Time-interleaved stimulation system for the treatment of alzheimer's disease and method thereof

Abstract

The application relates to a system and method for treating Alzheimer's disease, and belongs to the field of medical devices. The system comprises a multi-modal data acquisition module, an individualized simulation navigation module, a precise signal generation and driving module, and a closed-loop feedback control module. The system constructs an individual head model through finite element analysis to optimize electrode distribution, generates an interference envelope in the hippocampus area by using two high-frequency currents, and realizes closed-loop adjustment of parameters by combining a repeated continuous mode and physiological feedback. The application realizes non-invasive and accurate regulation of a deep target point, significantly improves hippocampal oscillation synchronization and synaptic plasticity, improves the memory of patients, reduces the activation of the surface cortex, and has good clinical safety.

Description

Technical Field

[0001] This invention belongs to the field of medical devices, and specifically relates to a time-interference stimulation system and method for treating Alzheimer's disease. Background Technology

[0002] Alzheimer's disease, a complex neurodegenerative disease, has become one of the most serious public health challenges facing aging societies worldwide. Its pathological features include β-amyloid protein deposition, tau protein hyperphosphorylation, and neuroinflammation, clinically accompanied by progressive memory loss, cognitive impairment, and a range of psychosocial symptoms. Despite significant progress in understanding the pathogenesis of Alzheimer's disease in modern biomedicine, clinical treatment options remain limited. Traditional pharmacological interventions, such as cholinesterase inhibitors and NMDA receptor inhibitors, primarily focus on short-term symptom relief and are unlikely to effectively reverse or block the disease's pathological progression. In recent years, while novel drugs such as anti-β-amyloid monoclonal antibodies have shown promise in clearing pathological proteins, their widespread clinical application faces multiple obstacles due to the blood-brain barrier's permeability limitations, high treatment costs, and potential safety risks such as cerebral edema and microbleeds.

[0003] Against the backdrop of bottlenecks in drug therapy, physical neuromodulation techniques have attracted significant attention due to their direct action on neural circuits. Existing neuromodulation protocols are mainly divided into two categories: invasive and non-invasive. While deep brain stimulation (DBS) can precisely reach key deep brain regions such as the hippocampus, its highly invasive nature requires surgical electrode implantation, posing significant risks of infection, bleeding, and surgical complications for elderly and frail Alzheimer's patients. In contrast, non-invasive techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (TCD) offer better safety. However, their physical characteristics mean that their electromagnetic fields attenuate drastically as they penetrate the scalp and cortex, making it difficult to effectively focus on deep targets without damaging superficial tissues. This inherent trade-off between "depth and focus" severely limits the effectiveness of non-invasive modulation in the core affected brain regions of Alzheimer's disease.

[0004] Temporal interference stimulation (TIS), an emerging non-invasive deep brain stimulation technique, applies two sets of slightly different high-frequency currents to the scalp. Utilizing the low-pass filtering properties of neuronal membranes to shield high-frequency signals, the two sets of currents interfere in the target deep brain region, generating a low-frequency modulated envelope signal. Theoretically, this mechanism allows for the precise induction of electrophysiological responses in deep neurons without activating the superficial cortex. However, in the in-depth practice of applying TIS to the clinical treatment of Alzheimer's disease, a deep-seated technical contradiction has gradually emerged: the contradiction between the "precise focusing" of TIS at the physical level and the "high heterogeneity" and "dynamic degeneration" of the Alzheimer's patient's brain.

[0005] Specifically, Alzheimer's disease is not an isolated lesion of a single brain region, but a systemic failure process involving the dynamic network of the entire brain. Its pathological progression is accompanied by significant brain atrophy, cortical thinning, and changes in the cerebrospinal fluid space. Current temporal interference stimulation techniques often employ standardized electrode arrangements and fixed frequency parameters, failing to fully consider the vast differences in individual anatomical structures. For Alzheimer's patients, the altered electric field impedance distribution caused by brain atrophy can lead to a shift in the physical center of the interference envelope, causing the originally designed stimulation target to deviate from the functionally impaired area. A deeper problem is that the firing rhythm of neurons exhibits a complex dynamic evolution at different stages of Alzheimer's disease. Without individualized frequency matching based on real-time physiological feedback, static interference stimulation may result in weak regulatory effects due to off-target effects from endogenous oscillations, or even interfere with normal neural compensation due to incorrect phase coupling. This lack of closed-loop integration of patient structural imaging and electrophysiological state makes it difficult for temporal interference stimulation to achieve the expected clinical robustness when treating highly individual-specific diseases like Alzheimer's disease.

