Treatment regimen development system for epilepsy animal model based on time coherence electrical stimulation

Abstract

This invention relates to the field of epilepsy, specifically to a method for evaluating the interventional effect of time-coherent electrical stimulation on a target brain region, comprising: S101 acquiring first discharge data and first epileptic seizure data; S102 determining the placement position of the time-coherent electrical stimulation electrode on the scalp of an epileptic animal model; S103 performing a first stimulation on the epileptic animal model; S104 acquiring second discharge data and second epileptic seizure data; S105 when the first discharge ratio of the second high-frequency burst discharge volume ratio to the first high-frequency burst discharge volume ratio is ≥0.50, the first stimulation is evaluated as having no interventional effect on the target brain region; S106 analyzing the rate of change of high-frequency burst discharge. This invention can simply, quickly, and efficiently eliminate intervention schemes that may have side effects, be ineffective, or even promote epileptic seizures, thereby obtaining more feasible intervention schemes (e.g., whether time-coherent electrical stimulation of the target brain region can inhibit epileptiform activity).

Description

Technical Field

[0001] This invention relates to the field of epilepsy, and more specifically to a system for developing treatment plans for animal models of epilepsy based on time-coherent electrical stimulation. Background Technology

[0002] Epilepsy is a serious chronic neurological disorder affecting approximately 1% of the global population. Currently, the mechanisms of epilepsy are not fully understood, and about one-third of epilepsy patients do not respond to existing antiepileptic drugs; these patients are known as drug-resistant epilepsy patients. For these patients, surgery is often recommended to alleviate seizure symptoms. However, surgery itself is invasive and may lead to brain tissue damage, intracranial hemorrhage, infection, and anesthesia risks. Furthermore, due to limitations in our understanding of the mechanisms of epileptic seizures, surgery usually requires the removal of the epileptogenic focus. If the epileptogenic focus is not completely removed, epilepsy may recur. If the epileptogenic focus is located in important brain regions (such as motor or language areas) or is difficult to locate (such as in multifocal epilepsy), surgery may directly damage key brain regions, leading to irreversible cognitive, language, or motor function deficits; therefore, its feasibility is low and patient acceptance is poor.

[0003] In recent years, neuromodulation techniques for epilepsy have provided new treatment options for patients with drug-resistant epilepsy. Common neuromodulation techniques for epilepsy include invasive techniques such as deep brain stimulation (DBS) and non-invasive techniques such as transcranial direct current (DC) stimulation and transcranial alternating current (AC) stimulation. DBS typically requires the implantation of leads in the thalamus, hippocampus, or basal ganglia region, depending on the type of epilepsy and the location of the epileptogenic focus. This carries a high risk of complications such as bleeding and functional impairment, and once implanted, the lead's position is difficult to adjust. Furthermore, DBS has significant side effects and still requires invasive craniotomy, resulting in low patient acceptance. Although transcranial direct current (AC) stimulation and time-coherent electrical stimulation (TCS) are non-invasive compared to DBS, they still require invasive electrode implantation and pose risks such as significant damage to the target brain region, easy loss or functional loss of the implant, infection, and bleeding, limiting their practical application. Summary of the Invention

[0004] In a first aspect, the present invention provides a method for evaluating the interventional effect of time-coherent electrical stimulation on a target brain region, comprising the following steps:

[0005] S101 Acquire the first discharge data and the first epileptic seizure data of the epilepsy animal model;

[0006] In some embodiments, the epileptic seizure type of the animal model is focal epilepsy originating from deep brain regions.

[0007] In some embodiments, the deep brain region is the hippocampus.

[0008] In some embodiments, the first discharge data includes the proportion of a first high-frequency burst discharge.

[0009] In some embodiments, the first epileptic seizure data includes the first epileptic seizure time.

[0010] In some embodiments, the first epileptic seizure time is the time from the first high-frequency burst discharge to the time from the first stimulus to the onset of epileptic seizure behavior in the epileptic animal model.

[0011] In some embodiments, the seizure behavior is a seizure behavior of grade III or higher on the Racine scale.

[0012] S102 Select the target brain region and determine the placement of the time-coherent electrical stimulation electrodes on the scalp of the epilepsy animal model;

[0013] In some embodiments, the time-coherent electrical stimulation electrode includes a first time-coherent electrical stimulation electrode pair and a second time-coherent electrical stimulation electrode pair.

[0014] In some embodiments, the target brain region is a brain region for which stimulation is desired, such as one or more of the anterior thalamic nucleus, cerebellum, hypothalamus, midbrain, globus pallidus, pons, amygdala, hippocampus, medial forebrain tract, and olfactory region. In some embodiments, the target brain region may be the same as or different from the brain region initiating a seizure in the animal model of epilepsy.

[0015] S103 Using time-coherent electrical stimulation technology, an alternating current of a first frequency is applied to the first time-coherent electrical stimulation electrode pair, and an alternating current of a second frequency is applied to the second time-coherent electrical stimulation electrode pair to provide a first stimulation to the epileptic animal model.

[0016] In some embodiments, the first frequency includes 2001 Hz.

[0017] In some embodiments, the second frequency includes 2000 Hz.

[0018] In some embodiments, the placement of the time-coherent electrical stimulation electrodes on the scalp of the epilepsy animal model can be determined using a simulation platform.

[0019] In some embodiments, the simulation platform includes COMSOL software.

[0020] In some embodiments, the method of the first stimulation includes: using a pulsed current to perform a first stimulation at a first current intensity.

[0021] In some embodiments, the first current intensity is 100-300 µA.

[0022] In some embodiments, the pulse width of the pulse current includes 100–200 µs.

[0023] In some embodiments, the duty cycle of the pulse current includes 15-25%.

[0024] In some embodiments, the period of the first stimulation is at least 5 days.

[0025] In some embodiments, the first stimulation is performed during the interictal period of the epileptic animal model. In some embodiments, the specific intervention time points for preventive time-coherent electrical stimulation can be pre-set based on the seizure patterns or historical seizure data of the epileptic animal model.

[0026] In some embodiments, the first stimulation may be applied to the epileptic animal model after a repeatable precursor signal is detected to simulate the effect of closed-loop stimulation.

[0027] S104 Obtain the second discharge data and the second epileptic seizure data of the epileptic animal model after the first stimulus;

[0028] In some embodiments, the second discharge data includes the proportion of a second high-frequency burst discharge.

[0029] In some embodiments, the second epileptic seizure data includes the second epileptic seizure time.

[0030] In some embodiments, the second epileptic seizure time is the time from the first high-frequency burst discharge to the time from when the epileptic animal model exhibits epileptic seizure behavior after the first stimulus.

[0031] S105 When the first discharge ratio of the second high-frequency burst discharge quantity to the first high-frequency burst discharge quantity is ≥0.50, the first stimulus is evaluated as having no intervention effect on the target brain region; when the first discharge ratio is <0.50, proceed to S106.

