A method for remodeling deep cervical lymph node drainage function by using low intensity focused ultrasound

Abstract

The application discloses a method for remodeling deep cervical lymph node drainage function optimization by using low-intensity focused ultrasound, and relates to the technical field of intelligent medical treatment, and has the technical scheme as follows: collecting multi-source heterogeneous data in an intervention process, and performing pretreatment to obtain pretreated data; taking the pretreated data as a dependent variable, and taking ultrasound intensity, frequency and single action time as independent variables to construct a response surface model; and through systematic traversal and fitting optimization of an experimental parameter space, specific optimal parameter combinations for different pathological stages are obtained. The application strengthens the comprehensive intervention ability in response to the complex pathological mechanism of AD, and improves the treatment effect on AD.

Description

Technical Field

[0001] This invention relates to the field of intelligent medical technology, and more specifically, to a method for optimizing the drainage function of deep cervical lymph nodes by reshaping them using low-intensity focused ultrasound. Background Technology

[0002] Alzheimer's disease (AD) is a common neurodegenerative disease that severely affects cognitive function in the elderly, characterized by high incidence, long course, and heavy burden. Treatment currently primarily involves medication to alleviate symptoms, such as cholinesterase inhibitors (e.g., donepezil, rivastigmine) and NMDA antagonists (e.g., memantine) to improve cognitive function. In addition, non-pharmacological treatments such as cognitive training, physical therapy, and music therapy can also help improve patients' quality of life; however, the effectiveness of these methods varies from person to person and requires long-term adherence to see results.

[0003] Clinical and basic research has confirmed that the pathogenesis of Alzheimer's disease (AD) is closely related to impaired clearance function of the cerebral lymphatic system, especially the accumulation of pathological products such as β-amyloid (Aβ) and Tau protein, which is highly correlated with decreased cerebral-peripheral lymphatic drainage efficiency. Deep cervical lymph nodes, as important drainage terminals of the meningeal lymphatic pathway, play a crucial role in the clearance of pathological metabolites in AD.

[0004] To restore the brain-peripheral lymphatic drainage pathway, current interventions mainly include surgical procedures and non-invasive stimulation techniques. Surgical methods, such as lymphovenous anastomosis (LVA), can significantly improve Aβ clearance efficiency by reconstructing lymphatic-venous connections. However, this procedure is complex, taking an average of 90 to 120 minutes, and requires high tolerance from elderly AD patients. Furthermore, the risk of postoperative complications such as infection and bleeding is high. In addition, approximately 30% of AD patients have structural fibrosis or functional degeneration of the deep cervical lymph nodes due to long-term pathological damage. Even after LVA surgery, drainage efficiency is difficult to restore to the expected level, and postoperative Aβ clearance in the brain is reduced by 40%-60% compared to expectations. In contrast, non-invasive methods such as transcranial low-intensity focused ultrasound (LIFU) stimulation have gained attention in AD treatment in recent years due to their non-invasiveness and high safety. However, this technology is limited by its energy penetration and focusing precision, and is mainly applicable to neuromodulation in superficial brain regions such as the cortex and hippocampus. Its effects on deep structures or the peripheral lymphatic system are limited. Studies have shown that while transcranial LIFU can improve cognitive function to some extent, its effect on clearing Aβ plaques or Tau protein deposits is not significant, often resulting in a disconnect between cognitive and pathological improvements. Furthermore, existing LIFU systems generally focus on intracranial targets and have not yet effectively integrated peripheral immune regulatory pathways, limiting their comprehensive intervention capabilities in addressing the complex pathological mechanisms of Alzheimer's disease (AD).

[0005] In view of this, the present invention proposes a method for optimizing the drainage function of deep cervical lymph nodes by reshaping them using low-intensity focused ultrasound. Summary of the Invention

[0006] This invention proposes a method for optimizing the drainage function of deep cervical lymph nodes by reshaping them using low-intensity focused ultrasound, thereby solving the above-mentioned problems.

[0007] The above-mentioned technical objective of the present invention is achieved through the following technical solution: The first aspect of this invention provides a method for optimizing the drainage function of deep cervical lymph nodes by reshaping them using low-intensity focused ultrasound, comprising the following steps: Collect heterogeneous data from multiple sources during the intervention process and preprocess the data to obtain the preprocessed data; Using the preprocessed data as the dependent variable and the ultrasonic intensity, frequency, and single-action time as independent variables, a response surface model was constructed. By systematically traversing and fitting the experimental parameter space, the optimal combination of parameters specific to different pathological stages is obtained.