[0006] In summary, although time-interference stimulation breaks through the limitations of non-invasive deep stimulation in principle, how to achieve individualized charge distribution optimization based on multimodal imaging in complex degenerative pathological environments, and construct a closed-loop interference mechanism in combination with real-time physiological indicators, has become a key technical bottleneck that urgently needs to be overcome in the field of neuromodulation.

[0007] Therefore, developing a time-interference stimulation system that can integrate multimodal neuroimaging data, achieve personalized navigation, and dynamically optimize interference parameters is of great clinical significance and technical necessity for improving the precision treatment of Alzheimer's disease. Summary of the Invention

[0008] This invention provides a time-interference stimulation system and method for treating Alzheimer's disease, aiming to solve the technical problems of poor deep target focusing, high invasive risks, and inability to dynamically adapt to the individual anatomical and electrophysiological characteristics of patients in the treatment of Alzheimer's disease by existing neuromodulation techniques.

[0009] The present invention employs a time-interference stimulation system for treating Alzheimer's disease, which consists of a multimodal data acquisition module, a personalized simulation navigation module, a precision signal generation and driving module, and a closed-loop feedback control module.

[0010] The precision signal generation and driving module includes at least two independent signal generation units. The first signal generation unit has a preset output frequency of [frequency value missing]. The sinusoidal alternating current, the second signal generation unit has a preset output frequency of sinusoidal alternating current.

[0011] In this invention, in order to avoid the activation threshold of surface cortical neurons and utilize the low-pass filtering properties of the neuronal membrane, the... Set to 2000Hz, the The frequency was set to 2006Hz. The two signals were connected to at least two pairs of electrodes placed on the subject's scalp via a constant current source drive circuit.

[0012] The constant current source drive circuit has high impedance characteristics, ensuring that the output current intensity remains constant at a preset value when the scalp contact resistance changes dynamically. The peak-to-peak range of the preset value is set to 1mA to 3mA.

[0013] The personalized simulation navigation module is implemented as follows: First, the multimodal data acquisition module acquires the subject's structural magnetic resonance imaging data, and the fine anatomical boundaries of the scalp, skull, cerebrospinal fluid, gray matter, and white matter are extracted using T1-weighted images. Then, a three-dimensional conductivity model of the subject's head is constructed using finite element analysis. In this model, the conductivity parameters of each tissue are set to predetermined nominal values: scalp 0.43 S / m, skull 0.01 S / m, cerebrospinal fluid 1.79 S / m, gray matter 0.33 S / m, and white matter 0.15 S / m. Based on this model, the Laplace equation is calculated... The simulation simulates the spatial distribution of two sets of high-frequency electric fields within the brain. The navigation module optimizes the coordinate positions of the electrodes on the scalp using an iterative algorithm, maximizing the interference envelope amplitude of the two sets of electric fields in the hippocampus. It reaches its maximum. The mathematical expression for the amplitude of the interference envelope is:

[0014] in, and Positions Two sets of high-frequency electric field vectors at the location.

[0015] The system employs a repetitive, continuous stimulation pattern. Due to the superposition of two high-frequency electric fields within the intracranial space, a low-frequency modulated electric field envelope with a frequency of 6 Hz (i.e., |2006-2000|=6 Hz) is generated in the bilateral hippocampal regions, based on the principle of sum-to-product of trigonometric functions. This envelope frequency falls within the theta band (4-8 Hz), matching the natural oscillation frequency of the hippocampus during memory encoding, thus enhancing synaptic plasticity through a phase-locking effect.

[0016] The closed-loop feedback control module monitors the subject's physiological feedback signals in real time through the multimodal data acquisition module; The feedback signals include the power spectral density of resting-state electroencephalogram and changes in blood oxygen levels recorded by functional near-infrared spectroscopy; The module has a built-in logic processing unit that performs calculations. Variation in frequency band power To assess the immediate effects of neural modulation; like If the current falls below a preset threshold, the system will automatically initiate a parameter fine-tuning program to adjust the phase difference of the output current or slightly correct the electrode current ratio within a range of ±10% until the feedback signal reaches the optimization target.

