Nuclear magnetic resonance compatible time interference neuromodulation system based on magnetic resonance BOLD signal feedback

Abstract

This application discloses a magnetic resonance-compatible time-interference neuromodulation system, comprising: an image acquisition module for acquiring structural magnetic resonance (SMR) images and functional magnetic resonance (fMRI) images; a localization simulation module for analyzing SMR images to determine the target brain region and construct a brain model, calculating an initial stimulation parameter set based on the brain model and initial stimulation commands, and updating the stimulation parameter set based on stimulation commands; an analysis module for analyzing fMRI images to obtain functional state determination results and spatial consistency determination results; an electrical stimulation module for receiving the initial stimulation parameter set and initial stimulation commands to output a time-interference electrical stimulation signal, and receiving stimulation commands to adjust the time-interference electrical stimulation signal; and a control module for generating the initial stimulation commands and generating stimulation commands based on the functional state determination results and spatial consistency determination results. The system provides highly real-time, multi-index closed-loop modulation of time-interference electrical stimulation, highly adaptable to clinical intervention and laboratory research tasks related to brain region modulation.

Description

Technical Field

[0001] This application belongs to the field of neuromodulation technology, specifically relating to a nuclear magnetic resonance compatible time-interference neuromodulation system and method based on magnetic resonance BOLD signal feedback. Background Technology

[0002] Brain activity modulation techniques can improve or reshape neural functions such as cognitive function, emotional state, and level of consciousness. Among them, non-invasive brain stimulation techniques have advantages such as high safety, strong repeatability, and wide applicability. These include transcranial direct current stimulation, transcranial alternating current stimulation, and transcranial magnetic stimulation, which typically modulate the excitability of cortical neurons by applying an electric or magnetic field to the scalp surface. However, due to the attenuation and diffusion effects of electromagnetic signals by tissues such as the scalp, skull, and cerebrospinal fluid, the stimulation intensity of deep brain regions is insufficient and the spatial resolution is limited. Furthermore, existing non-invasive deep brain stimulation techniques have poor targeting, making it difficult to achieve precise intervention in deep regions such as the hippocampus and thalamus.

[0003] Temporal interference (TI) electrical stimulation modulates deep brain regions by applying at least two alternating current signals with different high-frequency carrier frequencies to the scalp surface, creating a low-frequency modulated equivalent electric field within the brain tissue. This allows for the modulation of deep brain regions without significantly stimulating superficial brain areas. Compared to traditional methods, TI electrical stimulation offers advantages in terms of deep targeting and safety.

[0004] Existing TI (Transducer's Induction) electrical stimulation systems mostly employ an open-loop mode, with stimulation parameters typically preset based on experience or offline brain modeling results. This lack of dynamic perception and feedback regulation of the subject's real-time brain functional state is problematic. In practical applications, significant differences exist among individuals in anatomical structure, baseline brain function, and stimulation sensitivity. Offline stimulation parameters struggle to adapt to the changing neural activity characteristics between and within individuals over time, and the stimulation area may shift over time, leading to unstable stimulation effects and even unexpected neuromodulation results. Summary of the Invention

[0005] The purpose of this application is to provide a magnetic resonance compatible time-interference neuromodulation system that solves one or more of the above-mentioned problems. The system consists of an image acquisition module that acquires two types of magnetic resonance images, a localization simulation module and an analysis module that analyze the two types of magnetic resonance images respectively to determine the stimulation parameter set required for TI electrical stimulation and the functional state judgment result and spatial consistency judgment result required for dynamically adjusting TI electrical stimulation during the intervention process. The control module coordinates the localization simulation module and the analysis module to control the electrical stimulation module to provide precise and stable TI electrical stimulation to the target brain region of the subject according to the preset initial stimulation parameter set and the real-time updated stimulation parameter set. The system uses a low-frequency envelope interference electric field to support the intervention of the target brain region to improve symptoms.

[0006] Specifically, this application relates to the following aspects: A magnetic resonance imaging (MRI) compatible temporal interference neuromodulation system includes: an image acquisition module for acquiring structural MRI and functional MRI images; a localization simulation module for analyzing structural MRI images to determine the target brain region and construct a brain model, calculating an initial stimulation parameter set based on the brain model and initial stimulation commands, or updating the stimulation parameter set based on stimulation commands; an analysis module for analyzing functional MRI images to calculate baseline BOLD and stimulation BOLD signals, and analyzing the baseline and stimulation BOLD signals to obtain functional state determination results and spatial consistency determination results; an electrical stimulation module for receiving the initial stimulation parameter set and initial stimulation commands to output a temporal interference electrical stimulation signal, and receiving stimulation commands to adjust the temporal interference electrical stimulation signal; and a control module for receiving the baseline BOLD signal to generate an initial stimulation command, and receiving the functional state determination results and spatial consistency determination results to generate stimulation commands.

[0007] According to some implementation methods, the analysis module analyzes the baseline BOLD signal and the stimulus BOLD signal to obtain the functional state determination result and the spatial consistency determination result, including: the analysis module performs activation analysis on the stimulus BOLD signal, generates a brain activation statistical map, extracts the bright signal region to determine the activation peak coordinates, and calculates the activation centroid coordinates and activation volume; the analysis module calculates the real-time distance value and / or temporal distance value between the activation centroid coordinates or activation peak coordinates and the center coordinates of the target brain region to obtain the spatial offset, and uses the spatial offset as the spatial consistency determination result.

[0008] According to some implementation methods, the analysis module analyzes the baseline BOLD signal and the stimulus BOLD signal to obtain the functional state determination result and the spatial consistency determination result, including: the analysis module uses the baseline BOLD signal and the stimulus BOLD signal to calculate the preset functional index range and the real-time functional index that characterize the state of neural activity; the analysis module calculates the real-time deviation value of neural activity and / or the temporal deviation value of neural activity that the real-time functional index deviates from the preset functional index range, as the functional state determination result.

[0009] According to some implementation methods, the control module receives the functional state determination result and the spatial consistency determination result to generate a stimulation instruction, including: the control module responding to the real-time deviation value of neural activity being non-zero, and setting the stimulation instruction to adjust the stimulation parameter group to change the modulation electric field intensity when the spatial consistency determination result does not exceed a preset spatial threshold; the control module responding to the real-time deviation value of neural activity being non-zero, and setting the stimulation instruction to adjust the stimulation parameter group to change the modulation focus position of the modulation electric field or modify one or more stimulation parameters in the stimulation parameter group when the spatial consistency determination result exceeds a preset spatial threshold.

