephalogram feedback device 40, and is used to perform power distribution and monitoring; the safety isolator is connected to the power input module and the phase stimulation device 10, and is used to detect the real-time voltage of the power input module and perform a safety isolation action when the real-time voltage is abnormal; the heat dissipation device is located on the surface of the power input module.

[0072] As an example, the non-invasive nerve stimulation system for coordinated deep and shallow brain region stimulation may further include: a comprehensive oscilloscope display (not shown), which is connected to both the phase stimulation device 20 and the electroencephalogram acquisition device 30, and is used to display the current stimulation parameters, the low-frequency electrical stimulation signal, the high-frequency electrical stimulation signal, and the oscillation signal of the brain.

[0073] Specifically, the purpose of the time interference stimulation device 10 is to determine whether the TIS is successfully focused on the target site before implementing the same-frequency phase difference stimulation, adjust the parameters according to the computer simulation focusing situation until the simulation is successful, and then apply it to the same-frequency phase difference stimulation of the real head. The time interference stimulation device 10 uses the SimNIBS software to implement the brain electric field simulation and visualization based on the finite element method (FEM). The basic process includes: inputting the head MRI data, constructing a head finite element model based on the MRI data, simulating the TIS stimulation, solving the finite element model, and visualizing the TIS stimulation electric field. First, based on the individual MRI (T1-weighted image, T2-weighted image, diffusion tensor imaging DTI) data, a high-precision three-dimensional head model can be generated, including tissues such as the scalp, compact bone, cancellous bone, blood, muscle, eyeball CSF, gray matter, white matter, and stroke area. Then, use the mri2mesh tool for automatic head segmentation to generate an initial tetrahedral mesh, and then use Gmsh to manually edit the head model (such as correcting the lesion area). Define the positions, sizes, and current parameters of the two pairs of electrodes in SimNIBS_gui (such as the first pair of electrodes: 1 mA, 1000 Hz; the second pair of electrodes: 1 mA, 1010 Hz), and generate a low-frequency envelope electric field through the frequency difference (such as 10 Hz). Call the built-in femf solver in SimNIBS for time-harmonic finite element analysis, calculate the electric field distributions of the two high-frequency electric fields, and extract the envelope electric field intensity through the interference algorithm. Use the Post-Processing module of Gmsh to visualize the electric field distribution of the envelope electric field, or generate an interactive 3D rendering through simnibs.View.

[0074] Specifically, the phase stimulation device 20 receives power supply from the power management system, receives information input from the electroencephalogram (EEG) feedback device 40 and the time interference stimulation device 10, is connected to the comprehensive oscilloscope display for displaying parameters, receives information input for adjusting parameters from the comprehensive oscilloscope display, and outputs an electrical stimulation signal to the electrode unit. The phase stimulation device 20 can achieve precise control of the entire process from parameter setting to brain region stimulation. The phase stimulation device 20 may include a parameter input module, a voltage-controlled waveform generation module, a Howland constant current source, and an electrical stimulation signal output module. The parameter input module is used to set the stimulation parameters of the electrical stimulation signal, and the stimulation parameters include waveform, frequency, phase difference between multi-channel signals, and duration. The voltage-controlled waveform generation module is connected to the parameter input module and generates multiple voltage waveform signals corresponding to the low-frequency electrical stimulation signal and the high-frequency electrical stimulation signal based on the stimulation parameters. At the same time, using the Direct Digital Synthesis (DDS) algorithm, the voltage waveform signals are processed in real-time for frequency modulation and amplitude modulation, so that not only there is a preset phase difference between the voltage waveform signals, but also the amplitude can be adjusted according to the treatment requirements. The Howland constant current source is connected to the voltage-controlled waveform generation module and generates a low-frequency electrical stimulation signal and a high-frequency electrical stimulation signal based on the voltage waveform signals; the electrical stimulation signal output module is connected to the Howland constant current source, stimulates the superficial brain region of the brain based on the low-frequency electrical stimulation signal, and stimulates the deep brain region of the brain based on the high-frequency electrical stimulation signal.

[0075] Specifically, both the first electrode and the second electrode are high-precision and low-impedance output electrodes.