[0008] A second aspect of the present invention also provides an apparatus / device / system for reshaping and optimizing the drainage function of deep cervical lymph nodes using low-intensity focused ultrasound, comprising a memory, a processor, and a computer program stored in the memory, wherein the processor executes the computer program to implement the steps of the above method.

[0009] A third aspect of the present invention also provides a computer-readable storage medium having a computer program / instructions stored thereon, which, when executed by a processor, implement the steps of the above-described method.

[0010] A fourth aspect of the present invention also provides a computer program product, including a computer program / instructions that, when executed by a processor, implement the steps of the above-described method.

[0011] Beneficial effects: In summary, this invention, by regulating the stimulation parameters of low-intensity focused ultrasound applied to deep cervical lymph nodes and combining this with the acquisition and analysis of multi-source heterogeneous data, achieves targeted improvement in the drainage function of deep cervical lymph nodes, thereby promoting the clearance of pathological metabolites related to Alzheimer's disease and enhancing the comprehensive intervention capability for the complex pathological mechanisms of Alzheimer's disease. Simultaneously, this invention employs a non-invasive stimulation method, avoiding the risks associated with surgery and improving the safety and applicability of the intervention process. Attached Figure Description

[0012] Figure 1 This is a schematic diagram of the positioning and coupling component structure in Embodiment 1 of the present invention.

[0013] In the diagram: 1. Base; 2. Bracket; 3. Cross clamp; 4. Iron clamp; 5. Cable for fixing transducer; 6. Focused ultrasonic transducer; 7. Ultrasonic coupling agent; 8. Mold. Detailed Implementation

[0014] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0015] Example 1: The focused ultrasound transducer is precisely positioned at the deep cervical lymph node site, and the positioning and coupling components are as follows: Figure 1 As shown.

[0016] The support structure consists of a base 1, a bracket 2, a cross clamp 3, and an iron clamp 4. The cross clamp can be adjusted in height and angle on the bracket via a knob for multi-dimensional fine-tuning. The iron clamp is connected to the bracket via the cross clamp to secure the transducer cable 5. The focused ultrasonic transducer 6 is held by the iron clamp, and its emitting surface is connected to a 3D-printed custom mold 8 via an ultrasonic coupling agent 7. This mold is mainly used to load and fix the ultrasonic coupling agent, providing a stable and consistent medium environment for the propagation of ultrasonic waves, effectively improving sound wave transmission efficiency and reducing sound energy reflection and loss at the interface.

[0017] The location of the target lymph node is initially determined based on cervical anatomical landmarks. Then, a high-frequency ultrasound probe (e.g., 30 MHz) is used for real-time image guidance to precisely image the target area, which is then marked with a marker. With image assistance, the angle and height of the cross clamp on the support are adjusted to ensure the focused ultrasound transducer is accurately aligned with the central region of the target lymph node, ensuring that the sound beam energy is focused on the desired stimulation site.

[0018] The fixed and positioned focused ultrasound transducer is connected to the LIFU control device via a cable. The LIFU control device is used to precisely drive and adjust the parameters of the transducer, ensuring that the acoustic energy output meets the treatment or stimulation requirements. The LIFU control device includes the following modules: signal generation and amplification module, parameter adjustment module, human-machine interface module, data recording and export module, and power supply module.

[0019] The signal generation and amplification module is used to generate excitation signals with specific frequencies, waveforms, duty cycles, and pulse modes, and amplifies the signals through an amplifier to drive the transducer to transmit stably.

[0020] The parameter adjustment module is used to set and adjust LIFU output parameters, including center frequency, power density, waveform type (continuous wave / pulse wave), pulse repetition frequency, duty cycle, total action time, etc. It supports preset schemes and personalized settings to meet the differentiated needs of research or treatment.

[0021] The human-computer interaction module provides an intuitive user interface via a touchscreen and supports the following functions: real-time display of current parameters and device operating status, start / pause / terminate stimulation process, alarm prompts and interactive feedback (such as connection status, output abnormality, parameter over-limit, etc.).