[0017] Furthermore, the present invention relates to a time-intervention stimulation method for treating Alzheimer's disease, the steps of which strictly follow the following engineered process: The first step is a baseline multimodal assessment. Before intervention initiation, comprehensive baseline data collection is performed on the subjects. This assessment includes: clinical scale evaluation, sMRI structural imaging, long-term resting-state EEG, and peripheral blood biomarker detection. High-sensitivity single-molecule immunoassay array technology is used for blood biomarker detection to ensure absolute accuracy of baseline data, providing a biological anchor for subsequent efficacy assessment.

[0018] The second step involves customizing an individualized intervention plan. Based on the sMRI data obtained in the first step, the optimal projection coordinates of the subject's bilateral hippocampus are determined using an electric field distribution cloud map generated by the individualized simulation navigation module. Biocompatible gel electrodes are used, fixed to the calculated scalp positions using an elastic headgear.

[0019] The third step is to apply therapeutic intervention to the system. The intervention cycle is set for two consecutive weeks, six days a week, once a day, with each intervention lasting a fixed 30 minutes. During the intervention, the precision signal generation and drive module outputs the above... and The modulated current was applied. During the intervention, the subject remained at rest with eyes open, and the system monitored heart rate, blood pressure, and subcutaneous temperature rise in real time through a vital signs monitoring unit to ensure the safety of the intervention process.

[0020] The fourth step is efficacy evaluation and follow-up feedback. All assessment items from the first step are repeated after the 2-week intervention and at the 1st and 3rd month follow-up. The system calculates the following core indicators by comparing multimodal data before and after the intervention: Calculate the dynamic brain network changes of BOLD signals, especially the functional connectivity strength between the default mode network and the hippocampus.

[0021] Calculate the duration and transition probability of EEG microstates to assess the improvement in spatiotemporal dynamic characteristics of EEG.

[0022] The statistical inference of scale score changes was performed using a linear mixed-effects model, and the statistical formula is as follows:

[0023] in, For the first One subject in The scale scores at each time point This represents the intervention effect size.

[0024] The technical solution provided by this invention has the following deterministic effects: In terms of physical performance, this system successfully avoids the strong current density generated in the superficial cortex by traditional transcranial electrical stimulation through a time interference mechanism. Experimental tests show that, under the same electric field strength generated in the hippocampal target area, the activation level of the superficial cortex is reduced by at least 60%, effectively reducing the false activation of pain neurons.

[0025] In terms of clinical efficacy, this approach, combining individualized simulation navigation with a mode of enhancing motor cortex excitability through priming stimulation, can significantly improve hippocampal function. The synchronicity of oscillations. In clinical validation in patients with early-stage Alzheimer's disease, the subjects' total scores on the Clinical Dementia Rating Scale showed a significant decrease after the intervention, and their immediate and delayed recall scores on the Auditory-Verbal Learning Test showed definitive improvement. This indicates that the system is highly effective in enhancing synaptic plasticity and improving episodic memory function.

[0026] In terms of safety, this system integrates real-time impedance monitoring and automatic fuse protection mechanisms. When the scalp-electrode contact impedance exceeds 5kΩ or the instantaneous current exceeds 4mA, the system will cut off the output within 10ms, eliminating the risk of skin burns. Meanwhile, follow-up MRI results confirm that intervention using the parameters described in this invention does not induce adverse reactions such as cerebral edema or microbleeds.

[0027] In terms of biological effects, this invention, through tracking and detecting blood biomarkers, found that the level of astrocyte activation biomarkers in the plasma of subjects after intervention showed a decreasing trend, suggesting that time-interference magnetic poles may exert a long-term neuroprotective effect by reducing neuroinflammatory responses.

[0028] This invention, through the deep integration of mechanics, electrical engineering, and computational biology, constructs a complete, closed-loop adjustable neural regulation ecosystem, providing solid engineering technical support for the non-invasive precision treatment of Alzheimer's disease.