[0010] According to some implementation methods, the control module receives the functional state determination result and the spatial consistency determination result to generate a stimulation instruction, including: the control module responds to the neural activity timing deviation value moving away from the preset functional index range, and sets the stimulation instruction to correct one or more stimulation parameters in the stimulation parameter group.

[0011] According to some implementation methods, setting a stimulation instruction to change the modulation focus position of the modulation electric field or update the stimulation parameter group when the spatial consistency determination result is higher than a preset spatial threshold includes: the control module responding to the spatial consistency determination result exceeding the preset spatial threshold by setting a stimulation instruction to adjust the stimulation parameter group to change the modulation focus position of the modulation electric field; and the control module responding to the spatial consistency determination result continuously exceeding the preset spatial threshold by setting a stimulation instruction to correct one or more stimulation parameters in the stimulation parameter group.

[0012] According to some implementations, the MRI-compatible time-interference neuromodulation system further includes an MRI-compatible module, which includes an MRI-compatible adapter unit and an electrode interface unit. The MRI-compatible adapter unit processes the time-interference electrical stimulation signal output by the electrical stimulation module to make the time-interference electrical stimulation signal compatible with the working environment of the magnetic resonance imaging device. The electrode interface unit applies the processed time-interference electrical stimulation signal to the scalp surface of the subject through electrodes based on the initial stimulation parameter set or stimulation parameter set.

[0013] According to some implementation methods, the NMR compatibility adapter unit processes the time-interference electrical stimulation signal output by the electrical stimulation module by performing radio frequency interference suppression, electrical isolation and / or impedance matching on the time-interference electrical stimulation signal to eliminate interference between the magnetic resonance imaging device and the time-interference electrical stimulation signal.

[0014] According to some implementation methods, the initial stimulation parameter set and the stimulation parameters in the stimulation parameter set include: stimulation current intensity, carrier frequency, carrier frequency difference, stimulation current ratio and / or electrode placement; real-time functional indicators include: low-frequency amplitude, local consistency, functional connectivity strength and / or average variation amplitude of BOLD signal.

[0015] According to some implementations, the electrical stimulation module includes a stimulation signal generation unit and a stimulation mode control unit; the stimulation signal generation unit generates at least two time-interference electrical stimulation signals based on an initial stimulation mode command, and adjusts at least two time-interference electrical stimulation signals based on the stimulation mode command; the stimulation mode control unit receives an initial stimulation parameter set and an initial stimulation command to generate an initial stimulation mode command, and receives a stimulation parameter set and a stimulation command to generate a stimulation mode command.

[0016] The technical advantages of the NMR-compatible time-interference neuromodulation system disclosed in this application include: The system utilizes image information to construct individualized brain models of subjects. Combining these models with electric field simulation, it optimizes stimulation parameters, ensuring high focus of low-frequency envelope-modulated electric fields in the target brain region and improving the spatial selectivity of TI electrical stimulation. During electrical stimulation, the system acquires image information and establishes a feedback mechanism through index extraction and calculation. It performs joint judgments of functional convergence analysis and spatial consistency analysis to determine the adjustment direction of the stimulation parameter set, thereby improving the accuracy and real-time performance of deep brain region modulation. Furthermore, the system provides MRI compatibility, enabling stable output of electrical stimulation signals in a magnetic resonance imaging environment while avoiding interference with the imaging process, thus achieving integrated operation of TI electrical stimulation and real-time imaging feedback. Through this real-time feedback and simulation recalculation adjustment mechanism, the system can adaptively optimize stimulation parameters in a closed-loop manner based on the dynamic changes in each subject's brain structure and functional state (lacking prior knowledge), improving the consistency and safety of the modulation effect on the target brain region. Attached Figure Description

[0017] Figure 1 The figure shows a structural block diagram of an NMR-compatible time-interference neuromodulation system according to an embodiment of this application.

[0018] Figure 2 The illustration shows a flowchart of the use of the MRI-compatible time-interference neuromodulation system according to an embodiment of this application.

[0019] Figure 3 The figure shows a schematic diagram of an NMR compatibility module according to an embodiment of this application.

[0020] Figure 4 The figure illustrates a schematic diagram of the analysis module analyzing the BOLD signal according to an embodiment of this application.

[0021] Figure 5 The illustration shows a schematic diagram of the intervention effect of the MRI-compatible time-interference neuromodulation system according to an embodiment of this application. Detailed Implementation

[0022] The present application is further illustrated below with reference to embodiments. It should be understood that the embodiments are only used to further illustrate and explain the present application and are not intended to limit the present application.

[0023] Unless otherwise defined, technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. While similar or identical methods and materials may be applied in experimental or practical applications, materials and methods are described herein. In case of conflict, the definitions included herein shall prevail. Furthermore, materials, methods, and examples are for illustrative purposes only and are not intended to be limiting. The present application is further described below with reference to specific embodiments, but is not intended to limit the scope of the application.

[0024] Application Overview As mentioned above, existing TI (Transduction and Stimulation) technologies suffer from insufficient ability to adjust stimulation parameters and maintain sustained focus on stimulation targets when providing deep brain intervention, which affects their effectiveness in tasks involving the regulation of brain activity. Open-loop TI stimulation modulation systems perform poorly in patients exhibiting significant individual differences in psychiatric symptoms, requiring physicians to work with researchers to periodically determine the adjustment plan for their stimulation parameters. Alternatively, the system itself could provide corresponding initial adjustments based on the characteristics of the neural signals exhibited by the patient during stimulation. For example, it could determine the polarity of the stimulation current by judging the overexcitation or abnormal response of the target brain region, thus initially adapting to the specific neural characteristics exhibited by the patient throughout the intervention period. For instance, patent CN120617817B determines the required polarity of the stimulation based on the BOLD signal.

