Parameter positioning method and kit for inhibiting PCOS concurrent epilepsy based on focused ultrasound

Abstract

The invention relates to the field of focused ultrasound, in particular to a parameter positioning method and kit for inhibiting PCOS concurrent epilepsy based on focused ultrasound. The method comprises the following steps: acquiring different power and duty ratio combinations corresponding to a plurality of preset gears; according to the prior experiment data and the biological thermal model, predicting safety intervals of stimulation duration under different gears, and setting a plurality of experiment parameter combinations of different preset doses according to the safety intervals; performing ultrasonic stimulation on the experimental model based on the experimental parameter combination to obtain a biological response result; based on a preset dose effect relationship, according to the biological response result, respectively fitting a dose effect curve under each gear; and determining an optimal dose range of each gear based on the dose effect curve, and performing feasibility evaluation on the optimal dose range to determine an optimal parameter combination of focused ultrasound. On the premise of simple experimental operation, short period and low cost, a relatively accurate and effective ultrasonic parameter range is efficiently determined, and support is provided for personalized medical treatment.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of focused ultrasound, and in particular to a parameter positioning method and kit for inhibiting PCOS complicated with epilepsy based on focused ultrasound. BACKGROUND

[0002] Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder. Previous studies have shown that the prevalence of PCOS in female patients with epilepsy is significantly higher, about 15%-30%, which is 2-3 times that of healthy people, suggesting that there may be a close comorbidity between the two. And clinical observations have found that the frequency of seizures in female patients with PCOS complicated with epilepsy is higher than that in ordinary patients with epilepsy (such as 22.2% vs 13.4%), suggesting that PCOS may promote the susceptibility or seizure activity of epilepsy.

[0003] On this basis, animal experiments further support the above reverse correlation: the susceptibility of PCOS rats modeled by letrozole increases, and decreases after anti-androgen treatment. And in terms of mechanism, the sympathetic nerve fibers around small follicles in the ovary increase in the PCOS state, and abnormal follicles tend to be atretic, suggesting that the peripheral ovary and sympathetic axis may affect central excitability and thus participate in the occurrence and development of epilepsy.

[0004] Focused ultrasound (FUS) is a non-invasive physical control method. Focused ultrasound stimulation is performed on the ovary through the body surface. The thermal and mechanical effects of focused ultrasound may promote the atresia of abnormal follicles and change the distribution of nerve endings, achieve peripheral nerve regulation through afferent nerves, and thus alleviate the susceptibility of PCOS patients to epilepsy.

[0005] However, the therapeutic effect of focused ultrasound is highly dependent on the precise combination of parameters such as power, duty cycle, and frequency, simulated focal plane distance, and stimulation duration. Different parameter combinations may result in completely different biological effects, or even ineffective or adverse results. At present, there is a lack of efficient and systematic methods for quickly exploring effective parameter combinations suitable for inhibiting PCOS complicated with epilepsy. SUMMARY

[0006] The main purpose of the present application is to provide a parameter positioning method and kit for inhibiting PCOS complicated with epilepsy based on focused ultrasound. In order to solve the above-mentioned technical problems, the following technical solutions are adopted in the present application: The first aspect of the present application is to provide a parameter positioning method for inhibiting PCOS complicated with epilepsy based on focused ultrasound. The parameters of the focused ultrasound include power, duty cycle, and stimulation duration. The method comprises: S101, obtain a plurality of preset gears, each gear corresponding to a different power and duty cycle combination; according to prior experimental data and a biological heat model, predict a safe interval of a stimulation duration under different gears; S102, set a plurality of experimental parameter combinations of different preset doses according to the safe interval of the stimulation duration under each gear, the dose being a product of power, duty cycle and stimulation duration; S103, based on the plurality of experimental parameter combinations, respectively perform ultrasonic stimulation on an experimental model to obtain corresponding biological response results; S104, based on a preset dose-effect relationship, respectively fit a dose-effect curve under each gear according to the biological response results of each experimental parameter combination under each gear; the preset dose-effect relationship includes: a. the dose-effect curve is unimodal within a safe parameter interval; b. the peak dose of the dose-effect curve is inversely related to the values of power and duty cycle in the gear; S105, determine a preferred dose range of each gear based on the dose-effect curve, and perform a feasibility evaluation on the preferred dose range of each gear to determine a preferred parameter combination of focused ultrasound.