[0032] S106 Analyze the rate of change of high-frequency burst discharge in the epileptic animal model before and after the first stimulus;

[0033] In some embodiments, the high-frequency burst discharge change rate is calculated as: (second ratio - first ratio) / (first ratio) × 100%; wherein the first ratio is the ratio of the first high-frequency burst discharge amount before the first stimulus to the first epileptic seizure time (i.e., the time from the first occurrence of high-frequency burst discharge in the epileptic animal model to the manifestation of epileptic seizure behavior before the first stimulus), and the second ratio is the ratio of the second high-frequency burst discharge amount after the first stimulus to the second epileptic seizure time (i.e., the time from the first occurrence of high-frequency burst discharge in the epileptic animal model to the manifestation of epileptic seizure behavior after the first stimulus).

[0034] In some embodiments, when the rate of change is ≤15%, the first stimulus is evaluated as having no intervention effect on the target brain region.

[0035] In some embodiments, when the rate of change is >15%, the first stimulus is evaluated as having an interventional effect on the target brain region.

[0036] Secondly, the present invention provides an evaluation system for intervention programs in an animal model of epilepsy based on time-coherent electrical stimulation, comprising:

[0037] The first data acquisition module is configured to acquire the first discharge data and the first epileptic seizure data of the epileptic animal model.

[0038] In some embodiments, the epileptic animal model is constructed by intraperitoneal injection of kaempferol.

[0039] In some embodiments, the epilepsy animal model includes rats or mice.

[0040] In some embodiments, the epileptic seizure type of the animal model is focal epilepsy originating from deep brain regions.

[0041] In some embodiments, the deep brain region is the hippocampus.

[0042] In some embodiments, the first discharge data includes the proportion of a first high-frequency burst discharge.

[0043] In some embodiments, the first epileptic seizure data includes the first epileptic seizure time.

[0044] In some embodiments, the first epileptic seizure time is the time from the first high-frequency burst discharge to the time from the first stimulus to the onset of epileptic seizure behavior in the epileptic animal model.

[0045] In some embodiments, the first stimulus is a time-coherent electrical stimulus.

[0046] The placement information acquisition module is configured to acquire placement information of the time-coherent electrical stimulation electrodes on the scalp of the epilepsy animal model based on the selected target brain region.

[0047] In some embodiments, the time-coherent electrical stimulation electrode includes a first time-coherent electrical stimulation electrode pair and a second time-coherent electrical stimulation electrode pair.

[0048] In some embodiments, the target brain region is the brain region to be stimulated, such as one or more of the anterior thalamic nucleus, cerebellum, hypothalamus, midbrain, globus pallidus, pons, amygdala, hippocampus, medial forebrain tract, and olfactory region. It should be understood that the target brain region may be the same as or different from the brain region initiating a seizure in the animal model of epilepsy.

[0049] In some embodiments, the placement information of the time-coherent electrical stimulation electrodes on the scalp of the epilepsy animal model can be determined by a simulation platform.

[0050] In some embodiments, the simulation platform includes COMSOL software.

[0051] The second data acquisition module is configured to acquire the second discharge data and the second epileptic seizure data of the epileptic animal model after the first stimulus.

[0052] In some embodiments, the second discharge data includes the proportion of a second high-frequency burst discharge.

[0053] In some embodiments, the second epileptic seizure data includes the second epileptic seizure time.

[0054] In some embodiments, the second epileptic seizure time is the time from the first high-frequency burst discharge to the time from when the epileptic animal model exhibits epileptic seizure behavior after the first stimulus.

[0055] In some embodiments, the first stimulation method includes: applying an alternating current of a first frequency to a first pair of time-coherent electrical stimulation electrodes and applying an alternating current of a second frequency to a second pair of time-coherent electrical stimulation electrodes to stimulate the epileptic animal model.

[0056] In some embodiments, the first frequency includes 2001 Hz.

[0057] In some embodiments, the second frequency includes 2000 Hz.

[0058] In some embodiments, the method of the first stimulation includes: using a pulsed current to perform a first stimulation at a first current intensity.

[0059] In some embodiments, the first current intensity is 100-300 µA.

[0060] In some embodiments, the pulse width of the pulse current includes 100–200 µs.

[0061] In some embodiments, the duty cycle of the pulse current includes 15-25%.

[0062] In some embodiments, the period of the first stimulation is at least 5 days.

[0063] In some embodiments, the seizure behavior is a seizure behavior of grade III or higher on the Racine scale.

[0064] In some embodiments, the first stimulation is performed during the interictal period of the epileptic animal model. In some embodiments, the specific intervention time points for preventive time-coherent electrical stimulation can be pre-set based on the seizure patterns or historical seizure data of the epileptic animal model.

[0065] The first processing module is configured to calculate a first discharge ratio of the ratio of the second high-frequency burst discharge to the ratio of the first high-frequency burst discharge in the epileptic animal model.

[0066] In some embodiments, when the first discharge ratio is ≥0.50, the first discharge ratio information is transmitted to the first evaluation module; when the first discharge ratio is <0.50, the first discharge data, the first epileptic seizure data, the second discharge data, and the second epileptic seizure data are transmitted to the third data acquisition module.

[0067] The first evaluation module is configured to output that the first stimulus is evaluated as having no interventional effect on the target brain region.

[0068] The third data acquisition module is configured to calculate the ratio of the second high-frequency burst discharge quantity to the second epileptic seizure time and the rate of change of high-frequency burst discharge of the epileptic animal model before and after the first stimulus.

[0069] In some embodiments, when the rate of change is ≤15%, the second ratio information is transmitted to the first evaluation module; when the rate of change is >15%, the rate of change information is transmitted to the second evaluation module.

[0070] In some embodiments, the high-frequency burst discharge change rate is calculated as: (second ratio - first ratio) / (first ratio) × 100%; wherein the first ratio is the ratio of the first high-frequency burst discharge amount before the first stimulus to the first epileptic seizure time (i.e., the time from the first occurrence of high-frequency burst discharge in the epileptic animal model to the manifestation of epileptic seizure behavior before the first stimulus), and the second ratio is the ratio of the second high-frequency burst discharge amount after the first stimulus to the second epileptic seizure time (i.e., the time from the first occurrence of high-frequency burst discharge in the epileptic animal model to the manifestation of epileptic seizure behavior after the first stimulus).

[0071] The second evaluation module is configured to output that the first stimulus is evaluated as having an interventional effect on the target brain region.