[0076] Specifically, the main function of the EEG acquisition device 30 is to record the oscillation signals of the brain in real-time, transmit the oscillation signals to the EEG feedback device 40 for processing, and display the waveforms on the comprehensive oscilloscope display. The EEG signal recording device can collect brain wave activities in different frequency bands through the acquisition electrodes on the scalp and record the electrical activities of the brain in real-time, including various oscillation signals. The multi-channel data acquisition module can ensure that the device can obtain data from multiple electrode channels in real-time to more accurately monitor the oscillation signals of specific brain regions. The filter preprocesses the acquired data to eliminate noise and artifacts, thereby obtaining a clean signal.

[0077] Specifically, the EEG feedback device 40 receives information input from the EEG acquisition device 30, analyzes and processes the real-time signal; performs Hilbert transform on the acquired oscillation signals to obtain the instantaneous phase signal, and displays it on the comprehensive oscilloscope display. The phase comparison method is used to determine whether the preset target oscillation is reached. If it is monitored that the target oscillation state has been reached, the output of the electrode unit in the phase stimulation device 20 is automatically cut off to stop the stimulation.

[0078] Specifically, the comprehensive oscilloscope display interacts with the phase stimulation device 20 and the electroencephalogram acquisition device 30 through a serial port. Through the information interaction with the phase stimulation device 20, it can display the current stimulation parameters, adjust the stimulation parameters, control the start and end of the stimulation, and display the waveform diagrams of the low-frequency electrical stimulation signal and the high-frequency electrical stimulation signal and the phase states of each waveform. Through the information interaction with the electroencephalogram acquisition device 30, it can display in real time the oscillation signals of the brain recorded by the electroencephalogram acquisition device 30, present graphical waveforms and instant phase information, and prompt whether the target vibration state has been reached.

[0079] Specifically, the power management device adopts high-efficiency power conversion technology and intelligent power management solutions, aiming to provide continuous and stable power supply for the device, while significantly reducing the operating power consumption and thermal effects, and building a safety protection system to ensure the reliability of use. The power input module is compatible with AC or DC power supply modes and supports the access of a wide-range starting voltage of 0 - 8V; an internal filter is built to convert the input power into alternating current, and can remove clutter, eliminate noise and voltage spikes, improving the power quality. The voltage conversion module converts the input voltage into different voltage levels required by the system through a DC-DC converter, improving the power efficiency and stability. The battery management module can provide battery status monitoring, protection and optimization functions. The energy management module includes power distribution and monitoring to ensure that each subsystem operates within its allowed power range and prevent overload. The safety isolator is connected to the voltage-controlled waveform generation module and uses an optocoupler as the isolation technology; it detects the real-time voltage of the safe power supply, makes corresponding safety isolation actions after analysis, and protects the power supply system. The heat dissipation device uses heat sinks to dissipate heat through heat conduction and convection to ensure the long-term reliable operation of the power supply. Of course, the heat dissipation device can also be located on the surfaces of the time interference stimulation device 10, the phase stimulation device 20, the electroencephalogram acquisition device 30 and the electroencephalogram feedback device 40 to achieve heat dissipation for the time interference stimulation device 10, the phase stimulation device 20, the electroencephalogram acquisition device 30 and the electroencephalogram feedback device 40.

[0080] In the non-invasive nerve stimulation system for coordinated deep and shallow brain region stimulation of the present application, the low-frequency electrical stimulation signal (with a frequency of f and an initial phase of the low-frequency electrical stimulation signal of ) is output to the first electrode through the first channel to stimulate the shallow brain region of the brain, and the high-frequency electrical stimulation signal (with frequencies of f1 and f2 respectively and initial phases of the high-frequency electrical stimulation signals of and And f = f1 - f2, the amplitudes of the generated high-frequency electric fields are A1 and A2 respectively, and at time t) electrical stimulation is performed on the deep brain regions. According to the principle of time-interference stimulation, the envelope electric field frequency is f = f1 - f2 (f1 > f2 ≥ f), and the initial phase of the envelope electric field is

[0081] The goal to be achieved by the same-frequency phase difference stimulation of the deep brain region and the shallow brain region is:

[0082]

[0083] The two high-frequency electric fields for realizing time-interference stimulation are respectively:

[0084]

[0085] The superimposed electric field is:

[0086]

[0087] The envelope electric field formula obtained by processing this formula is relatively complex, especially when A1 ≠ A2, and the situation where A1 and A2 differ greatly at the target point often occurs under time-interference stimulation.