[0029] Furthermore, the constant current source circuit in the precision signal generation and driving module employs a high-precision operational amplifier and a power MOSFET to form a feedback loop. This loop adjusts the gate drive voltage of the operational amplifier and power MOSFET in real time by detecting the voltage drop across a precision sampling resistor connected in series in the electrode branch, thereby compensating for fluctuations in the electrochemical impedance of human skin over time and due to sweat secretion. The sampling resistor has a resistance accuracy of no less than 0.1% and a temperature drift coefficient of less than 25 ppm / ℃, ensuring the absolute stability of the output current.

[0030] In a preferred embodiment of the present invention, the multimodal data acquisition module synchronously records fNIRS signals during the intervention process. The fNIRS probes are arranged in a ring around the hippocampal projection area and employ dual-wavelength continuous wave technology. The system calculates the changes in the concentrations of oxyhemoglobin and deoxyhemoglobin in real time using a modified Beer-Lambert law; the specific calculation formula is as follows:

[0031] in, For the first Light-absorbing substances at wavelength The extinction coefficient, This is due to concentration changes. The closed-loop feedback control module dynamically adjusts the stimulation intensity based on the oscillation amplitude of oxyhemoglobin, maintaining the blood oxygen metabolism level in the hippocampus within the optimal control range.

[0032] In summary, this invention achieves precise reshaping of the deep brain electrophysiological environment of Alzheimer's patients through the physical connection and logical collaboration of the hardware modules and the standardized implementation steps of the method. The entire system strictly adheres to medical device electrical safety standards in its electrical design and achieves multi-dimensional fusion of imaging and electrophysiology in its algorithm, exhibiting extremely high non-obviousness and significant technological advancements. Attached Figure Description

[0033] To more clearly illustrate the technical solution of the present invention, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0034] Figure 1 This is a schematic diagram of the overall platform of a digital human intelligent service system based on multimodal interaction provided by the present invention; Figure 2 This is an execution flowchart of a digital human intelligent service method based on multimodal interaction provided by the present invention. Detailed Implementation

[0035] The technical solution of the present invention will now be described in detail with reference to the accompanying drawings.

[0036] This invention provides a time-interference stimulation system and method for treating Alzheimer's disease, the engineering implementation of which is based on a deep integration of human neuroelectrophysiological characteristics and electric field physical properties. The system integrates a multimodal data acquisition module, a personalized simulation navigation module, a precision signal generation and driving module, and a closed-loop feedback control module in its overall architecture. Through hardware interconnection and logical coupling between these modules, a closed-loop ecosystem for precise regulation of the hippocampus, a deep brain region, is constructed.

[0037] The present invention relates to a time-interference stimulation system for treating Alzheimer's disease, comprising: A precision signal generation and driving module. It contains at least two logically and physically independent signal generation units. The first signal generation unit has a preset output frequency of... The sinusoidal alternating current uses a high-stability temperature-controlled crystal oscillator as its oscillation source. Waveform data is generated through direct digital frequency synthesis (DDS) technology and then converted into an analog signal via a digital-to-analog converter (DAC). In this embodiment, the... The frequency is strictly set to 2000Hz. The second signal generation unit uses the same technical architecture, but its preset output frequency is different. Set to 2006Hz.

[0038] The frequency difference between these two high-frequency signals is exactly 6Hz, which is in the low-frequency range where neurons can generate envelope responses. Their high-frequency carrier characteristics ensure that the current can penetrate the skin and skull with low impedance, avoiding the depolarization effect in the superficial cortex that could cause pain or twitching.

[0039] The precision signal generation and driving module integrates a constant current source driving circuit with high impedance characteristics. To ensure current stability during the intervention process, the constant current source driving circuit consists of a dynamic negative feedback loop composed of a high-precision operational amplifier and a power MOSFET.

[0040] Specifically, the system incorporates a precision sampling resistor connected in series in each branch of the electrode output. The resistance accuracy of this sampling resistor is no less than 0.1%, and its temperature drift coefficient is strictly controlled within 25 ppm / ℃ to eliminate measurement deviations caused by increased ambient temperature or high-current heating. The non-inverting input of the operational amplifier receives the command voltage from the DDS unit, while the inverting input is connected to the signal extraction point of the sampling resistor. By comparing the command voltage with the voltage drop across the sampling resistor in real time, the operational amplifier dynamically adjusts the gate drive voltage of the power MOSFET. This adjustment mechanism automatically compensates for dynamic impedance fluctuations caused by subject sweat secretion, changes in scalp contact pressure, or electrode polarization, ensuring that the peak-to-peak value of the output current remains stable within the preset range of 1mA to 3mA.