[0025] In actual intervention, existing TI (Transient Induction) electrical stimulation techniques suffer from insufficient real-time performance and limited effectiveness. For example, the polarity of the stimulation current is not the only parameter required to control the direction of TI stimulation, and the real-time capabilities provided by analyzing the patient's neural characteristics after each stimulation session are also limited. Therefore, it is necessary to explore a scheme that utilizes appropriate brain data to determine a better set of parameters for the patient's electrical stimulation pattern and execute corresponding modulation, while further overcoming the real-time problems of parameter set optimization and electrical stimulation modulation while avoiding interference with the collection of patient brain data.

[0026] To address the aforementioned issues, this application provides a magnetic resonance-compatible time-interference neuromodulation system. This system integrates real-time analysis of BOLD signals from structural and functional magnetic resonance imaging (fMRI) with time-interference electrical stimulation (TI) techniques within a magnetic resonance imaging (MRI) environment to construct a dual-closed-loop neuromodulation mechanism encompassing functional modulation and spatial stimulation. The system's localization simulation module determines the target brain region location based on structural MRI images acquired by the image acquisition module and establishes an individual-based brain model to simulate and optimize the distribution of the low-frequency envelope modulation electric field of TI electrical stimulation, obtaining an initial set of stimulation parameters. During stimulation, the system simultaneously acquires fMRI images and uses an analysis module to analyze the BOLD signals of the target brain region, extracting real-time functional indicators to analyze the activation spatial distribution of TI electrical stimulation in the subject's brain, determining whether neural activity converges to a preset reference indicator range and whether the activation location of TI electrical stimulation is consistent with or deviates from the preset target brain region.

[0027] In this way, the system dynamically adjusts electrical stimulation parameters such as stimulation intensity, carrier frequency, frequency difference, and current ratio based on real-time judgment results of electrical stimulation on the subject. When necessary, it re-simulates using a positioning simulation module to determine a new set of stimulation parameters, achieving adaptive optimization and control. The system also features MRI compatibility, ensuring the safe and coordinated operation of TI electrical stimulation and MRI, improving the accuracy of deep brain region stimulation while overcoming the limitations of real-time data acquisition and electrical stimulation control.

[0028] After introducing the basic principles and advantages of this application, various non-limiting embodiments of this application will be described in detail below with reference to the accompanying drawings.

[0029] Exemplary System Figure 1 The figure shows a schematic block diagram of a magnetic resonance-compatible time-interference neuromodulation system according to an embodiment of this application. Figure 2 The illustration shows a flowchart of the complete process of implementing closed-loop TI electrical stimulation using an MRI-compatible time-interference neuromodulation system according to an embodiment of this application.

[0030] refer to Figure 1 The following will describe the components included in the MRI-compatible time-interference neuromodulation system according to embodiments of this application, and in conjunction with... Figure 2 This application describes in detail the use of each component of the MRI-compatible time-interference neural modulation system according to embodiments of the present application, and the functions achieved by the coordinated use of the components.

[0031] The image acquisition module is used to acquire structural and functional MRI images of subjects in a magnetic resonance imaging (MRI) environment. During the structural imaging stage, this module acquires the anatomical information of the subject's head from the structural MRI images to construct an individualized finite element brain model of the subject and determine the coordinate location of the target brain region to be stimulated in the brain model.

[0032] During the functional imaging phase, the module acquires functional MRI images of the subjects before TI electrical stimulation is applied and extracts the baseline BOLD signal in the images at the baseline state. This baseline BOLD signal is used to establish an individualized functional reference interval as the subject's preset functional index interval. Furthermore, during TI electrical stimulation, the module continuously acquires functional MRI images of the subjects and extracts the stimulation BOLD signal in the images at the stimulation state to form a stimulation BOLD signal sequence. This stimulation BOLD signal sequence will be used for subsequent TI electrical stimulation effect analysis, where each real-time functional index and its temporal changes are used to assess the functional modulation effect and spatial consistency effect of the electrical stimulation module. The image acquisition module outputs the acquired structural MRI images to the localization simulation module and the functional MRI images to the analysis module.

[0033] In one example, the image acquisition module has a network interface that allows it to connect to the local area network of a clinical MRI system or device to receive images. The image acquisition module has local storage or communicates with a server to receive scan sequences / image sets pushed by the MRI system or device, or to query and retrieve scan sequences / image sets from the MRI system or device. The image acquisition module also has a server-side component, which includes a processor for parsing the scan sequences / image sets, typically parsing DICOM format scan sequence / image set data streams to extract metadata and image pixel data as image data; the processor converts this data into an input format for the analysis model, such as NIFTI format, to output data to the localization simulation module and the analysis module, respectively.

[0034] The localization simulation module analyzes structural magnetic resonance images to determine the extent of the target brain region and construct a brain model. Based on the brain model and initial stimulation commands, it calculates an initial set of stimulation parameters or updates the stimulation parameter set according to the stimulation commands. The localization simulation module uses structural MRI images to build a finite element brain model of the subject, and on this basis, determines the location range of the target brain region to be stimulated within the brain model. Receiving the initial stimulation command, the localization simulation module performs TI electric field simulation on the brain model using two electrodes to a single stimulation target point and / or multiple electrodes to multiple stimulation targets. This allows it to calculate and optimize the set of stimulation parameters required for TI electrical stimulation, generating an initial set of stimulation parameters that matches the spatial location of the target brain region. This parameter set includes stimulation current intensity, carrier frequency, carrier frequency difference, stimulation current ratio, and / or electrode placement.

[0035] In one example, the localization simulation module segments and measures the volume of structural MRI image data in a processable format provided by the image acquisition module. Based on the structural MRI image data, it determines the region of interest (ROI) of the target brain region to be stimulated and records its spatial coordinates and center position. The localization simulation module constructs a finite element brain model based on the processed data. Within the brain model, it performs electric field distribution simulation analysis on combinations of different electrical stimulation parameters. Through parameter optimization algorithms, it optimizes the stimulation current intensity, stimulation current ratio, carrier frequency, frequency difference between carriers, and the electrode placement on the scalp, converging the simulation results towards the target brain region to achieve maximum modulation electric field intensity and / or maximum spatial focus. The optimized stimulation parameter set is sent by the localization simulation module to the electrical stimulation module as the initial stimulation parameter set. When the control module issues a stimulation command, the localization simulation module re-optimizes one or more stimulation parameters based on the functional state and / or spatial activation distribution of the current subject as contained in the stimulation command, using electric field simulation to generate a new stimulation parameter set to improve the subject's functional state and / or the focus of the TI envelope modulation electric field in the target brain region.