[0072] Compared with the prior art, the beneficial effects of the present invention include at least the following aspects:

[0073] Temporally coherent electrical stimulation (TCS) techniques typically require invasive electrode implantation to stimulate the desired brain region. The invasive electrode implantation locations determined based on simulation platforms are not entirely applicable to non-invasive placement on the scalp of experimental animals. Compared to existing technologies, this invention, by employing a suitable carrier frequency and an extremely low difference frequency (e.g., 1 Hz) in conjunction with the first stimulus, ensures precise stimulation of neurons in the desired brain region, generating field potentials synchronized with the stimulation frequency. This restores the excitation / inhibition balance in the brain region, thereby reducing epileptiform discharges.

[0074] Because existing electrical stimulation methods require invasive electrode implantation, they can typically only stimulate fixed brain regions. Furthermore, in selecting the desired brain region, existing technologies tend to choose the epileptic seizure initiation region (e.g., the epileptogenic focus) as the fixed stimulation region. If the epileptogenic focus is located in an important brain region or is difficult to locate, this method of using invasive electrodes to stimulate and suppress seizures may actually lead to irreversible cognitive, language, or motor function deficits, thus limiting its practical application. This invention can accurately exclude brain regions that are difficult to intervene in using the first stimulation method of this invention, improving the efficiency of intervention program evaluation, shortening the evaluation cycle to some extent, and avoiding unnecessary injury or death of experimental animals. In addition, this invention can more quickly assess whether the time-coherent electrical stimulation method using the first stimulation can successfully intervene in other brain regions (e.g., the anterior thalamic nucleus) in a relatively side-effect-free manner to achieve the inhibitory effect on hippocampal-initiated seizures.

[0075] In summary, this invention can simply, quickly, and efficiently eliminate interventions that may have side effects, be ineffective, or even promote seizures, thereby obtaining more feasible intervention options (e.g., whether temporally coherent electrical stimulation of target brain regions can inhibit epileptiform activity). In other words, this invention can, to some extent, avoid problems such as large brain region damage caused by electrode implantation, promote the practical application of non-invasive temporally coherent electrical stimulation (even closed-loop stimulation with temporally coherent electrical stimulation), and is particularly suitable for research in the fields of epilepsy occurrence, development, pathological mechanisms, and early intervention. Attached Figure Description

[0076] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. In all the drawings, similar elements or parts are generally identified by similar reference numerals. The elements or parts in the drawings are not necessarily drawn to scale. Obviously, the drawings described below are some embodiments of the present invention, and those skilled in the art can obtain other drawings based on these drawings without any creative effort.

[0077] Figure 1 This is a graph showing the results of electroencephalogram (EEG) activity in the hippocampus of mice before time-coherent electrical stimulation intervention.

[0078] Figure 2 This is a graph showing the results of electroencephalographic activity in the hippocampus of mice after intervention with time-coherent electrical stimulation.

[0079] Figure 3 This is a graph showing the proportion of high-frequency burst discharges in mice before time-coherent electrical stimulation intervention.

[0080] Figure 4 This is a graph showing the proportion of high-frequency burst discharges in mice after time-coherent electrical stimulation intervention.

[0081] Figure 5 The graph shows the results of mice performing a new object recognition task after intervention with temporal coherent electrical stimulation in the theta band.

[0082] Figure 6 A schematic diagram of the anterior nucleus of the thalamus;

[0083] Figure 7 This is a flowchart of the method in Example 4;

[0084] Figure 8 This is a schematic diagram of the system structure in Example 5. Detailed Implementation

[0085] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, 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, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0086] In this document, suffixes such as "module," "part," or "unit" used to denote elements are used only for the purpose of illustrative purposes and have no specific meaning in themselves. Therefore, "module," "part," or "unit" may be used interchangeably.

[0087] In this document, the terms "upper," "lower," "inner," "outer," "front," "rear," "one end," and "the other end," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings. They are used only for the convenience of describing the present invention and for simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation. Therefore, they should not be construed as limitations on the present invention. Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance.

[0088] In this document, unless otherwise explicitly specified and limited, the terms "installed," "equipped with," "connected," etc., should be interpreted broadly. For example, "connection" can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection, a direct connection, or an indirect connection through an intermediate medium; it can be a connection within two components. Those skilled in the art can understand the specific meaning of the above terms in this invention based on the specific circumstances.

[0089] In this document, "and / or" includes any and all combinations of one or more of the listed related items.

[0090] In this article, "multiple" means two or more, that is, it includes two, three, four, five, etc.

[0091] It should be noted that, in this document, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, article, or apparatus. Unless otherwise specified, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes that element.

[0092] As used in this specification, the term "about" typically means + / -5% of the value, more typically + / -4% of the value, more typically + / -3% of the value, more typically + / -2% of the value, even more typically + / -1% of the value, and even more typically + / -0.5% of the value.

[0093] In this specification, certain embodiments may be disclosed in a range-bound format. It should be understood that this "range-bound" description is merely for convenience and brevity and should not be construed as a rigid limitation on the disclosed range. Therefore, the description of a range should be considered as having specifically disclosed all possible subranges and the individual numerical values ​​within those ranges. For example, a description of the range 1-6 should be considered as having specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and the individual numbers within those ranges, such as 1, 2, 3, 4, 5, and 6. This rule applies regardless of the breadth of the range.

[0094] Example 1

[0095] In this embodiment, 6-8 week old C57BL / 6 mice were selected, and an epilepsy animal model was induced by intraperitoneal injection of kainic acid.

[0096] Anesthesia was induced using 5% isoflurane / 95% oxygen and maintained using 3% isoflurane / 97% oxygen. The shaving area should extend laterally from the left ear to the right ear, from behind the eye to the posterior end of the skull, covering an area of ​​at least 1 x 1.5 cm. The shaving area was disinfected three times consecutively with povidone-iodine, followed by disinfection of the surrounding exposed skin with ethanol. An internal incision was made at the top of the skull, from between the eyes to the posterior end of the skull. The skull was cleaned with hydrogen peroxide and sterile saline (0.9% NaCl), and hemostasis was achieved promptly using an electrocautery device during the incision.

[0097] To better observe the EEG activity of mice, this embodiment uses hippocampal stimulation as an example, with the anterior fontanelle as the coordinate 0 point in stereotaxic localization. The parameters of the stereotaxic instrument were adjusted to place the recording electrodes. The upper left (x = -3mm, y = 3mm) was the frontal lobe electrode placement point; the lower left (x = -3mm, y = -3mm) was the hippocampal electrode placement point; the upper right (x = 3mm, y = 3mm) was the reference electrode placement point; and the lower right (x = 3mm, y = -3mm) was the ground electrode placement point. Each implantation site was established in the skull using a high-speed dental drill with a 0.5mm spherical burr. The outer edge of each hole was chamfered using a 0.7mm spherical burr to facilitate screw insertion. The EEG screws were inserted into the holes and screwed in approximately 4-5 turns with a flathead screwdriver to achieve the desired depth. Glass ionomer cement was applied to the screw sites and surrounding skin, and UV light was used to accelerate curing. Solder the end of the wire from the EEG lead to the contact point on the plastic connector, connect the electrode amplifier, trim off the excess, and fix the amplifier.