[0041] The individualized simulation navigation module begins its operation with the raw structural MRI data of the subject acquired by the multimodal data acquisition module. The system performs bias field correction, scalp removal, and multi-tissue segmentation on the T1-weighted images through a preprocessing procedure. During this process, the algorithm finely divides the subject's head structure into five main compartments: scalp, skull, cerebrospinal fluid, gray matter, and white matter. Based on the finely segmented anatomical boundaries, a three-dimensional tetrahedral mesh model is constructed using the finite element method. To ensure the physical realism of the simulation calculations, the conductivity parameters of each tissue in the model are assigned specific nominal values: scalp 0.43 S / m, skull 0.01 S / m, cerebrospinal fluid 1.79 S / m, gray matter 0.33 S / m, and white matter 0.15 S / m.

[0042] Based on this three-dimensional conductivity model, the system solves the Laplace equation. This simulates the spatial vector distribution of two sets of high-frequency electric fields within the brain. The navigation module incorporates an optimization iterative algorithm based on maximizing the amplitude of the interference envelope, with the objective function being to achieve the following at the hippocampus in the target brain region: It reaches its peak value. This envelope amplitude is composed of two high-frequency electric field vectors. and The difference between the absolute values ​​of the vector sum and the vector difference is used to determine the optimal arrangement of the electrodes. By iterating the placement coordinates of the electrode group in the three-dimensional coordinate system of the subject's scalp, the system finally determines the optimal arrangement of the electrodes and drives the mechanical positioning device or guides the manual fixation of the gel electrodes to the designated holes in the elastic headgear.

[0043] The system of this invention employs a highly biomimetic repetitive continuous stimulation pattern. Due to the superposition of two high-frequency electric fields in the intracranial space, based on the principle of sum-to-product of trigonometric functions, a low-frequency modulated electric field envelope with a frequency of 6 Hz (i.e., |2006-2000|=6 Hz) is generated in the bilateral hippocampal regions. This envelope frequency is in the theta band (4-8 Hz), simulating the endogenous stimulation of the hippocampus. Oscillatory rhythm. When hippocampal neuronal populations are subjected to this frequency-modulated temporal interference electric field, long-term enhancement is induced through the phase-locking effect, thereby enhancing synaptic plasticity. This is manifested at the molecular level as an increased translocation of AMPA receptors to the postsynaptic membrane.

[0044] The closed-loop feedback control module is key to achieving dynamic adaptation in this invention. This module receives physiological signals in real time from the multimodal data acquisition module. Specifically, the resting-state electroencephalogram (EEG) signal is captured by conductive electrodes placed on the scalp, amplified by a high-magnification, low-noise preamplifier, and then its power spectral density is calculated in real time. The logic processing unit focuses on monitoring... Power variation in frequency band Meanwhile, the functional near-infrared spectroscopy probes are arranged in a ring around the hippocampal projection area, using dual-wavelength continuous wave technology to detect tissue metabolism in real time.

[0045] Based on the modified Lambert-Beer law, the system calculates the concentration change curves of oxyhemoglobin and deoxyhemoglobin in real time. The specific calculation formula is as follows:

[0046] in, For the first Light-absorbing substances at wavelength The extinction coefficient, This is due to concentration changes. The closed-loop feedback control module dynamically adjusts the stimulation intensity based on the oscillation amplitude of oxyhemoglobin, maintaining the blood oxygen metabolism level in the hippocampus within the optimal control range.

[0047] If monitoring detects If the oscillation amplitude of oxyhemoglobin falls below a preset response threshold, the closed-loop feedback control module will immediately initiate a parameter fine-tuning procedure. This fine-tuning involves changing the initial phase difference between the two signals within a range of ±10%. Alternatively, the intensity ratio of the two currents can be adjusted in 0.1mA increments until the feedback signal shows that the neural activity in the hippocampus has reached the predetermined enhancement target.

[0048] Based on the above system architecture, the time-intervention stimulation method for treating Alzheimer's disease involved in this invention is implemented strictly according to the following engineering process. The first step is a baseline multimodal assessment. Comprehensive baseline data must be collected before subjects are enrolled.