[0088] Therefore, in order to reduce the complexity, the initial phases and of the two high-frequency electrical stimulation signals of time-interference stimulation can both be set to 0, and the superimposed electric field at this time can be:

[0089] E(t) = A1sin(2πf1t) + A2sin(2πf2t)

[0090] The envelope electric field is:

[0091]

[0092] Then, the initial phase of the envelope electric field has a frequency of 10 Hz.

[0093] Since the initial phase of the low-frequency electrical stimulation signal applied to the shallow brain region should be According to the requirements of, adjust to achieve the same-frequency phase difference stimulation of the deep brain region and the shallow brain region.

[0094] Taking an example of a device and an animal research embodiment for coupling non-invasive deep brain region stimulation and transcranial shallow brain region stimulation:

[0095] The time interference stimulation device 10 is used to simulate and determine the precise focusing of TIS on the hippocampus (HPC) in the deep brain region before stimulation. The time interference stimulation device 10 uses open-source software SimNIBS to implement brain electric field simulation and visualization based on the finite element method (FEM). First, MRI is performed on the mouse brain to obtain T1-weighted images, T2-weighted images, and diffusion tensor imaging DTI data, and a high-precision three-dimensional head model is generated. The high-precision three-dimensional head model includes tissues such as the scalp, compact bone, spongy bone, blood, muscle, eyeball CSF (contrast sensitivity function), gray matter, white matter, and stroke area. The volume conductor model is used to process the T1 and T2 data to calculate the conductivity of tissues except white matter, and the linear relationship of the effective medium model is used to process the DTI data to calculate the anisotropic conductivity of white matter. Then, the mri2mesh and Gmsh tools are used to segment and correct the model. Next, the SimNIBS_gui tool is used to define the positions, sizes, and current parameters of two pairs of electrodes (the first pair of electrodes: 1 mA, 1000 Hz; the second pair of electrodes: 1 mA, 1010 Hz). The envelope electric field is generated by the frequency difference (Δf = 10 Hz) of two equal-amplitude currents. The built-in femf solver in SimNIBS is called to perform time-harmonic finite element analysis, calculate the electric field distributions of two high-frequency electric fields (corresponding to two high-frequency electrical stimulation signals), and extract the envelope electric field intensity through the interference algorithm. The Post-Processing module of Gmsh is used to visualize the electric field distribution of the envelope electric field, or an interactive 3D rendering is generated through simnibs.View. Thus, simulations are continuously carried out until the electrode parameters that can most precisely stimulate the target brain region HPC are obtained. The electrode unit receives the stimulation instruction of the phase stimulation device 20 and outputs electrical stimulation. Specifically, the prefrontal cortex (PFC) electrode in the shallow brain region performs transcranial alternating current stimulation, and the HPC electrode in the deep brain region performs high-frequency time-coherent stimulation. The phase stimulation device 20 is used to output stimulation and adjustment to the electrode unit after TIS simulation. The voltage-controlled waveform generation module is connected to the Howland constant current source. According to the simulation results of the time interference stimulation device 10, the specific parameters of the electrode unit are determined, and the following parameters are input. The second electrode terminals in the electrode unit respectively output high-frequency alternating currents (i.e., high-frequency electrical stimulation signals) of 1 mA, 1000 Hz and 1 mA, 1010 Hz with an initial phase of 0 (the initial phase of the envelope electric field is π / 2); at the same time, a low-frequency alternating current (i.e., low-frequency electrical stimulation signal) of 1 mA, 10 Hz with an initial phase of 0.383 (i.e., 69°) is output to the tACS electrode (i.e., the first electrode in the electrode unit), and the phase difference from the envelope electric field of the second electrode terminal is 0.117 (i.e., 21°).The Howland constant current source is connected to the electrical stimulation signal output device, and outputs electrical stimulation signals of each end to the corresponding electrodes to achieve phase difference stimulation of deep brain regions and shallow brain regions. At the same time, using the Direct Digital Synthesis (DDS) algorithm, the wave signal is processed in real-time for frequency modulation and amplitude modulation, and the amplitude and frequency of the wave can be adjusted according to research needs. The electroencephalogram feedback device 40 receives the data of the electroencephalogram acquisition device 30 in real-time, and is used to automatically cut off the output of the electrodes and stop the stimulation when the stimulation of the two brain regions of the HPC and PFC reaches the preset value. The electroencephalogram acquisition device 30 is used to obtain the electroencephalogram signal data of the HPC and PFC in real-time, transmit the data information to the electroencephalogram feedback device 40 for processing, eliminate noise and artifacts, and display the waveform of the clean signal on the comprehensive oscilloscope display. The comprehensive oscilloscope display is used to display the current stimulation parameters and adjust the stimulation parameters, control the start and end of the stimulation; display the waveform diagrams of each wave signal and the phase states of each wave; display the brain signals and stimulation states recorded by the electroencephalogram acquisition device 30, present the graphical waveform and instant phase information, and prompt whether the preset threshold has been reached. The power management device is used for voltage supply and protection of other devices. Among them, when the safety isolator detects that the real-time voltage or current of the safe power supply exceeds 3% of the preset voltage or current threshold, it triggers an alarm as a safety isolation action, and when the real-time voltage or current exceeds 5% of the voltage or current threshold, it performs a power-off process as a safety isolation action to prevent damage to the circuit and harm to the mice. In a specific example,