[0036] Specifically, the localization simulation module can be configured to target different brain regions in different application scenarios. In one example, the localization simulation module can select a specific target brain region according to the research or intervention needs. For example, in applications related to Alzheimer's disease brain function research or intervention, the localization simulation module can set the target brain region to the hippocampus or its subregions, and in applications related to consciousness state regulation research or intervention, it can set the target brain region to the amygdala or other deep brain regions.

[0037] The analysis module analyzes functional magnetic resonance imaging (fMRI) images to calculate baseline BOLD and stimulation BOLD signals. It then analyzes these signals to obtain functional state and spatial consistency assessment results. Through functional state and spatial consistency analysis, the analysis module determines the implementation effect or cumulative effect of TI electrical stimulation on the subject. The analysis results are output to the control module for generating stimulation commands, supporting the closed-loop neural modulation process of the system.

[0038] Specifically, for functional state analysis, the analysis module acquires the BOLD signal within the target brain region's region of interest (ROI) from the functional MRI image data provided by the image acquisition module and performs preprocessing. This preprocessing includes time correction, head movement correction, noise reduction, and frequency domain filtering steps. Based on the processed signal, it calculates multiple functional indicators characterizing the neural activity state. In one example, functional indicators may include one or more of the following: amplitude of low-frequency response (ALFF), local consistency (ReHo), functional connectivity strength, and amplitude of BOLD signal variation (preferably average amplitude of BOLD signal variation). The analysis module first calculates the initial functional indicators corresponding to the baseline BOLD signal and sends them to the control module. The control module generates initial control commands to determine the direction of regulation of the target brain region. For example, it may be necessary to generate an initial set of stimulation parameters for activating the target brain region or an initial set of stimulation parameters for inhibiting abnormal excitatory activity in the target brain region.

[0039] During the process of providing TI electrical stimulation to the subject, the analysis module compares the real-time functional indicators calculated based on the stimulation BOLD signal with the preset functional indicator reference range set by medical personnel in the system to determine the deviation of the subject's current neural activity state from the reference range. The preset functional indicator reference range is the range of normal neural activity state indicators that medical personnel expect the subject to reach or approach after TI electrical stimulation intervention. In one example, the preset functional indicator reference range can be determined based on the range of functional indicator values ​​for healthy individuals.

[0040] When the real-time functional index is below the lower limit of the reference interval, the analysis module determines that the target brain region is in a state of insufficient neural activity and generates an excitatory stimulus instruction. This instruction is used to cause the localization simulation module to re-simulate and determine the stimulus parameter set to activate the target brain region and increase its excitability. When the real-time functional index is above the upper limit of the reference interval, the analysis module determines that the target brain region is in a state of overactive neural activity and generates an inhibitory stimulus instruction. This instruction is used to cause the localization simulation module to re-simulate and determine the stimulus parameter set to inhibit the target brain region and reduce its excitability. When the real-time functional index falls within the reference interval or shows a temporal trend of continuous convergence towards the reference interval as determined by temporal analysis, it is determined that the functional state is stabilizing or the regulation is effective, and the stimulus instruction remains unchanged.

[0041] For spatial consistency analysis, the analysis module acquires the stimulation BOLD signal within the target brain region's ROI from functional MRI image data provided by the image acquisition module during TI electrical stimulation to perform spatial activation analysis. In one example, spatial activation analysis includes generating a brain activation statistical map of the subject under TI electrical stimulation using a general linear model based on the stimulation BOLD signal, extracting the highlighted signal region in the map to determine the activation peak coordinates, and simultaneously calculating the activation centroid coordinates and activation volume. The activation centroid coordinates and activation volume are used to assess the activation center and activation range of TI electrical stimulation at the target brain region, respectively. The brain activation statistical map confirms whether the activation peak coordinates are located on the coordinates of the target brain region. The coordinates of the target brain region can be determined, for example, by applying an existing neuronavigation system to the subject, including the target brain region center coordinates, target brain region edge coordinates, etc. Subsequently, in one example, the analysis module calculates the real-time spatial distance between the activation centroid coordinates / activation peak coordinates and the target brain region center coordinates. This distance is used as the spatial offset between the TI electrical stimulation activation region and the target brain region, serving as a basis for spatial consistency judgment. The analysis module can also calculate the temporal value of the spatial distance between the activation centroid coordinates / activation peak coordinates and the target brain region center coordinates as an additional spatial offset. In addition, in other examples, the analysis module can also calculate the average distance between the activation volume and the center coordinates of the target brain region, the average distance between the activation volume and the edge coordinates of the target brain region, or the degree of overlap between the activation volume and the target brain region volume represented by the edge coordinates of the target brain region, as spatial offsets, and the temporal values ​​of these values ​​as additional spatial offsets.

[0042] Spatial offset reflects the degree of deviation of the activated region of TI electrical stimulation relative to the target brain region. For different subjects, the activated region and its degree of offset produced by TI electrical stimulation under the initial stimulation parameter set may vary significantly. This depends on the individual's actual deep brain matching with the simulation, brain neural structure, differences in brain neural activity, etc. Medical personnel cannot accurately judge based on prior clinical knowledge to implement open-loop adjustment of stimulation parameters. When the spatial offset is less than or equal to the preset spatial threshold configured for the analysis module, the analysis module determines that the activated region of TI electrical stimulation is spatially consistent with or highly overlaps with the target brain region, and the envelope modulation electric field has high focus and effectively covers the target brain region. When the spatial offset is greater than the preset spatial threshold, the analysis module determines that the current activated region has a spatial offset relative to the target brain region, and the envelope modulation electric field has low focus. This offset will reduce the intervention effect and may also have adverse effects on surrounding brain regions. The analysis module sends the spatial consistency determination result to the control module, which generates a spatial adjustment stimulation command to enable the localization simulation module to adjust the stimulation parameter set and improve the focus of the envelope modulation electric field on the target brain region.