[0049] This includes not only traditional clinical scales such as CDR-SB, Alzheimer's disease AS-cog, and AVLT, but also resting-state EEG signals lasting up to 10 minutes and sMRI structural images. Specifically, this method requires the collection of peripheral blood biomarkers from subjects and the use of highly sensitive single-molecule immunoassay array technology to detect the 42 / 40 ratio of β-amyloid deposition, p-tau217, NfL, and GFAP concentrations. These biological data constitute objective anchors for assessing treatment efficacy.

[0050] After baseline assessment, the individualized intervention plan is customized. Using the aforementioned simulation navigation module, an electric field distribution cloud map is generated based on the subject's anatomical features to determine the optimal projection coordinates of both hippocampi. The system then administers the treatment intervention. The intervention cycle is set for two consecutive weeks, performed daily except Sundays, with each intervention session strictly limited to 30 minutes. During the intervention, the subject wears an elastic headgear integrating gel electrodes and an fNIRS probe, remaining at rest with eyes open. The system's real-time vital signs monitoring unit samples heart rate, blood pressure, and skin temperature once per second. If real-time impedance monitoring detects an electrode contact impedance exceeding 5kΩ, or a transient current abnormality exceeding 4mA, the system's integrated automatic fuse protection mechanism cuts off all current output within 10ms to ensure the subject's absolute safety.

[0051] Finally, the efficacy evaluation and follow-up feedback steps are performed. All assessment items from the first step are repeated after the 2-week intervention, and at the 1st and 3rd month follow-up. The system calculates the following core indicators by comparing multimodal data before and after the intervention: Calculate the dynamic brain network changes of BOLD signals, especially the functional connectivity strength between the default mode network and the hippocampus.

[0052] Calculate the duration and transition probability of EEG microstates to assess the improvement in spatiotemporal dynamic characteristics of EEG.

[0053] The statistical inference of scale score changes was performed using a linear mixed-effects model, and the statistical formula is as follows:

[0054] in, For the first One subject in The scale scores at each time point This represents the intervention effect size.

[0055] To further demonstrate the superiority and effectiveness of the technical solution of the present invention, specific embodiments and comparative data are provided below.

[0056] In Example 1, the complete system described above was used to intervene in a group of Alzheimer's disease patients in the mild cognitive impairment stage. (Settings) and The stimulus intensity was 2 mA, and the mode was repetitive continuous.

[0057] As a comparative example 1, traditional transcranial direct current stimulation was used, with electrodes placed in the F3 and F4 areas, and the current intensity was also set to 2mA. The intervention duration and frequency were consistent with those of Example 1.

[0058] As a comparative example 2, a fixed-frequency non-interference high-frequency stimulation was used, that is, both pairs of electrodes output a current of 2000Hz, without generating a low-frequency difference envelope.

[0059] After two weeks of continuous intervention, the core evaluation indicators of the subjects in each group were compared as shown in the table below: Table 1: Comparison of Clinical and Physiological Indicators between the Embodiments and Comparative Examples of the Invention

[0060] The data in Table 1 clearly demonstrate that Example 1 significantly improved AVLT delayed recall scores compared to the two comparative examples, proving the definitive efficacy of temporal interference stimulation in improving core memory symptoms in Alzheimer's disease. At the physiological level, Example 1 induced hippocampal... The frequency band power increase rate reached 42.8%, while that of traditional tDCS was only 12.5%, which directly confirms the technological advancement of this invention in deep target focusing. Meanwhile, the superficial cortical pain score in Example 1 was extremely low, comparable to fixed high-frequency stimulation, and far lower than traditional DC stimulation, demonstrating the engineering advantage of high-frequency carrier waves avoiding the activation threshold of superficial neurons.

[0061] Further analysis of blood biomarker data revealed a significant decrease in plasma GFAP levels after intervention using the method described in this invention. This result suggests that time-interference stimulation not only works through electrophysiological pathways but may also alleviate neuroinflammation and exert a long-term neuroprotective effect by regulating the state of astrocytes. In contrast, Comparative Example 2, due to the lack of effective low-frequency envelope modulation, failed to elicit significant electrophysiological or biochemical responses despite the current reaching deep regions, demonstrating the non-obviousness of the combination of interference frequency pairing and repetitive continuous modes.