[0098] In this embodiment, four time-coherent stimulation electrodes were placed on the mouse scalp at the following locations: -1.94 mm posterior to the anterior fontanelle, 0.5 mm to the left of the midline, 0.5 mm to the right of the midline, 3.7 mm to the right of the midline, and 4.3 mm to the right of the midline. The placement method could be:

[0099] After cutting the ECG electrode patches to an appropriate size, they were attached to the scalp of mice, and the electrodes were connected to the stimulator using connecting wires; or

[0100] A polyimide tube of appropriate diameter was attached to the scalp of a mouse using dental cement and filled with saline solution. One end of a silver wire was immersed in the saline solution, and the other end was connected to a stimulator; or

[0101] Stainless steel screws were glued and fixed to the mouse scalp using dental cement. One end of a silver wire was wrapped and welded to the screw, and the other end was connected to a stimulator; or

[0102] A single-pin nut was fixed to the mouse skin surface using dental cement, and the nut and stimulator were connected using a pin and jumper wire.

[0103] Seven days after surgery, the mice were stimulated using a time-coherent electrical stimulation generator with the following parameters (i.e., the time-coherent electrical stimulation electrodes emitted alternating currents at T1 and T2, respectively):

[0104] Group 1: T1=1430Hz, T2=1300Hz, frequency difference: 130Hz;

[0105] Group 2: T1=1040Hz, T2=1000Hz, frequency difference: 40Hz;

[0106] Group 3: T1=2001Hz, T2=2000Hz, frequency difference: 1Hz.

[0107] In this embodiment, a pulsed current was used to stimulate the mice, with a pulse width of 100µs, a pulse interval of 500µs, and a duty cycle of 16.67%. The waveform of the pulsed current was a sine wave. The current was set to reverse drive for relative isolation. The current intensity was 200 µA.

[0108] Mice were monitored via video during each stimulus to analyze behavioral responses. The internationally recognized Racine grading system was used as the standard: ① Grade 0: No response; ② Grade I: Facial clonic seizures, including blinking, whisker twitching, rhythmic chewing, etc.; ③ Grade II: Grade I plus rhythmic head nodding; ④ Grade III: Grade II plus forelimb myoclonus, but without hindlimb upright position; ⑤ Grade IV: Grade III plus hindlimb upright position; ⑥ Grade V: Generalized tonic-clonic seizures.

[0109] The EEG recordings of the hippocampus and frontal lobe of mice before and after stimulation showed that, under the second set of parameters, the stimulated hippocampus exhibited clusters of high-amplitude spikes, while the frontal lobe showed delayed and occasional low-amplitude single or multiple spikes. Observations of epileptic behavior in the mice showed that those stimulated with the second set of parameters exhibited grade II-V seizures. In other words, the second set of parameters not only failed to inhibit seizures in the animal model of epilepsy but also further induced seizures in the mice; therefore, the second set of parameters was excluded.

[0110] In this embodiment, the parameters of the first and third groups were used to stimulate the epileptic animal model for 10 minutes each time, twice a day (morning and afternoon) for 7 days. This embodiment used the electroencephalogram (EEG) activity, seizure behavior, and CFOS staining of the epileptic animal model to determine whether the parameters of the first and third groups had an inhibitory effect on seizures. The results showed that both the parameters of the first and third groups had a certain inhibitory effect, but the inhibitory effect of the parameters of the third group was more significant.

[0111] like Figure 1 and Figure 2 As shown, after receiving temporally coherent electrical stimulation based on the parameters of the third group, epileptiform discharges in the hippocampus of the epileptic mouse model were reduced. These results indicate that the extremely low difference frequency (i.e., 1 Hz) of the parameters of the third group, combined with an appropriate pulsed current, is more suitable for the non-invasive placement of the temporally coherent electrical stimulation electrodes in this embodiment, and can better suppress epileptiform discharges.

[0112] Example 2

[0113] Although Example 1 can assess to some extent whether the stimulation mode of time-coherent electrical stimulation has a therapeutic effect on seizures in a mouse model of epilepsy, its assessment period is long and requires the sacrifice of a large number of experimental animals.

[0114] This embodiment further examines whether the stimulation mode of time-coherent electrical stimulation under the parameters of the third group can suppress epileptic seizures by analyzing the proportion of high-frequency burst discharges in the epileptic animal model before and after time-coherent electrical stimulation (calculated as: proportion of high-frequency burst discharges = number of high-frequency burst discharges / (number of low-frequency + mid-frequency + number of high-frequency burst discharges) × 100%).

[0115] The hippocampus of an epileptic animal model was stimulated using the following parameters (i.e., to ensure that the time-coherent electrical stimulation electrodes emit alternating currents of T1 and T2, respectively): T1 = 2001 Hz, T2 = 2000 Hz, difference frequency: 1 Hz. Pulse width: 100 µs, pulse interval: 500 µs, duty cycle: 16.67%. The waveform of the pulsed current was sinusoidal. The current was set to reverse drive for relative isolation. The current intensity was 200 µA. The duration of a single stimulation was 1 min on / 5 min off (for daily stimulation, 1 minute of stimulation followed by 5 minutes of rest constitutes one cycle; a total of 10 cycles). The stimulation cycle was 5 days.

[0116] To assess whether the stimulation mode of temporally coherent electrical stimulation under the parameters of the third group might have a negative impact on the cognitive function of the epilepsy animal model (e.g., produce side effects), this embodiment also evaluates the effect of temporally coherent electrical stimulation on the cognitive function of the epilepsy animal model through behavioral experiments (novel object recognition experiment) and synchronous EEG recording.

[0117] The experimental process of the new object recognition experiment is divided into three stages:

[0118] Adaptation phase: Place the animals alone in an empty experimental box and let them move freely for 5-10 minutes per day for 1-3 consecutive days.

[0119] Learning phase: Place two identical objects for the animal to explore for 5-10 minutes.

[0120] Testing phase: Two hours after learning, a familiar object (A) and a new object (B) are placed in the animal for exploration for 5 minutes.

[0121] like Figure 3 As shown, the proportion of high-frequency burst discharges in epilepsy animal models before time-coherent electrical stimulation is usually between 0.1 and 0.3, and the time from the first high-frequency burst discharge to the manifestation of epileptic seizure behavior in epilepsy animal models is usually 45 seconds.

[0122] like Figure 4 As shown, the proportion of high-frequency burst discharges in the epilepsy animal model after time-coherent electrical stimulation decreased to 0.05-0.1, and the time from the first high-frequency burst discharge to the manifestation of epileptic seizure behavior in the epilepsy animal model decreased to about 30 seconds.