[0043] In this way, the analysis module outputs the functional state determination results and spatial consistency determination results to the control module. The control module generates corresponding excitatory stimulation instructions, inhibitory stimulation instructions, and / or spatial regulation stimulation instructions, and sends them to the localization simulation module and the electrical stimulation module. The localization simulation module updates the stimulation parameter set according to the instructions and sends it to the electrical stimulation module. The electrical stimulation module adjusts the TI electrical stimulation signal output to the subject based on the new stimulation parameter set and corresponding instructions. For example, by changing the stimulation current intensity, carrier frequency, carrier frequency difference, and / or stimulation current ratio, it can provide targeted excitatory stimulation, inhibitory stimulation, or an alternating combination of the two to improve the value of real-time functional indicators, and / or change the electrode placement to correct the activation area to focus on the target brain region and overlap it as possible.

[0044] Typically, real-time functional indicators of the target brain region and the focus of the activated region toward the target brain region can be considered and improved simultaneously. However, in more complex real-world tasks, due to the different locations and neurophysiological characteristics of target brain regions, changing the intensity, frequency, and / or ratio of the current can help TI electrical stimulation be more focused on the target brain region, but this may negatively impact the intervention effect on the functional state of the target brain region. Therefore, in one example, the control module can, according to its preset configuration, increase the priority of one of the functional state determination results and the spatial consistency determination results, to prioritize either the improvement of the functional state of the target brain region or the high focus of the activated region on the target brain region, thereby achieving different TI electrical stimulation goals.

[0045] The control module receives the baseline BOLD signal to generate the initial stimulation command, and receives the functional state determination result and spatial consistency determination result to generate the stimulation command. The control module is the core decision-making component of the system. It continuously updates the stimulation mode of the electrical stimulation module based on real-time acquired image data to adjust the system's intervention effect on the target brain region of the subject and / or spatial focus, thereby achieving precise two-factor closed-loop control and regulation.

[0046] Specifically, during the system's startup phase, the control module determines the initial stimulation direction and initial stimulation parameter set based on the analysis results of the analysis module's assessment of the subject's baseline neural activity. When the analysis module determines that the neural activity in the target brain region is below the lower limit of the functional reference interval, the control module generates an excitatory initial stimulation command and sends the corresponding initial stimulation parameter set to the electrical stimulation module via the localization simulation module. Conversely, when the analysis module determines that the neural activity in the target brain region is above the upper limit of the functional reference interval, the control module generates an inhibitory initial stimulation command and sends the corresponding initial stimulation parameter set to the electrical stimulation module via the localization simulation module. The direction of stimulation modulation received by the subject matches the type of neural activity abnormality, ensuring that the starting point of the TI electrical stimulation intervention is oriented in the correct modulation direction.

[0047] During the stimulation application phase of the system, the control module continuously receives real-time functional indicators, temporal trends of these indicators, and / or spatial offsets of the TI electrical stimulation output from the analysis module to make dynamic stimulation adjustment decisions. Specifically, the control module provides the following decisions to respond to subjects exhibiting different states by generating specific stimulation commands: When the real-time functional indicators remain within the reference range or gradually converge toward the reference range over time, and the spatial offset is less than or equal to the preset spatial threshold, the current stimulation parameter set is kept unchanged so that neural activity continues to transition to a stable state.

[0048] When the spatial offset is less than or equal to a preset threshold, but the real-time functional index still does not fall into the reference range after a certain period of electrical stimulation, the control module instructs the positioning simulation module to adjust the stimulation current intensity or frequency difference according to the current direction of neural activity deviation. Specifically, when the functional index is below the lower limit of the reference range, the intensity of the excitatory stimulation current is increased, for example, by adjusting the frequency difference to a specific value corresponding to the excitatory stimulus and increasing the field strength of the envelope modulation electric field by increasing the stimulation current intensity; when the functional index is above the upper limit of the reference range, the intensity of the inhibitory stimulation current is increased, for example, by adjusting the frequency difference to a specific value corresponding to the inhibitory stimulus and increasing / decreasing the field strength of the envelope modulation electric field by changing the stimulation current intensity.

[0049] When the real-time functional index fails to fall into the reference range after a certain period of electrical stimulation and the spatial offset is greater than the preset spatial threshold, the control module instructs the positioning simulation module to fine-tune the stimulation current ratio to change the modulation focus position of the envelope modulation electric field, so that the activation area of ​​TI electrical stimulation gradually moves closer to the target brain region.

[0050] If the real-time functional indicators fail to fall within the reference range after a certain number of electrical stimulation cycles, and the temporal value of the spatial offset consistently exceeds the preset spatial threshold, the control module instructs the positioning simulation module to recalculate the simulation. The positioning simulation module updates the electric field optimization objective based on the current BOLD activation spatial distribution information to recalculate the finite element simulation, generating a new set of stimulation parameters, such as changing the current intensity, current ratio, and / or electrode placement. The electrical stimulation module is then reconfigured with the updated set of stimulation parameters and enters a new stimulation cycle to continue performing TI electrical stimulation intervention.

[0051] Furthermore, when the temporal changes of real-time functional indicators show a trend of deviating in the opposite direction to the reference interval, the control module determines that the current stimulus modulation direction is incorrect. Based on the functional state analysis results provided by the analysis module, it instructs the localization simulation module to switch between the stimulus parameter sets for excitatory stimuli and inhibitory stimuli to correct the direction of neural modulation. This switching can be stopped when the temporal changes of real-time functional indicators show that the reverse trend has stopped.

[0052] Thus, during stimulation, the control module continuously performs a dual closed-loop analysis of functional state determination and spatial consistency determination. It adjusts the stimulation parameter set through command control of the localization simulation module, enabling the electrical stimulation module to provide different stimulation modes to the subject. In the optimal scenario, when the indicators of neural activity in the target brain region under TI electrical stimulation enter the functional reference interval and remain stable within a preset time window, and the BOLD signal shows that the activation centroid coordinates, activation peak coordinates, or activation volume of the TI electrical stimulation remain within the preset spatial threshold range of the target brain region within the preset time window, the control module can generate a stimulation termination command to stop the TI electrical stimulation signal output and enter the post-stimulation monitoring phase. In other cases, the control module can also generate a stimulation termination command based on a preset configuration, provided some of the above conditions are met. Alternatively, the operator of the system can instruct the control module to generate a stimulation termination command to stop the operation of the electrical stimulation module at any time.