[0096] The closed-loop feedback invasive nerve stimulation system of the present application realizes precise coordinated stimulation of cross-brain region nerve activities through the precise modeling of the time interference stimulation device 10, the dynamic regulation of the phase stimulation system, the safety guarantee of the closed-loop feedback mechanism, and the efficient support of the power management device. It not only solves the problems of insufficient deep stimulation and single-phase of traditional tACS, but also provides a safe and repeatable non-invasive treatment tool for clinical use.

[0097] In another embodiment, please combine Figure 1 refer to Figure 2 and the present application also provides a non-invasive nerve stimulation method for coordinated stimulation of deep and shallow brain regions. The non-invasive nerve stimulation method for coordinated stimulation of deep and shallow brain regions includes:

[0098] S10: Perform brain electric field simulation to obtain the brain electric field simulation result;

[0099] S20: Generate a low-frequency electrical stimulation signal and a high-frequency electrical stimulation signal based on the brain electric field simulation result, and stimulate the shallow brain region of the brain based on the low-frequency electrical stimulation signal, and stimulate the deep brain region of the brain based on the high-frequency electrical stimulation signal; the envelope electric field generated by the interference of the high-frequency electrical stimulation signal has a phase difference with the low-frequency electrical stimulation signal;

[0100] S30: During the process of the phase stimulation device stimulating the superficial brain region and the deep brain region of the brain, the oscillation signal of the brain is recorded in real time;

[0101] S40: Based on the oscillation signal of the brain recorded by the electroencephalogram acquisition module, it is judged whether the target oscillation state is reached; if so, the phase stimulation device is controlled to stop stimulating the superficial brain region and the deep brain region of the brain.

[0102] In the above non-invasive nerve stimulation system and method for coordinated stimulation of superficial and deep brain regions, by generating a low-frequency electrical stimulation signal for stimulating the superficial brain region of the brain and a high-frequency electrical stimulation signal for stimulating the deep brain region of the brain, dual-modal coordinated stimulation of the superficial brain region and the deep brain region can be achieved, thus solving the problem of insufficient stimulation of the deep brain region and being unable to effectively stimulate the deep brain region.

[0103] As an example, the non-invasive nerve stimulation method for coordinated stimulation of superficial and deep brain regions of the present application can be based on, for example Figure 1 and the non-invasive nerve stimulation system for coordinated stimulation of superficial and deep brain regions in related embodiments and executed.