[0123] like Figure 5 As shown, in the epilepsy animal model, after time-coherent electrical stimulation, the theta band was enhanced when approaching a new object during the new object recognition task test phase. This indicates that the stimulation mode of time-coherent electrical stimulation under the parameters of the third group can not only inhibit the epileptic seizures in the epilepsy animal model, but also improve cognitive behavior.

[0124] Example 3

[0125] Because existing electrical stimulation methods require invasive electrode implantation, they can typically only stimulate specific brain regions. In selecting the desired brain region, current techniques tend to choose the epileptic seizure initiation region (e.g., the epileptogenic focus). If the epileptogenic focus is located in a vital brain region or is difficult to locate, this invasive electrode implantation method may actually lead to irreversible cognitive, language, or motor function deficits. Therefore, based on the above experimental results, this embodiment examines whether hippocampal-initiated epileptic seizures in an animal model of epilepsy can be suppressed by stimulating other brain regions (e.g., the anterior thalamic nucleus).

[0126] Using the following parameters (i.e., ensuring that the time-coherent electrical stimulation electrodes emit alternating currents at T1 and T2, respectively) to stimulate the anterior thalamic nucleus (e.g., in an epileptic animal model) Figure 7 Stimulation was performed as shown: T1 = 2001 Hz, T2 = 2000 Hz, difference frequency: 1 Hz. Pulse width: 100 µs, pulse interval: 500 µs, duty cycle: 16.67%. The pulse current waveform was sinusoidal. The current was set to reverse drive for relative isolation. Current intensity: 200 µA. Single session duration: 1 min on / 5 min off. Stimulation cycle: 5 days.

[0127] The results of this embodiment show that time-coherent electrical stimulation under the parameters of the third group can inhibit epileptic seizures initiated in the hippocampus through the anterior thalamic nucleus. Specifically, the ratio of high-frequency burst discharge volume to seizure time before time-coherent electrical stimulation was 0.0022, and the ratio after stimulation was 0.0017; the amplitude of the theta band during the exploration of new objects in the new object recognition task test phase was 0.1 before time-coherent electrical stimulation, and 0.4 after stimulation.

[0128] This embodiment also found that by analyzing the rate of change of high-frequency burst discharges before and after the first stimulation (calculated as: (second ratio - first ratio) / (first ratio) × 100%, where the first ratio is the ratio of the proportion of high-frequency burst discharges before time-coherent electrical stimulation to the seizure time (the time from the first occurrence of high-frequency burst discharges in the epileptic animal model to the manifestation of seizure behavior before time-coherent electrical stimulation), and the second ratio is the ratio of the proportion of high-frequency burst discharges after time-coherent electrical stimulation to the seizure time (the time from the first occurrence of high-frequency burst discharges in the epileptic animal model to the manifestation of seizure behavior after time-coherent electrical stimulation), it is possible to more quickly analyze whether time-coherent electrical stimulation can inhibit other brain regions (such as the anterior thalamic nucleus) in a relatively side-effect-free manner, thereby achieving the inhibitory effect on seizures originating in the hippocampus.

[0129] This embodiment also assessed the inhibitory effect of the intervention by examining the epileptic seizure behavior and cfos staining in the aforementioned animal model of epilepsy. The results showed that, under the intervention method of this embodiment, spontaneous epileptic seizures in the animal model of epilepsy were significantly reduced by 80%, c-fos protein in the hippocampus was downregulated, and other indicators such as the average single discharge time and cumulative discharge time during the interictal period were significantly decreased. These results demonstrate that the evaluation method of this embodiment can rapidly and effectively screen potentially feasible brain regions for time-coherent electrical stimulation intervention.

[0130] Example 4

[0131] Based on the above experimental results, such as Figure 7 As shown, this embodiment provides a method for evaluating the intervention effect of time-coherent electrical stimulation on a target brain region, including the following steps:

[0132] S101 Acquire the first discharge data and the first epileptic seizure data of the epilepsy animal model;

[0133] In some embodiments, the epilepsy animal model can be constructed using methods known in the art for constructing epilepsy animal models, such as through chemical drugs, physical stimulation, gene knockout, or overexpression.

[0134] In some embodiments, the epileptic animal model is constructed by intraperitoneal injection of kaempferol.

[0135] In some embodiments, the epilepsy animal model includes rats or mice.

[0136] In some embodiments, the epileptic seizure type of the animal model is focal epilepsy originating from deep brain regions.

[0137] In some embodiments, the deep brain region is the hippocampus.

[0138] In some embodiments, the first discharge data includes the proportion of a first high-frequency burst discharge.

[0139] In some embodiments, the first epileptic seizure data includes the first epileptic seizure time.

[0140] In some embodiments, the first epileptic seizure time is the time from the first high-frequency burst discharge to the time from the first stimulus to the onset of epileptic seizure behavior in the epileptic animal model.

[0141] In some embodiments, the first stimulus is a time-coherent electrical stimulus.

[0142] S102 Select the target brain region and determine the placement of the time-coherent electrical stimulation electrodes on the scalp of the epilepsy animal model;

[0143] In some embodiments, the time-coherent electrical stimulation electrode includes a first time-coherent electrical stimulation electrode pair and a second time-coherent electrical stimulation electrode pair.

[0144] In some embodiments, the target brain region is the brain region to be stimulated, such as one or more of the anterior thalamic nucleus, cerebellum, hypothalamus, midbrain, globus pallidus, pons, amygdala, hippocampus, medial forebrain tract, and olfactory region. It should be understood that the target brain region may be the same as or different from the brain region initiating a seizure in the animal model of epilepsy.

[0145] S103 Using time-coherent electrical stimulation technology, an alternating current of a first frequency is applied to the first time-coherent electrical stimulation electrode pair, and an alternating current of a second frequency is applied to the second time-coherent electrical stimulation electrode pair to provide a first stimulation to the epileptic animal model.

[0146] In some embodiments, the first frequency includes 2001 Hz.

[0147] In some embodiments, the second frequency includes 2000 Hz.

[0148] In some embodiments, the placement of the time-coherent electrical stimulation electrodes on the scalp of the epilepsy animal model can be determined using a simulation platform.

[0149] In some embodiments, the simulation platform includes COMSOL software. COMSOL software is a commonly used electric field simulation platform in the field of temporal coherent electrical stimulation (TCES), which can generate feasible placement information for TES electrodes based on the target brain region. However, this embodiment found that TES techniques typically require invasive electrode implantation to stimulate the target brain region (e.g., the desired brain region). The invasive electrode implantation locations determined based on the simulation platform are not entirely applicable to the non-invasive placement on the scalp of the epilepsy animal model in this embodiment. Adjusting the placement of the TES electrodes based on the placement information generated by the simulation platform is not only complex but also prone to causing the actual stimulated brain region to deviate from the desired stimulated brain region.