[0062] In safety testing, the system of this invention demonstrated extremely high robustness. During 300 hours of continuous full-load operation, the frequency drift of the precision signal generation and drive module was less than 0.01Hz, and the constant current source output current fluctuation was less than 0.5%. In an experiment simulating sudden changes in scalp impedance, the system triggered the fuse protection within 8.5ms, fully complying with the engineering requirements related to electrical safety of medical devices.

[0063] In summary, this invention, through complex circuit design, multidimensional image computation, precise timing control, and sensitive closed-loop feedback, successfully solves a long-standing problem in neuroscience: how to achieve precise physical intervention in the hippocampus, a deep brain region of Alzheimer's patients, without invasive procedures. Its components are not simply a collection of hardware, but rather form an organic and highly specialized medical engineering system constrained by strict physical equations and physiological feedback logic. The parameter selection, algorithm model, and implementation process described in this invention are all optimal engineering solutions verified through repeated experiments, possessing a high degree of technical disclosure and reproducibility.

Claims

1. A time-interference stimulation system for treating Alzheimer's disease, characterized in that, The system includes: The multimodal data acquisition module is used to acquire the subject's anatomical data, electrophysiological feedback signals, and brain metabolic data. The individualized simulation navigation module is communicatively connected to the multimodal data acquisition module. It is used to construct a three-dimensional conductivity model of the subject's head based on the anatomical structure data, and to determine the optimal electrode arrangement coordinates for the hippocampus, the target brain region, by calculating the spatial vector distribution of the high-frequency electric field in the brain. The precision signal generation and driving module is connected to the individualized simulation navigation module and the electrode group arranged on the subject's scalp, respectively. It is used to output at least two high-frequency sinusoidal alternating currents with a preset frequency difference according to the optimal electrode arrangement coordinates, so as to generate a low-frequency interference envelope in the hippocampus. A closed-loop feedback control module is connected to the multimodal data acquisition module and the precision signal generation and driving module, respectively, and is used to evaluate the regulatory effect in real time based on the electrophysiological feedback signal and brain metabolism data, and dynamically adjust the output parameters of the precision signal generation and driving module. The precision signal generation and driving module includes a first signal generation unit, a second signal generation unit, and a constant current source driving circuit; the first signal generation unit is configured to output a frequency of The first sinusoidal alternating current, and the second signal generation unit configured to output a frequency of The second sinusoidal alternating current; the constant current source drive circuit is connected between the signal generation unit and the electrode group, and is used to maintain the output current intensity constant within the preset peak-to-peak range when the scalp contact resistance changes dynamically; The stimulation pattern of the system adopts a repetitive continuous mode. Due to the superposition of two high-frequency electric fields in the intracranial space, according to the principle of sum-to-product of trigonometric functions, a low-frequency modulated electric field envelope with a frequency of 6Hz is generated in the bilateral hippocampal regions. The frequency of this envelope is in the theta band, which matches the natural oscillation frequency of the hippocampus during memory encoding, thereby enhancing synaptic plasticity through the phase-locking effect.

2. The time-interference stimulation system for treating Alzheimer's disease according to claim 1, characterized in that, In the precision signal generation and driving module and A 6Hz difference frequency interference envelope is formed; the peak-to-peak range of the output current of the constant current source drive circuit is set to 1mA to 3mA; The constant current source driving circuit includes a high-precision operational amplifier, a power MOSFET, and a precision sampling resistor connected in series in the electrode branch. The non-inverting input of the operational amplifier receives a command voltage signal, and the inverting input is connected to the signal extraction point of the precision sampling resistor. The operational amplifier dynamically adjusts the gate driving voltage of the power MOSFET by comparing the command voltage signal with the voltage drop across the precision sampling resistor in real time, so as to compensate for the fluctuation of the subject's skin electrochemical impedance.

3. The time-interference stimulation system for treating Alzheimer's disease according to claim 1, characterized in that, The specific process for constructing a three-dimensional conductivity model using the individualized simulation navigation module includes: The multimodal data acquisition module acquires the subject's structural magnetic resonance imaging data, and uses T1-weighted images to extract the fine anatomical boundaries of the subject's scalp, skull, cerebrospinal fluid, gray matter, and white matter. A three-dimensional tetrahedral mesh model of the subject's head was constructed using the finite element analysis method, and conductivity parameters were assigned to each tissue. Based on this model, the formula is: Simulate the spatial vector distribution of two sets of high-frequency electric fields within the brain, where Let be the conductivity tensor. It represents the electrical potential.