[0022] The data recording and export module records parameters, operation logs, and fault prompts for each ultrasound stimulation process. It supports data export via USB for easy subsequent analysis and traceability.

[0023] The power supply module provides a stable multi-channel DC voltage output for the entire system and has overvoltage, overcurrent and short-circuit protection functions to ensure operational safety.

[0024] After connection is established, users can configure various parameters through the human-computer interaction module. Once the settings are complete, the system enters standby mode, ready to execute subsequent ultrasound stimulation tasks. After confirming that all parameter settings are correct, users can choose to save the settings for future reuse.

[0025] The user initiates the stimulation program via the human-computer interaction module to implement LIFU treatment. This stage delivers ultrasound energy to the target deep cervical lymph node region in a highly precise and controllable manner to regulate its drainage function and thus improve the pathological state of Alzheimer's disease (AD). The entire treatment process strictly adheres to the set parameters. The LIFU control device activates the signal generation and amplification module according to preset parameters, driving the focused ultrasound transducer to emit ultrasound signals. The ultrasound waves are focused and transmitted to the deep cervical lymph node region through a coupling agent and a 3D-printed mold. The touchscreen displays parameters such as the output time countdown and cumulative energy value in real time. After the set treatment time is reached, the system automatically stops output and prompts "Treatment complete."

[0026] Focused ultrasound waves act on lymph nodes, producing multiple mechanistic effects: mechanical effects, where sound pressure waves activate the Piezo1 and TRPV4 mechanosensitive channels, triggering calcium ion influx, regulating macrophage activity, and promoting dendritic cell maturation and antigen presentation; thermal effects, inducing the expression of heat shock proteins HSP70 and HSP90, activating cell repair and metabolic pathways; cavitation effects, where low-intensity steady-state cavitation forms a microfluidic force field, enhancing lymphatic microcirculation; simulated lymphatic pump effects, where periodic sound wave vibrations enhance the frequency and amplitude of lymphatic vessel contraction; and shear force effects, activating endothelial function and increasing lymphatic fluid transport flux.

[0027] Treatment cycle control: once a day, 5 days as one cycle, record the dynamic changes of lymphatic drainage 24 hours, 72 hours and 1 week after intervention.

[0028] After completing the LIFU treatment cycle, the intervention effect was comprehensively evaluated using multidimensional and multimodal detection methods, including changes in deep cervical lymph node drainage function and improvements in Alzheimer's disease-related pathological indicators in the brain. This step aims to verify the regulatory effect of LIFU stimulation on deep cervical lymph node function and further explore its potential impact on brain metabolism, immunity, and cognitive status.

[0029] In assessing changes in lymphatic drainage function, indocyanine green (ICG) near-infrared fluorescence tracing was used. ICG (0.5–2 mg / kg) was injected via the tail vein, and the staining process of lymphatic vessels was observed in real-time using a near-infrared fluorescence microscope. The time to initial visualization of lymph nodes was recorded. Key time parameters such as time to peak fluorescence intensity (TTP) and peak intensity (IMAX) were measured, and the continuity and uniformity of lymphatic vessel imaging were observed. The effects of LIFU stimulation on lymph flow rate and pathway patency were dynamically quantified to determine whether the function of deep cervical lymph nodes was enhanced.

[0030] In assessing the improvement of Alzheimer's disease-related pathological markers in the brain, cerebrospinal fluid samples were collected via cerebral puncture and analyzed using ELISA. and Content, and calculate The ratio, combined with mass spectrometry analysis, is used for evaluation. Metabolomic profiles were analyzed to reveal whether LIFU promotes Aβ clearance in the brain. In assessing neuroimmune status, changes in mRNA expression of hippocampal inflammation-related factors IL-1β, TNF-α, and IL-10 were detected using real-time quantitative PCR (qPCR). Western blot analysis was used to analyze the expression levels and polarity shifts of microglial activation markers (such as Iba-1 and CD68) to determine whether LIFU modulates the brain's immune microenvironment through the distal lymphatic system.

[0031] In the behavioral dynamic assessment, the Morris water maze test was used to test the spatial learning and memory abilities of the test animals, record the escape latency and the time spent in the target quadrant, and calculate the spatial memory index (SMI); the discrimination index (DI) was measured through the new object recognition test (NOR) to reflect the individual's perception and short-term memory level.

[0032] Optimize ultrasound output parameters to improve the effectiveness and stability of LIFU intervention.