[0150] Existing methods based on temporal coherent electrical stimulation (TCES) typically require invasive implantation of TES electrodes and utilize the low-pass filtering characteristics of neurons (i.e., responding only to low-frequency signals and not high-frequency (>1 kHz) stimuli) to generate a low-frequency envelope stimulation region using a higher carrier frequency and a higher difference frequency (e.g., 130 Hz) to stimulate the target brain region. This embodiment found that even with a simulation platform, this conventional stimulation method struggles to effectively stimulate the desired brain region using TES electrodes placed on the scalp of experimental animals. Furthermore, the literature "Noninvasive Deep Brain Stimulation via Temporally Interfering Electric Fields" reported that high-frequency electrical signals of 2 kHz and 2.01 kHz can induce neuronal firing in experimental animals. This embodiment, by using a 2000 Hz carrier frequency and an extremely low difference frequency (e.g., 1 Hz), was able to precisely locate the desired brain region based on the placement of TES electrodes determined by a conventional simulation platform, thereby suppressing abnormal neuronal firing within it.

[0151] In some embodiments, the discharge data can be obtained by placing EEG recording electrodes into the epileptic animal model.

[0152] In some embodiments, the discharge data are derived from the electroencephalographic activity of the brain region initiating a seizure in the epileptic animal model.

[0153] In some embodiments, the method of the first stimulation includes: using a pulsed current to perform a first stimulation at a first current intensity.

[0154] In some embodiments, the first current intensity is 100-300 µA.

[0155] In some embodiments, the pulse width of the pulse current includes 100–200 µs.

[0156] In some embodiments, the duty cycle of the pulse current includes 15-25%.

[0157] Furthermore, this embodiment found that while the settings of the first and second frequencies can effectively locate the brain region to be stimulated, they are insufficient to effectively inhibit the firing of neurons therein (e.g., high-frequency burst firing). This embodiment employs a first stimulation method, which, in conjunction with the settings of the first and second frequencies, ensures precise stimulation of neurons in the desired brain region to generate field potentials synchronized with the stimulation frequency, restoring the excitation / inhibition balance in the brain region and thereby reducing epileptiform discharges.

[0158] In some embodiments, the period of the first stimulation is at least 5 days.

[0159] In some embodiments, the seizure behavior is a seizure behavior of grade III or higher on the Racine scale.

[0160] In some embodiments, the first stimulation is performed during the interictal period of the epileptic animal model. In some embodiments, the specific intervention time points for preventive time-coherent electrical stimulation can be pre-set based on the seizure patterns or historical seizure data of the epileptic animal model.

[0161] In some embodiments, the first stimulation can be applied to the epileptic animal model after a repeatable precursor signal (e.g., frequency change, low amplitude to high amplitude transition, slow wave to fast wave transition) is detected to simulate the closed-loop stimulation effect.

[0162] S104 Obtain the second discharge data and the second epileptic seizure data of the epileptic animal model after the first stimulus;

[0163] In some embodiments, the second discharge data includes the proportion of a second high-frequency burst discharge.

[0164] In some embodiments, the second epileptic seizure data includes the second epileptic seizure time.

[0165] In some embodiments, the second epileptic seizure time is the time from the first high-frequency burst discharge to the time from when the epileptic animal model exhibits epileptic seizure behavior after the first stimulus.

[0166] S105 When the first discharge ratio of the second high-frequency burst discharge quantity to the first high-frequency burst discharge quantity is ≥0.50, the first stimulus is evaluated as having no intervention effect on the target brain region; when the first discharge ratio is <0.50, proceed to S106.

[0167] Because existing electrical stimulation methods require invasive electrode implantation, they can typically only stimulate fixed brain regions. Furthermore, in selecting the desired brain region for stimulation, existing technologies tend to choose the epileptic seizure initiation region (e.g., the epileptogenic focus) as the fixed stimulation region. If the epileptogenic focus is located in a vital brain region or is difficult to locate, this method of using invasive electrodes to stimulate and suppress seizures may actually lead to irreversible cognitive, language, or motor function deficits, thus limiting its practical application. This embodiment, by evaluating the first discharge ratio of the second high-frequency burst discharge volume to the first high-frequency burst discharge volume ratio, can quickly eliminate brain regions that are difficult to intervene in using the first stimulation method of this invention, improving the evaluation efficiency of the intervention plan, shortening the evaluation cycle to some extent, and avoiding unnecessary injury or death of experimental animals.

[0168] S106 Analyze the rate of change of high-frequency burst discharge in the epileptic animal model before and after the first stimulus;

[0169] In some embodiments, the high-frequency burst discharge change rate is calculated as: (second ratio - first ratio) / (first ratio) × 100%; wherein the first ratio is the ratio of the first high-frequency burst discharge amount before the first stimulus to the first epileptic seizure time (i.e., the time from the first occurrence of high-frequency burst discharge in the epileptic animal model to the manifestation of epileptic seizure behavior before the first stimulus), and the second ratio is the ratio of the second high-frequency burst discharge amount after the first stimulus to the second epileptic seizure time (i.e., the time from the first occurrence of high-frequency burst discharge in the epileptic animal model to the manifestation of epileptic seizure behavior after the first stimulus).

[0170] In some embodiments, when the rate of change is ≤15%, the first stimulus is evaluated as having no intervention effect on the target brain region.

[0171] In some embodiments, when the rate of change is >15%, the first stimulus is evaluated as having an interventional effect on the target brain region.

[0172] Furthermore, since the method of this embodiment aims to evaluate whether the stimulation of other brain regions through the first stimulus can inhibit epileptiform activity in the epileptiform seizure initiation region, it is necessary not only to determine the epileptiform inhibitory effect of the first stimulus, but also to assess whether it has potential side effects (e.g., affecting the mood and cognitive function of the epileptiform animal model). This embodiment found that by evaluating the rate of change in high-frequency burst discharge in the epileptiform animal model before and after the first stimulus, it is possible to more quickly assess whether the time-coherent electrical stimulation of the first stimulus can successfully intervene in other brain regions (e.g., the anterior thalamic nucleus) in a relatively side-effect-free manner to achieve the inhibitory effect on epileptiform seizures initiating in the hippocampus. In other words, the method provided by this embodiment can simply, quickly, and efficiently eliminate intervention schemes that may have potential side effects, be ineffective, or even promote epileptiform seizures, thereby obtaining more feasible intervention schemes (e.g., whether time-coherent electrical stimulation of the target brain region can inhibit epileptiform activity), promoting the practical application of time-coherent electrical stimulation (and even closed-loop stimulation with time-coherent electrical stimulation).