4. A time-interference stimulation system for treating Alzheimer's disease according to claim 2, characterized in that, The personalized simulation navigation module incorporates an optimization iterative algorithm based on maximizing the interference envelope amplitude. The navigation module iteratively optimizes the placement coordinates of the electrode array within the three-dimensional coordinate system of the subject's scalp, ensuring that the interference envelope amplitude of the two electric fields at the hippocampus is maximized. The mathematical expression for the amplitude of the interference envelope is: ， in, and Positions Two sets of high-frequency electric field vectors at the location.

5. A time-interference stimulation system for treating Alzheimer's disease according to claim 1, characterized in that, The closed-loop feedback control module includes a logic processing unit for receiving physiological feedback signals monitored by the multimodal data acquisition module in real time. The physiological feedback signals include the power spectral density of resting-state electroencephalogram and changes in blood oxygen levels recorded by functional near-infrared spectroscopy. The logic processing unit performs calculations. Variation in frequency band power Assess the immediate effects of neural modulation; like If the response is below the preset response threshold, the closed-loop feedback control module automatically starts the parameter fine-tuning program to adjust the initial phase difference of the output current within ±10% or slightly correct the electrode current ratio.

6. A time-interference stimulation system for treating Alzheimer's disease according to claim 5, characterized in that, The multimodal data acquisition module includes fNIRS probes arranged in a ring in the hippocampal projection area; the fNIRS probes employ dual-wavelength continuous wave technology and apply a modified Beer-Lambert law to calculate the changes in the concentrations of oxyhemoglobin and deoxyhemoglobin in real time. ， in, For the first Light-absorbing substances at wavelength The extinction coefficient, This is due to concentration changes. The closed-loop feedback control module dynamically adjusts the stimulation intensity based on the oscillation amplitude of oxyhemoglobin, maintaining the blood oxygen metabolism level in the hippocampus within the optimal control range.

7. A time-interference stimulation system for treating Alzheimer's disease according to any one of claims 1 to 7, characterized in that, The precision signal generation and driving module also integrates a real-time impedance monitoring and automatic fuse protection mechanism; the system monitors the contact impedance between the electrode group and the subject's scalp in real time. When the contact impedance exceeds 5kΩ, or the system detects that the instantaneous output current exceeds 4mA, the automatic fuse protection mechanism cuts off the current output within 10ms.

8. A time-interference stimulation system for treating Alzheimer's disease according to claim 8, characterized in that, The system also includes an elastic headgear, and the electrode assembly uses biocompatible gel electrodes, which are integrated with the fNIRS probe on the elastic headgear.

9. A time-interference stimulation method for treating Alzheimer's disease using the system described in any one of claims 1 to 8, characterized in that, The method includes the following steps: Step 1, Baseline Multimodal Assessment: Before the intervention is initiated, clinical scale data, structural magnetic resonance imaging data, and long-term resting-state electroencephalogram data of the subjects are collected, and peripheral blood biomarkers of the subjects are detected using high-sensitivity single-molecule immunoassay array technology. Step 2, Customization of individualized intervention plan: Based on the structural MRI data obtained in Step 1, an electric field distribution cloud map is generated through an individualized simulation navigation module to determine the optimal projection coordinates of the subject's bilateral hippocampus, and the gel electrodes are fixed accordingly. Step 3, Apply therapeutic intervention: The precision signal generation and drive module outputs modulated current. During the intervention, the system monitors the subject's heart rate, blood pressure and subcutaneous temperature rise through the real-time vital signs monitoring unit, and dynamically adjusts the stimulation parameters based on real-time physiological signals through the closed-loop feedback control module. Step Four, Efficacy Evaluation and Follow-up Feedback: After the intervention and during the follow-up period, the assessment items in Step One were repeated. A linear mixed-effects model was applied to statistically infer the changes in scale scores, brain network functional connectivity, and blood biomarkers. The statistical formula for the linear mixed-effects model is as follows: ， in, For the first One subject in The scale scores at each time point This represents the intervention effect size.

10. A time-interference stimulation method for treating Alzheimer's disease according to claim 9, characterized in that, The blood biomarkers include the Aβ42 / 40 ratio, p-tau217, NfL, and GFAP concentration.

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