[0053] The electrical stimulation module is used to receive the initial stimulation parameter set and the initial stimulation command to output a TI electrical stimulation signal, and to receive the stimulation command to adjust the TI electrical stimulation signal. The electrical stimulation module can operate in a magnetic resonance imaging environment and supports updating the stimulation parameter set during stimulation.

[0054] Specifically, in one example, the electrical stimulation module includes a stimulation signal generation unit and a stimulation mode control unit. The stimulation signal generation unit generates two, four, or more paired AC stimulation signals with different carrier frequencies as multi-channel TI electrical stimulation signals based on an initial or updated set of stimulation parameters. Each pair of signals is paired to form an initial or updated carrier frequency difference between the two channels, delivering multiple channels of TI electrical stimulation signals to the subject via scalp electrodes, generating one or more low-frequency envelope-modulated electric fields in the target brain region. In one example, the stimulation signal generation unit has a two-channel, four-channel, or more-channel configuration, with each channel including a signal generator and a current source for generating AC stimulation signals as TI electrical stimulation signals.

[0055] Furthermore, the stimulation mode control unit receives and configures the stimulation mode for the stimulation signal generation unit based on the initial stimulation command, stimulation instructions, and corresponding stimulation parameter sets output by the control module. Specifically, during the system startup phase, the stimulation mode control unit receives the initial stimulation command. When informed that the subject's baseline state is an abnormal inhibitory state, it configures the initial stimulation parameter set sent by the positioning simulation module to the stimulation signal generation unit, thereby creating an envelope modulation electric field in the target brain region that enhances neural activity. When informed that the subject's baseline state is an abnormal excitatory state, it configures the initial stimulation parameter set sent by the positioning simulation module to the stimulation signal generation unit, thereby creating an envelope modulation electric field in the target brain region that reduces neural activity. During stimulation, the stimulation mode control unit configures the stimulation parameter set between excitatory stimulation, inhibitory stimulation, and spatial offset correction based on the received stimulation command and the corresponding updated stimulation parameter set, in order to quickly respond and generate new TI electrical stimulation signals and promptly correct the modulation direction.

[0056] It is understood that the stimulation mode control unit is an independent control submodule of the electrical stimulation module, which controls the operation of the stimulation signal generation unit by receiving instructions. However, in other examples, the electrical stimulation module may not include a stimulation mode control unit, and instead, the control module may directly control the operation of the stimulation signal generation unit through initial stimulation instructions and / or stimulation instructions.

[0057] Specifically, the system also includes an MRI compatibility module, which enables the TI electrical stimulation signal output by the electrical stimulation module to be safely applied to the subject's body surface in an MRI environment, limits electromagnetic interference to the MRI system / equipment during stimulation, and prevents the MRI system from adversely affecting the stimulation signal. This MRI compatibility module is positioned between the electrical stimulation module and the subject, adapts the TI electrical stimulation signal to the MRI environment, and forms the interface between the system and the MRI system / equipment.

[0058] Specifically, the MRI compatibility module includes an MRI compatibility adapter unit and an electrode interface unit. The MRI compatibility adapter unit adapts the TI electrical stimulation signal from the electrical stimulation module to meet safety and compatibility requirements in an MRI environment. In one example, the MRI compatibility adapter unit is electrically connected to the stimulation signal generation unit, and its adaptation processing includes at least one or more of the following: radio frequency interference suppression, electrical isolation, common-mode interference suppression, and impedance matching, to avoid mutual interference between signals. The electrode interface unit applies the TI electrical stimulation signal processed by the MRI compatibility adapter unit to the subject using one or more electrode pairs.

[0059] The system can operate in an MRI environment and is based on a dual closed-loop control of functional state regulation and spatial target regulation. By acquiring image information of the subject in real time, it simultaneously analyzes the neural activity functional state and spatial activation distribution of the target brain region, and dynamically adjusts one or more parameters of TI electrical stimulation based on the analysis results. This achieves precise and adaptive regulation of deep brain regions, solving the problem of traditional TI electrical stimulation systems lacking real-time functional feedback and spatial verification mechanisms. It realizes dual-factor closed-loop control regulation of electric field focal position and neural functional state.

[0060] The following examples illustrate the practical application and effects of the NMR-compatible time-interference neuromodulation system described in this application.

[0061] Example 1: Use of the NMR Compatibility Module like Figure 3 As shown, the MRI-compatible module adapts the system to the operating space of the MRI equipment in TI neuromodulation based on MRI-BOLD feedback. It is positioned between the electrical stimulation module and the subject to ensure the safe transmission and application of TI electrical stimulation signals within the MRI environment. The MRI-compatible module includes an MRI-compatible adapter as an MRI-compatible adaptation unit and electrode connection lines as electrode interface units for connecting the electrical stimulation module and the stimulation electrode group. One end of the MRI-compatible adapter is connected to the electrical stimulation module via the connection line to receive the TI electrical stimulation signal output by the electrical stimulation module; the other end of the MRI-compatible adapter is connected to the stimulation electrode group arranged on the surface of the subject's head via the adapter and electrode connection lines to apply the TI electrical stimulation signal adapted to the MRI environment to the subject's scalp. The stimulation electrode group is fixed at a predetermined position on the subject's head, and its arrangement corresponds to the electrode arrangement position determined by the positioning simulation module to form the expected low-frequency envelope modulation electric field within the target brain region. Through the above connection, the TI electrical stimulation signal is transmitted and applied to the subject via the MRI-compatible module, realizing the coordinated operation of stimulation signal delivery and image acquisition during MRI, thereby supporting closed-loop neuromodulation based on MRI-BOLD feedback.

[0062] Example 2: Image Data Analysis 1 like Figure 4 As shown, the system was used to perform TI electrical stimulation intervention on the right subthalamic nucleus (STN) of the subject, and the BOLD signal change curves before, during and after stimulation were obtained and analyzed using the analysis module. Figure 4 The horizontal axis represents time points, and the vertical axis represents the BOLD signal value. The curves show the baseline state before intervention, the first 10 minutes of intervention, the last 10 minutes of intervention, and the changes in the BOLD signal after intervention.