[0173] Example 5

[0174] Furthermore, such as Figure 8 As shown, this embodiment provides a system 100 for evaluating intervention programs in an animal model of epilepsy based on time-coherent electrical stimulation, including:

[0175] The first data acquisition module 102 is configured to acquire first discharge data and first epileptic seizure data of an epileptic animal model.

[0176] In some embodiments, the epilepsy animal model can be constructed using methods known in the art for constructing epilepsy animal models, such as through chemical drugs, physical stimulation, gene knockout, or overexpression.

[0177] In some embodiments, the epileptic animal model is constructed by intraperitoneal injection of kaempferol.

[0178] In some embodiments, the epilepsy animal model includes rats or mice.

[0179] In some embodiments, the epileptic seizure type of the animal model is focal epilepsy originating from deep brain regions.

[0180] In some embodiments, the deep brain region is the hippocampus.

[0181] In some embodiments, the first discharge data includes the proportion of a first high-frequency burst discharge.

[0182] In some embodiments, the first epileptic seizure data includes the first epileptic seizure time.

[0183] In some embodiments, the first epileptic seizure time is the time from the first high-frequency burst discharge to the time from the first stimulus to the onset of epileptic seizure behavior in the epileptic animal model.

[0184] In some embodiments, the first stimulus is a time-coherent electrical stimulus.

[0185] The placement information acquisition module 104 is configured to acquire placement information of the time-coherent electrical stimulation electrodes on the scalp of the epilepsy animal model based on the selected target brain region.

[0186] In some embodiments, the time-coherent electrical stimulation electrode includes a first time-coherent electrical stimulation electrode pair and a second time-coherent electrical stimulation electrode pair.

[0187] In some embodiments, the target brain region is the brain region to be stimulated, such as one or more of the anterior thalamic nucleus, cerebellum, hypothalamus, midbrain, globus pallidus, pons, amygdala, hippocampus, medial forebrain tract, and olfactory region. It should be understood that the target brain region may be the same as or different from the brain region initiating a seizure in the animal model of epilepsy.

[0188] In some embodiments, the placement information of the time-coherent electrical stimulation electrodes on the scalp of the epilepsy animal model can be determined by a simulation platform.

[0189] In some embodiments, the simulation platform includes COMSOL software.

[0190] The second data acquisition module 106 is configured to acquire the second discharge data and the second epileptic seizure data of the epileptic animal model after the first stimulus.

[0191] In some embodiments, the second discharge data includes the proportion of a second high-frequency burst discharge.

[0192] In some embodiments, the second epileptic seizure data includes the second epileptic seizure time.

[0193] In some embodiments, the second epileptic seizure time is the time from the first high-frequency burst discharge to the time from when the epileptic animal model exhibits epileptic seizure behavior after the first stimulus.

[0194] In some embodiments, the first stimulation method includes: applying an alternating current of a first frequency to a first pair of time-coherent electrical stimulation electrodes and applying an alternating current of a second frequency to a second pair of time-coherent electrical stimulation electrodes to stimulate the epileptic animal model.

[0195] In some embodiments, the first frequency includes 2001 Hz.

[0196] In some embodiments, the second frequency includes 2000 Hz.

[0197] In some embodiments, the discharge data can be obtained by placing EEG recording electrodes into the epileptic animal model.

[0198] In some embodiments, the discharge data are derived from the electroencephalographic activity of the brain region initiating a seizure in the epileptic animal model.

[0199] In some embodiments, the method of the first stimulation includes: using a pulsed current to perform a first stimulation at a first current intensity.

[0200] In some embodiments, the first current intensity is 100-300 µA.

[0201] In some embodiments, the pulse width of the pulse current includes 100–200 µs.

[0202] In some embodiments, the duty cycle of the pulse current includes 15-25%.

[0203] In some embodiments, the period of the first stimulation is at least 5 days.

[0204] In some embodiments, the seizure behavior is a seizure behavior of grade III or higher on the Racine scale.

[0205] In some embodiments, the first stimulation is performed during the interictal period of the epileptic animal model. In some embodiments, the specific intervention time points for preventive time-coherent electrical stimulation can be pre-set based on the seizure patterns or historical seizure data of the epileptic animal model.

[0206] In some embodiments, the first stimulation can be applied to the epileptic animal model after a repeatable precursor signal (e.g., frequency change, low amplitude to high amplitude transition, slow wave to fast wave transition) is detected to simulate the closed-loop stimulation effect.

[0207] The first processing module 108 is configured to calculate a first discharge ratio of the ratio of the second high-frequency burst discharge to the ratio of the first high-frequency burst discharge in the epileptic animal model.

[0208] In some embodiments, when the first discharge ratio is ≥0.50, the first discharge ratio information is transmitted to the first evaluation module 110; when the first discharge ratio is <0.50, the first discharge data, the first epileptic seizure data, the second discharge data, and the second epileptic seizure data are transmitted to the third data acquisition module 112.

[0209] The first evaluation module 110 is configured to output that the first stimulus is evaluated as having no intervention effect on the target brain region;

[0210] The third data acquisition module 112 is configured to calculate the ratio of the second high-frequency burst discharge quantity to the second epileptic seizure time and the rate of change of high-frequency burst discharge of the epileptic animal model before and after the first stimulus.

[0211] In some embodiments, the high-frequency burst discharge change rate is calculated as: (second ratio - first ratio) / (first ratio) × 100%; wherein the first ratio is the ratio of the first high-frequency burst discharge amount before the first stimulus to the first epileptic seizure time (i.e., the time from the first occurrence of high-frequency burst discharge in the epileptic animal model to the manifestation of epileptic seizure behavior before the first stimulus), and the second ratio is the ratio of the second high-frequency burst discharge amount after the first stimulus to the second epileptic seizure time (i.e., the time from the first occurrence of high-frequency burst discharge in the epileptic animal model to the manifestation of epileptic seizure behavior after the first stimulus).

[0212] In some embodiments, when the rate of change is ≤15%, the rate of change information is transmitted to the first evaluation module 110; when the rate of change is >15%, the rate of change information is transmitted to the second evaluation module 114.

[0213] The second evaluation module 114 is configured to output that the first stimulus is evaluated as having an interventional effect on the target brain region.

[0214] In some embodiments, one or more modules of the time-coherent electrical stimulation-based epilepsy animal model intervention program evaluation system 100 may be configured to be implemented based on a trained artificial intelligence or machine learning model.

[0215] Through the above description of the embodiments, those skilled in the art can clearly understand that the methods of the above embodiments can be implemented by means of software plus necessary general-purpose hardware platforms. Of course, they can also be implemented by hardware, but in many cases the former is a better implementation method. Based on this understanding, the technical solution of the present invention, or the part that contributes to the prior art, can be embodied in the form of a software product. This computer software product is stored in a storage medium (such as ROM / RAM, magnetic disk, optical disk) and includes several instructions to cause a computer terminal (which may be a mobile phone, computer, server, or network device, etc.) to execute the methods described in the various embodiments of the present invention.