[0104] Compared with the prior art, the non-invasive nerve stimulation system and method for coordinated stimulation of superficial and deep brain regions of the present application have the following beneficial effects:

[0105] 1. Break through the limitation of single brain region stimulation: Integrate the superficial tACS and deep transcranial interference stimulation (TIS) technologies, generate low-frequency difference frequency signals (such as 10 Hz) through high-frequency electric field interference (such as 1000 Hz and 1010 Hz), and achieve dual-modal coordinated stimulation across brain regions (such as the hippocampus and the medial prefrontal cortex).

[0106] 2. Improve the activation efficiency of deep brain regions: Through the TIS technology, the electric field intensity of deep targets is increased to 0.5 - 0.6 V / m, reaching the neuron activation threshold, and solving the problem of insufficient stimulation of deep brain regions.

[0107] 3. Individualized precise adaptation: Based on individual MRI data, construct a head finite element model, optimize the electrode layout and stimulation parameters, ensure that the TIS focuses on the target brain region, and improve the controllability and repeatability of the treatment effect.

[0108] 4. Dynamic phase difference simulating physiological processes: The electroencephalogram feedback device 40 collects EEG signals in real time, extracts the instantaneous phase information through Hilbert transform, and compares it with a preset target phase difference (such as a 21° lag from HPC→mPFC). The voltage-controlled waveform generation module of the phase stimulation device uses the DDS algorithm to dynamically adjust the phase difference of multi-channel signals (range 0° - 180°, accuracy ±5°) to simulate the delay of physiological information transmission. Animal experiments show that the power of the θ band in the prefrontal lobe and hippocampus of rats in the phase difference stimulation group increased significantly (p<0.01) (as shown in Figures E to H in Figure 3 ), and the time-frequency diagram shows enhanced neural activity synchronization (as shown in Figures E to H in Figure 4 ). Among them, Figure 3 : In Figure A, it is the power of each frequency band in the resting prefrontal cortex under tACS stimulation without phase difference; in Figure B, it is the power of each frequency band in the prefrontal cortex after tACS stimulation without phase difference; in Figure C, it is the power of each frequency band in the resting hippocampus under tACS stimulation without phase difference; in Figure D, it is the power of each frequency band in the hippocampus after tACS stimulation without phase difference; in Figure E, it is the power of each frequency band in the resting prefrontal cortex under tACS stimulation with phase difference; in Figure F, it is the power of each frequency band in the prefrontal cortex after tACS stimulation with phase difference; in Figure G, it is the power of each frequency band in the resting hippocampus under tACS stimulation with phase difference; in Figure H, it is the power of each frequency band in the hippocampus after tACS stimulation with phase difference; Figure 4 : In Figure A, it is the resting prefrontal cortex under tACS stimulation without phase difference; in Figure B, it is the prefrontal cortex after tACS stimulation without phase difference; in Figure C, it is the resting hippocampus under tACS stimulation without phase difference; in Figure D, it is the hippocampus after tACS stimulation without phase difference; in Figure E, it is the resting prefrontal cortex under tACS stimulation with phase difference; in Figure F, it is the prefrontal cortex after tACS stimulation with phase difference; in Figure G, it is the resting hippocampus under tACS stimulation with phase difference; in Figure H, it is the hippocampus after tACS stimulation with phase difference.

[0109] 5. Precision and safety: The time interference stimulation device 10 uses the mri2mesh tool to segment MRI data to generate an individualized head model, and combines Gmsh to correct the lesion area to ensure the precise matching of the electrode layout and the target position. The closed-loop feedback mechanism is jointly realized by the electroencephalogram acquisition device 30 and the electroencephalogram feedback device 40: It monitors the electroencephalogram signal (EEG) in real time. If the preset oscillation threshold (such as the phase difference tolerance ±5°) is reached, the stimulation signal of the output electrode is automatically cut off to avoid over-stimulation.

[0110] 6. High efficiency, low power consumption and stable operation: The power management device integrates a wide-range voltage input (0 - 8V), a DC-DC converter and an intelligent heat dissipation module: The voltage converter efficiently converts the input power into multiple levels of voltage required by the system, reducing energy consumption by 30% - 40%. The heat dissipation system maintains the stable temperature of the module through heat conduction and convection design to ensure the long-term operation of the device.