[0063] In this embodiment, the system first acquires the baseline BOLD signal of the right STN region of the subject during the initiation phase, as a reference level for their individualized functional indicators. Subsequently, TI electrical stimulation is applied under MRI conditions, and the changes in BOLD signal are extracted for the first 10 minutes after stimulation begins and for the last 10 minutes after stimulation. After the intervention, BOLD signal is acquired again during the post-stimulation monitoring phase after stimulation stops as post-intervention status data. It can be seen that the overall trend of BOLD signal in the right STN region of the subject is as follows: the BOLD signal value is highest in the first 10 minutes of the intervention; the baseline state before intervention is second; it decreases again in the last 10 minutes of the intervention; and the BOLD signal is lowest after the intervention. The overall signal change is: first 10 minutes of intervention > before intervention > last 10 minutes of intervention > after intervention.

[0064] These results indicate that in the initial stage of electrical stimulation, the right STN region exhibited a significant functional activation effect, with the BOLD signal exceeding baseline levels. This suggests that the envelope-modulated electric field effectively modulated the target brain region and induced enhanced local neural activity. As stimulation continued, the BOLD signal decreased in the latter 10 minutes of the intervention compared to the first 10 minutes, suggesting that the nervous system may have developed adaptive regulation or homeostatic feedback mechanisms, gradually bringing neural activity levels towards a new dynamic equilibrium. After the intervention, the BOLD signal fell below baseline levels, indicating that the time-interference electrical stimulation produced a certain degree of aftereffect on the right STN region, possibly involving changes in neural network plasticity or enhanced local inhibitory regulation. These findings suggest that the system provides effective intervention for neural activity in deep brain regions under magnetic resonance imaging (MRI) conditions.

[0065] This embodiment also verifies that the system can acquire images in real time during stimulation to obtain BOLD signals of the target brain region in order to accurately determine the dynamic changes in neural activity; and that the difference between BOLD signals in the early and late stages of stimulation provides a basis for functional status assessment of the control module, which can be used to determine whether a small-scale adjustment of the stimulation parameter set or simulation recalculation is required; in addition, the comparison results before, during and after the intervention prove that the system has the ability to regulate and monitor deep brain regions in real time.

[0066] Example 3: Image Data Analysis 2 like Figure 5 As shown, the system analyzed the activation differences of BOLD signals obtained during TI electrical stimulation of the target brain region, including activation differences in three scenarios: "10 min before stimulation - before stimulation", "10 min after stimulation - before stimulation", and "after stimulation - before stimulation". All differences were obtained based on statistical analysis of BOLD signal data from functional magnetic resonance imaging (fMRI), where "-" indicates the difference in BOLD signals between two time periods.

[0067] In this embodiment, the total stimulation time of the system is configured to be 20 minutes. During the stimulation process, two functional magnetic resonance imaging (fMRI) BOLD scans are continuously acquired, corresponding to the first 10 minutes and the last 10 minutes after the start of stimulation, respectively. The difference between the BOLD data of the first 10 minutes of stimulation and the baseline data before stimulation is calculated to obtain an activation map of "first 10 minutes of stimulation - before stimulation"; the difference between the BOLD data of the last 10 minutes of stimulation and the baseline data is calculated to obtain an activation map of "last 10 minutes of stimulation - before stimulation"; and the difference between the BOLD data after stimulation and the baseline data is calculated to obtain an activation map of "after stimulation - before stimulation". In the graph, warm-colored areas represent positive differences, that is, the BOLD signal in this area is enhanced compared to the baseline level, representing positive activation of neural activity; cool-colored areas represent negative differences, that is, the BOLD signal is reduced compared to the baseline level, representing inhibition of neural activity.

[0068] Depend on Figure 5It can be seen that in the activation map of "first 10 minutes during stimulation - before stimulation", the target brain region showed a significant increase in warm-toned signals, and the activated areas were concentrated within the pre-set target point space, indicating that TI electrical stimulation had formed an effective envelope modulation electric field in the target brain region in the early stage of stimulation, and caused enhanced local neural activity. In the activation map of "last 10 minutes during stimulation - before stimulation", the target brain region still had activated areas, but the range and intensity of warm tones were weakened compared to the first 10 minutes, and some areas showed a slightly cool-toned signal, indicating that as stimulation continued, the neural activity in the target brain region gradually underwent adaptive changes, and the regulatory effect tended to stabilize or partially decline. In the activation map of "after stimulation - before stimulation", the target brain region showed a cool-toned distribution as a whole, and the BOLD signal was lower than the baseline level, suggesting that the target brain region experienced a certain degree of inhibitory aftereffect or functional remodeling effect after stimulation.

[0069] Based on the time-series analysis results of the BOLD signal in Example 2, it can be confirmed that the system can achieve spatial focused activation of deep target brain regions in the early stage of stimulation, and the activation center is basically consistent with the preset target point, verifying the effectiveness of electric field simulation optimization and individualized localization. Furthermore, the phased changes in activation intensity during stimulation indicate that the system can dynamically reflect the temporal evolution characteristics of neural activity, providing an objective basis for the control module to determine whether the functional indicators have converged. In addition, the differential activation map after stimulation further verifies that the TI electrical stimulation of the system has a detectable aftereffect on the target brain region, proving its effectiveness in regulating neural activity in deep brain regions.

[0070] The basic principles of this application have been described above with reference to specific embodiments. However, it should be noted that the advantages, benefits, and effects mentioned in this application are merely examples and not limitations, and should not be considered as essential features of each embodiment of this application. Furthermore, the specific details disclosed above are for illustrative and facilitative purposes only, and are not limitations. These details do not limit the application to the necessity of employing the aforementioned specific details for implementation.

[0071] The block diagrams of devices, apparatuses, devices, and systems involved in this application are merely illustrative examples and are not intended to require or imply that they must be connected, arranged, or configured in the manner shown in the block diagrams. As those skilled in the art will recognize, these devices, apparatuses, devices, and systems can be connected, arranged, and configured in any manner. Words such as “comprising,” “including,” “having,” etc., are open-ended terms meaning “including but not limited to,” and are used interchangeably with them. The terms “or” and “and” as used herein refer to the terms “and / or,” and are used interchangeably with them unless the context clearly indicates otherwise. The term “such as” as used herein refers to the phrase “such as but not limited to,” and is used interchangeably with it.

[0072] It should also be noted that in the apparatus, equipment, and methods of this application, the components or steps can be disassembled and / or recombined. These disassemblies and / or recombinations should be considered as equivalent solutions of this application.