[0033] First, the multi-source heterogeneous data collected during the intervention were preprocessed uniformly. Z-score normalization was used to analyze lymphatic flow velocity, Multidimensional indicators such as ratios and inflammatory factor expression levels were normalized to eliminate bias caused by differences in the units of different indicators. Subsequently, principal component analysis (PCA) was used for dimensionality reduction, aggregating representative variables into several principal components to reduce model complexity while maintaining information integrity. Specifically, indicators related to lymphatic flow rate and Aβ clearance rate were classified as the first principal component (PC1), and indicators related to inflammatory factors were classified as the second principal component (PC2), constructing a low-dimensional feature space reflecting the biological effects of the intervention.

[0034] Parametric modeling was used to model key response variables of LIFU intervention (including lymph flow rate increase, etc.). Using the increase in the ratio and the degree of improvement in cognitive behavior as dependent variables, and ultrasound intensity, frequency, and duration of a single application as independent variables, a response surface model (RSM) is constructed. This model is based on a quadratic polynomial regression equation: Wherein, Y is the efficacy response variable, used to characterize the effect of low-intensity focused ultrasound on the drainage function of deep cervical lymph nodes and the improvement of Alzheimer's disease-related pathology, specifically including but not limited to: 1) Lymphatic fluid flow rate increase rate; 2) In lymph nodes or peripheral blood The range of change in the ratio; 3) The degree of improvement in cognitive behavioral test indicators.

[0035] For parameters that are independent variables in ultrasound intervention, at least the following should be included: 1) Ultrasonic intensity; 2) Ultrasonic operating frequency; 3) : Duration of a single action.

[0036] For constant terms, These represent the main effect coefficient, interaction effect coefficient, and second-order nonlinear effect coefficient for each parameter, respectively.

[0037] By designing multi-level combined experiments on the above parameter space and fitting the response surface model based on experimental data, specific optimal combinations of ultrasound stimulation parameters for different pathological stages or individual conditions can be obtained to guide the precise control of deep cervical lymph nodes.

[0038] Example 2: The present invention also provides a device / equipment / system for optimizing the drainage function of deep cervical lymph nodes by using low-intensity focused ultrasound, comprising a memory, a processor, and a computer program stored in the memory, characterized in that the processor executes the computer program to implement the steps of the above method.

[0039] The present invention also provides a computer-readable storage medium having a computer program / instructions stored thereon, which, when executed by a processor, implement the steps of the above-described method.

[0040] The present invention also provides a computer program product, including a computer program / instructions that, when executed by a processor, implement the steps of the above-described method.

[0041] Finally, it should be noted that the above descriptions are merely preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for optimizing the drainage function of deep cervical lymph nodes by reshaping using low-intensity focused ultrasound, characterized by: Collect heterogeneous data from multiple sources during the intervention process and preprocess the data to obtain the preprocessed data; Using the preprocessed data as the dependent variable and the ultrasonic intensity, frequency, and single-action time as independent variables, a response surface model was constructed. By systematically traversing and fitting the experimental parameter space, the optimal combination of parameters specific to different pathological stages is obtained.

2. The optimization method according to claim 1, characterized in that: The multi-source heterogeneous data includes lymph flow rate, The ratio, the level of expression of inflammatory factors, and the degree of improvement in cognitive behavior.

3. The optimization method according to claim 1, characterized in that: The preprocessing includes dimensionality normalization and dimensionality reduction.

4. The optimization method according to claim 1, characterized in that: The response surface model is: Where Y is the therapeutic response variable, For constant terms, These represent the main effect coefficient, interaction effect coefficient, and second-order nonlinear effect coefficient for each parameter, respectively.

5. A device / equipment / system for optimizing the drainage function of deep cervical lymph nodes by reshaping using low-intensity focused ultrasound, comprising a memory, a processor, and a computer program stored in the memory, characterized in that, The processor executes the computer program to implement the steps of the method according to any one of claims 1-4.

6. A computer-readable storage medium having a computer program / instructions stored thereon, characterized in that, When the computer program / instructions are executed by the processor, they implement the steps of the method described in any of claims 1-4.

7. A computer program product comprising a computer program / instructions, characterized in that, When the computer program / instructions are executed by the processor, they implement the steps of the method described in any of claims 1-4.

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