[0111] The technical features of the above embodiments can be combined arbitrarily. For the sake of concise description, not all possible combinations of the technical features of the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope recorded in this specification.

[0112] The above embodiments only represent several implementation manners of the present application, and the description thereof is relatively specific and detailed. However, it should not be construed as a limitation on the scope of the patent application. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present application, several modifications and improvements can still be made, and these all belong to the protection scope of the present application. Therefore, the protection scope of the patent of the present application shall be subject to the appended claims.

Claims

1. A non-invasive neurostimulation system for coordinated stimulation of deep and superficial brain regions, characterized in that: include: A time interference stimulation device is used for brain electric field simulation to obtain brain electric field simulation results; A phase stimulation device, for generating a low-frequency electrical stimulation signal and a high-frequency electrical stimulation signal based at least on the brain electric field simulation result, and stimulating the superficial brain area of ​​the brain based on the low-frequency electrical stimulation signal, and stimulating the deep brain area of ​​the brain based on the high-frequency electrical stimulation signal; the envelope electric field generated by the interference of the high-frequency electrical stimulation signal has a phase difference with the low-frequency electrical stimulation signal; An electroencephalogram (EEG) acquisition device, used to record the oscillation signal of the brain in real time during the process of the phase stimulation device stimulating the superficial brain area and the deep brain area of ​​the brain; An EEG feedback device, connected to both the phase stimulation device and the EEG acquisition module, for determining whether a target oscillation state is reached based on the oscillation signal of the brain recorded by the EEG acquisition module; If so, the phase stimulation device is controlled to stop stimulating the superficial and deep brain regions of the brain.

2. The non-invasive neurostimulation system for coordinated stimulation of deep and superficial brain regions according to claim 1, characterized in that: The time interference stimulation device comprises: A head model generation module, used to construct a three-dimensional head model based on magnetic resonance imaging data; A segmentation module, used for automatically segmenting the three-dimensional head model to generate an initial tetrahedral mesh; A correction module, used for correcting the diseased area of ​​the three-dimensional head model; A simulation module, used for performing the brain electric field simulation to obtain the brain electric field simulation result, wherein the brain electric field simulation result includes an envelope electric field; A visualization module is used to visualize the electric field distribution of the envelope electric field or the generated interactive 3D rendering.

3. The non-invasive neurostimulation system for coordinated stimulation of deep and superficial brain regions according to claim 1, characterized in that: The phase stimulation device comprises: A parameter input module, used for setting stimulation parameters of the electrical stimulation signal based on the brain electric field simulation result; A voltage-controlled waveform generation module, connected to the parameter input module, for generating a plurality of voltage waveform signals corresponding to the low-frequency electrical stimulation signal and the high-frequency electrical stimulation signal based on the stimulation parameters; A Howland constant current source, connected to the voltage-controlled waveform generation module, for generating the low-frequency electrical stimulation signal and the high-frequency electrical stimulation signal based on the voltage waveform signal; The electrical stimulation signal output module is connected to the Howland constant current source and is used to stimulate the superficial brain area based on the low-frequency electrical stimulation signal and to stimulate the deep brain area based on the high-frequency electrical stimulation signal.

4. The non-invasive neurostimulation system for coordinated stimulation of deep and superficial brain regions according to claim 3, characterized in that: The electrical stimulation signal output device comprises: An electrical stimulation signal output unit, connected to the Howland constant current source, comprising a first channel and a plurality of second channels; the first channel is used to output the low-frequency electrical stimulation signal, and the plurality of second channels are used to output the high-frequency electrical stimulation signal; The electrode unit includes a plurality of pairs of first electrodes and a plurality of pairs of second electrodes; the first electrodes are connected to the first channel and are used to stimulate the superficial brain areas based on the low-frequency electrical stimulation signal; the second electrodes are connected to the second channel and are used to stimulate the deep brain areas based on the high-frequency electrical stimulation signal.