[0073] The above description of the disclosed aspects is provided to enable any person skilled in the art to make or use this application. Various modifications to these aspects will be readily apparent to those skilled in the art, and the general principles defined herein can be applied to other aspects without departing from the scope of this application. Therefore, this application is not intended to be limited to the aspects shown herein, but rather to be accorded the widest scope consistent with the principles and novel features disclosed herein.

[0074] The above description has been given for purposes of illustration and description. Furthermore, this description is not intended to limit the embodiments of this application to the forms disclosed herein. Although numerous exemplary aspects and embodiments have been discussed above, those skilled in the art will recognize certain variations, modifications, alterations, additions, and sub-combinations thereof.

Claims

1. An NMR-compatible time-interference neural modulation system, characterized in that, include: The image acquisition module acquires structural magnetic resonance images and functional magnetic resonance images; The localization simulation module analyzes structural magnetic resonance images to determine the range of the target brain region and constructs a brain model. It calculates an initial set of stimulation parameters based on the brain model and the initial stimulation command, or updates the set of stimulation parameters based on the stimulation command. The analysis module analyzes functional magnetic resonance images to calculate baseline BOLD signals and stimulation BOLD signals, and analyzes the baseline BOLD signals and stimulation BOLD signals to obtain functional state determination results and spatial consistency determination results. The electrical stimulation module receives the initial stimulation parameter set and the initial stimulation command to output a time-interference electrical stimulation signal, and receives the stimulation command to adjust the time-interference electrical stimulation signal. The control module receives the baseline BOLD signal to generate the initial stimulation command, and receives the functional state determination result and spatial consistency determination result to generate the stimulation command.

2. The NMR-compatible time-interference neural modulation system according to claim 1, wherein, The analysis module analyzes the baseline BOLD signal and the stimulus BOLD signal to obtain functional state determination results and spatial consistency determination results, including: The analysis module performs activation analysis on the stimulus BOLD signal, generates a brain activation statistics map, extracts the bright signal region to determine the activation peak coordinates, and calculates the activation centroid coordinates and activation volume. The analysis module calculates the real-time distance and / or temporal distance between the activation centroid coordinates or activation peak coordinates and the center coordinates of the target brain region to obtain the spatial offset, and uses the spatial offset as the spatial consistency determination result.

3. The NMR-compatible time-interference neural modulation system according to claim 1, wherein, The analysis module analyzes the baseline BOLD signal and the stimulus BOLD signal to obtain functional state determination results and spatial consistency determination results, including: The analysis module uses the baseline BOLD signal and the stimulation BOLD signal to calculate the preset functional index range and real-time functional index that characterize the state of neural activity. The analysis module calculates the real-time deviation value of neural activity and / or the temporal deviation value of neural activity when the real-time functional index deviates from the preset functional index range, as the result of the functional state determination.

4. The NMR-compatible time-interference neural modulation system according to claim 3, wherein, The control module receives the functional state determination result and the spatial consistency determination result to generate the stimulus instruction, including: In response to the real-time deviation value of the neural activity being non-zero, the control module sets the stimulation instruction to adjust the stimulation parameter group to change the modulation electric field strength when the spatial consistency determination result does not exceed the preset spatial threshold. In response to the real-time deviation value of the neural activity being non-zero, when the spatial consistency determination result exceeds a preset spatial threshold, the control module sets the stimulation command to adjust the stimulation parameter group to change the modulation focus position of the modulation electric field and / or modify one or more stimulation parameters in the stimulation parameter group.

5. The NMR-compatible time-interference neural modulation system according to claim 3, wherein, The control module receives the functional state determination result and the spatial consistency determination result to generate the stimulus instruction, including: In response to the neural activity timing deviation value moving away from the preset functional index range, the control module sets the stimulation command to correct one or more stimulation parameters in the stimulation parameter group.

6. The NMR-compatible time-interference neural modulation system according to claim 4, wherein, When the spatial consistency determination result exceeds a preset spatial threshold, setting the stimulus instruction to adjust the stimulus parameter group includes: In response to the spatial consistency determination result exceeding a preset spatial threshold, the control module sets the stimulation command to adjust the stimulation parameter set to change the modulation focus position of the modulation electric field; and In response to the spatial consistency determination result continuously exceeding a preset spatial threshold, the control module sets the stimulation instruction to correct one or more stimulation parameters in the stimulation parameter group.

7. The NMR-compatible time-interference neural modulation system according to claim 1 further includes an NMR-compatible module, wherein the NMR-compatible module includes an NMR-compatible adapter unit and an electrode interface unit; The NMR compatibility adaptation unit processes the time-interference electrical stimulation signal output by the electrical stimulation module to make the time-interference electrical stimulation signal compatible with the working environment of the magnetic resonance imaging equipment. The electrode interface unit applies the processed time-interference electrical stimulation signal to the scalp surface of the subject through electrodes, based on the initial stimulation parameter set or stimulation parameter set.

8. The NMR-compatible time-interference neural modulation system according to claim 7, wherein, The NMR-compatible adapter unit processes the time-interference electrical stimulation signal output by the electrical stimulation module, including: The NMR-compatible adapter unit performs radio frequency interference suppression, electrical isolation, common-mode interference suppression, and / or impedance matching on the time-interference electrical stimulation signal to eliminate interference between the magnetic resonance imaging equipment and the time-interference electrical stimulation signal.

9. The NMR-compatible time-interference neural modulation system according to claim 1, wherein, The initial stimulation parameter set and the stimulation parameters in the stimulation parameter set include: stimulation current intensity, carrier frequency, carrier frequency difference, stimulation current ratio and / or electrode placement. The real-time functional indicators include: low-frequency amplitude, local consistency, functional connection strength, and / or the average variation amplitude of the BOLD signal.

10. The NMR-compatible time-interference neural modulation system according to claim 1, wherein, The electrical stimulation module includes a stimulation signal generation unit and a stimulation mode control unit; The stimulation signal generation unit generates at least two time-interference electrical stimulation signals based on the initial stimulation mode, and adjusts at least two time-interference electrical stimulation signals based on the stimulation mode. The stimulation mode control unit receives the initial stimulation parameter set and the initial stimulation command to configure the initial stimulation mode to the stimulation signal generation unit, and also receives the stimulation parameter set and the stimulation command to configure the stimulation mode to the stimulation signal generation unit.

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