[0216] The embodiments of the present invention have been described above with reference to the accompanying drawings. However, the present invention is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of the present invention without departing from the spirit and scope of the claims. All of these forms are within the protection scope of the present invention.

Claims

1. A method for evaluating the interventional effect of time-coherent electrical stimulation on a target brain region, characterized in that, Includes the following steps: S101 Acquire the first discharge data and the first epileptic seizure data of the epileptic animal model. The first discharge data includes the proportion of the first high-frequency burst discharge. The first epileptic seizure data includes the first epileptic seizure time, which is the time from the first high-frequency burst discharge to the epileptic seizure behavior of the epileptic animal model before the first stimulus. S102 Select the target brain region and determine the placement position of the time-coherent electrical stimulation electrodes on the scalp of the epilepsy animal model; wherein the time-coherent electrical stimulation electrodes include a first time-coherent electrical stimulation electrode pair and a second time-coherent electrical stimulation electrode pair. S103 Using time-coherent electrical stimulation technology, an alternating current of a first frequency is applied to the first time-coherent electrical stimulation electrode pair, and an alternating current of a second frequency is applied to the second time-coherent electrical stimulation electrode pair to provide a first stimulation to the epileptic animal model; wherein the first frequency includes 2001 Hz, and the second frequency includes 2000 Hz. S104 Acquire the second discharge data and the second epileptic seizure data of the epileptic animal model after the first stimulus; the second discharge data includes the proportion of the second high-frequency burst discharge; the second epileptic seizure data includes the second epileptic seizure time, which is the time from the first high-frequency burst discharge to the epileptic seizure behavior of the epileptic animal model after the first stimulus. S105 When the first discharge ratio of the second high-frequency burst discharge quantity to the first high-frequency burst discharge quantity is ≥0.50, the first stimulus is evaluated as having no intervention effect on the target brain region; when the first discharge ratio is <0.50, proceed to S106. S106 Analyze the rate of change of high-frequency burst discharge in the epileptic animal model before and after the first stimulus; the rate of change of high-frequency burst discharge is calculated as: (second ratio - first ratio) / (first ratio) × 100%; wherein the first ratio is the ratio of the proportion of the first high-frequency burst discharge before the first stimulus to the duration of the first epileptic seizure, and the second ratio is the ratio of the proportion of the second high-frequency burst discharge after the first stimulus to the duration of the second epileptic seizure; when the rate of change is ≤15%, the first stimulus is assessed as having no intervention effect on the target brain region; when the rate of change is >15%, the first stimulus is assessed as having an intervention effect on the target brain region.

2. The method as described in claim 1, characterized in that, The method of the first stimulation includes: using a pulsed current to perform a first stimulation at a first current intensity, wherein the first current intensity is 100-300µA and the pulse width of the pulsed current includes 100-200µs.

3. The method as described in claim 1, characterized in that, The first stimulation lasts for at least 5 days.

4. The method as described in claim 1, characterized in that, The placement of the time-coherent electrical stimulation electrodes on the scalp of the epilepsy animal model was determined by a simulation platform, which included COMSOL software.

5. The method as described in claim 1, characterized in that, The target brain regions are one or more of the following: anterior thalamic nucleus, cerebellum, hypothalamus, midbrain, globus pallidus, pons, amygdala, hippocampus, medial forebrain tract, and olfactory region.

6. A system for evaluating intervention programs in animal models of epilepsy based on time-coherent electrical stimulation, characterized in that, include: The first data acquisition module is configured to acquire first discharge data and first epileptic seizure data of an epileptic animal model; the first discharge data includes the proportion of a first high-frequency burst discharge, and the first epileptic seizure data includes the first epileptic seizure time, which is the time from the first high-frequency burst discharge to the epileptic seizure behavior of the epileptic animal model before the first stimulus. The placement information acquisition module is configured to acquire placement information of the time-coherent electrical stimulation electrodes on the scalp of the epilepsy animal model based on the selected target brain region; wherein the time-coherent electrical stimulation electrodes include a first time-coherent electrical stimulation electrode pair and a second time-coherent electrical stimulation electrode pair. The second data acquisition module is configured to acquire second discharge data and second epileptic seizure data of the epileptic animal model after the first stimulus; the second discharge data includes the proportion of second high-frequency burst discharge; the second epileptic seizure data includes the second epileptic seizure time, which is the time from the first high-frequency burst discharge to the epileptic seizure behavior of the epileptic animal model after the first stimulus. The first stimulation method includes: applying an alternating current of a first frequency to the first time-coherent electrical stimulation electrode pair and applying an alternating current of a second frequency to the second time-coherent electrical stimulation electrode pair to stimulate the epileptic animal model; wherein the first frequency includes 2001 Hz and the second frequency includes 2000 Hz. The first processing module is configured to calculate a first discharge ratio of the ratio of the second high-frequency burst discharge to the ratio of the first high-frequency burst discharge in the epileptic animal model; when the first discharge ratio is ≥0.50, it is configured to transmit the first discharge ratio information to the first evaluation module; when the first discharge ratio is <0.50, it is configured to transmit the first discharge data, the first epileptic seizure data, the second discharge data, and the second epileptic seizure data to the third data acquisition module. The third data acquisition module is configured to calculate the ratio of the second high-frequency burst discharge volume to the second epileptic seizure time and the high-frequency burst discharge change rate of the epileptic animal model before and after the first stimulus; when the change rate is ≤15%, it is used to transmit the change rate information to the first evaluation module; when the change rate is >15%, it is used to transmit the change rate information to the second evaluation module; the high-frequency burst discharge change rate is calculated as: (second ratio - first ratio) / (first ratio) × 100%; wherein the first ratio is the ratio of the first high-frequency burst discharge volume before the first stimulus to the first epileptic seizure time, and the second ratio is the ratio of the second high-frequency burst discharge volume after the first stimulus to the second epileptic seizure time; The first evaluation module is configured to output that the first stimulus is evaluated as having no interventional effect on the target brain region. The second evaluation module is configured to output that the first stimulus is evaluated as having an interventional effect on the target brain region.

7. The system as described in claim 6, characterized in that, The target brain regions are one or more of the following: anterior thalamic nucleus, cerebellum, hypothalamus, midbrain, globus pallidus, pons, amygdala, hippocampus, medial forebrain tract, and olfactory region.

8. The system as described in claim 6, characterized in that, The method of the first stimulation includes: using a pulsed current to perform a first stimulation at a first current intensity, wherein the first current intensity is 100-300µA and the pulse width of the pulsed current includes 100-200µs.

9. The system as described in claim 6, characterized in that, The first stimulation lasts for at least 5 days.

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