5. The non-invasive neurostimulation system for coordinated stimulation of deep and superficial brain regions according to claim 1, characterized in that: The EEG acquisition device comprises: A multi-channel data acquisition module, connected to a plurality of acquisition electrodes located on the head, for real-time acquisition of the oscillation signal of the brain; An electroencephalogram signal recording device, connected to the multi-channel data acquisition module, for recording the collected brain oscillation signals in real time; The filter is connected to the electroencephalogram signal recording device and is used to pre-process the recorded brain oscillation signal to obtain the final feedback oscillation signal.

6. The non-invasive neurostimulation system for coordinated stimulation of deep and superficial brain regions according to claim 1, characterized in that: The electroencephalogram feedback device comprises: A Hilbert transform module, connected to the EEG acquisition device, for performing a Hilbert transform on the brain oscillation signal to obtain an instantaneous phase signal; A comparison and judgment module, connected to the Hilbert transform module, for comparing the instantaneous phase signal with the target phase to determine whether the oscillation signal of the brain reaches the target oscillation state; A feedback control module is connected to the comparison and judgment module and the phase stimulation device, and is used to generate a feedback control signal when the oscillation signal of the brain reaches a target oscillation state, and control the phase stimulation device to stop stimulating the superficial and deep brain regions of the brain based on the feedback control signal.

7. The non-invasive neurostimulation system for coordinated stimulation of deep and superficial brain regions according to claim 1, characterized in that: The non-invasive neurostimulation system for coordinated stimulation of deep and superficial brain regions also includes: A power management device is connected to at least the time interference stimulation device, the phase stimulation device, the EEG acquisition device and the EEG feedback device, and is used to at least supply power to the time interference stimulation device, the phase stimulation device, the EEG acquisition device and the EEG feedback device.

8. The non-invasive neurostimulation system for coordinated stimulation of deep and superficial brain regions according to claim 7, characterized in that: The power management device comprises: The power input module is compatible with both AC and DC power supply modes, and is used to convert DC power into AC power, and remove clutter, noise, and voltage spikes from the converted AC power; A voltage conversion module, connected to the power input module, the time interference stimulation device, the phase stimulation device, the EEG acquisition device and the EEG feedback device, and used for converting the input voltage obtained by the power input module into different voltages required by the time interference stimulation device, the phase stimulation device, the EEG acquisition device and the EEG feedback device; Power management module, used to monitor, protect and optimize the power supply status; An energy management device, connected to the voltage conversion module, the time interference stimulation device, the phase stimulation device, the EEG acquisition device and the EEG feedback device, for power distribution and monitoring; A safety isolator connected to the power input module and the phase stimulation device, used to detect the real-time voltage of the power input module and perform a safety isolation action when the real-time voltage is abnormal; The heat dissipation device is located on the surface of the power input module.

9. The non-invasive neurostimulation system for coordinated stimulation of deep and superficial brain regions according to any one of claims 1 to 8, characterized in that: The non-invasive neurostimulation system for coordinated stimulation of deep and superficial brain regions also includes: A comprehensive oscilloscope display is connected to the phase stimulation device and the EEG acquisition device, and is used to display current stimulation parameters, the low-frequency electrical stimulation signal, the high-frequency electrical stimulation signal and the brain oscillation signal.

10. A non-invasive neurostimulation method for coordinated stimulation of deep and superficial brain regions, characterized in that: include: Perform brain electric field simulation to obtain brain electric field simulation results; Based on the brain electric field simulation result, a low-frequency electrical stimulation signal and a high-frequency electrical stimulation signal are generated, and the shallow brain area of ​​the brain is stimulated based on the low-frequency electrical stimulation signal, and the deep brain area of ​​the brain is stimulated based on the high-frequency electrical stimulation signal; the envelope electric field generated by the interference of the high-frequency electrical stimulation signal has a phase difference with the low-frequency electrical stimulation signal; During the process of the phase stimulation device stimulating the superficial brain area and the deep brain area of ​​the brain, recording the oscillation signal of the brain in real time; Determining whether a target oscillation state is reached based on the oscillation signal of the brain recorded by the EEG acquisition module; If so, the phase stimulation device is controlled to stop stimulating the superficial and deep brain regions of the brain.

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