[0007] The second aspect of the present application provides a test kit, which comprises: a safe interval test module for obtaining a plurality of preset gears, each gear corresponding to a different power and duty cycle combination; according to prior experimental data and a biological heat model, predicting a safe interval of a stimulation duration under different gears; an experimental parameter setting module for setting a plurality of experimental parameter combinations of different preset doses according to the safe interval of the stimulation duration under each gear, the dose being a product of power, duty cycle and stimulation duration; an ultrasonic stimulation execution module for performing ultrasonic stimulation on an experimental model based on the plurality of experimental parameter combinations to obtain corresponding biological response results; a dose-effect curve module for fitting a dose-effect curve under each gear based on a preset dose-effect relationship according to the biological response results of each experimental parameter combination under each gear; the preset dose-effect relationship includes: a. the dose-effect curve is unimodal within a safe parameter interval; b. the peak dose of the dose-effect curve is inversely related to the values of power and duty cycle in the gear; a preferred dose range module for determining a preferred dose range of each gear based on the dose-effect curve, and performing a feasibility evaluation on the preferred dose range of each gear to determine a preferred parameter combination of focused ultrasound.

[0008] Advantages: The embodiment of the application provides a parameter positioning method and kit for inhibiting PCOS complicated with epilepsy based on focused ultrasound, limited data are obtained through a simple experiment, a preset dose effect relationship is combined to realize rapid locking of an effective parameter range, under the premise of ensuring simple experiment operation, short cycle and low cost, a relatively accurate and effective ultrasound parameter range is efficiently determined, personalized medical treatment is supported, and the feasibility and safety of treatment for PCOS complicated with epilepsy are improved.

[0009] In the initial stage, a small amount of prior experimental data (for example, a critical time of causing tissue damage in a certain gear) is combined with a mature biological heat model to quickly predict a safe interval of the stimulation time length under different gears, so that high animal cost investment caused by traditional large-scale pre-experiments is avoided, and the early exploration cycle is greatly shortened.

[0010] In the experimental design stage, the dose is introduced as a unified standard, limited and representative dose groups (for example, high, medium and low doses) are set, each group includes parameter combinations (for example, 3 gears for 30 seconds, 2 gears for 70 seconds and 1 gear for 100 seconds, and the dose is about 75) of different gears but similar doses, a small amount of experiments cover a wide parameter space, and the number of experiment operations and resource consumption are reduced. Further, the experiment process is simple and efficient: the ultrasound stimulation is performed once every other day and the epilepsy seizure time test is alternately performed, without complex pathological section, in vitro organ operation or invasive detection, data are quickly and directly obtained, the experiment cycle is further shortened, and the technical threshold and cost are reduced.

[0011] On this basis, the preset dose effect relationship assumption (for example, unimodal distribution, slope, peak value and the like) is used to effectively compensate for the modeling uncertainty caused by limited experimental data, and the dose benefit curve under each gear is quickly fitted based on the limited experimental data. The dose effect curve quickly generated in this way may have some sacrifices in absolute accuracy, but can reliably reflect the overall trend, accurately define the preferred dose range with potential, and realize efficient conversion from simple experiment to effective parameter derivation. Further, if the preliminary fitting result has uncertainty (for example, multiple peaks or too wide range), a high-low dose verification group can be set in the preferred interval for fine exploration.

[0012] The parameter positioning method for inhibiting PCOS complicated with epilepsy based on focused ultrasound provided in the embodiment of the application is especially suitable for personalized medical treatment scenarios. For example, when the parameters determined according to the average ovarian depth of a group and a disease (such as frequency and simulated focal plane distance) are combined, doctors or researchers can quickly explore and determine personalized effective parameters for specific groups (such as differences in ovarian depth caused by different races and body types) or different PCOS diseases. BRIEF DESCRIPTION OF DRAWINGS

[0013] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or prior art description. In all the drawings, similar elements or parts are generally identified by similar reference signs. In the drawings, the elements or parts are not necessarily drawn according to the actual proportions. Obviously, the drawings described below are some embodiments of the present application, and for those skilled in the art, other drawings can also be obtained without creative labor.

[0014] Figure 1 is a schematic flow chart of a parameter positioning method for inhibiting PCOS and concurrent epilepsy based on focused ultrasound provided by an embodiment of the present application; Figure 2 is an epilepsy seizure trend graph in an ultrasonic stimulation process provided by an embodiment of the present application; Figure 3 is a schematic diagram of a dose-effect curve under each gear provided by an embodiment of the present application; Figure 4 is a schematic diagram of a dose-effect curve under each gear provided by another embodiment of the present application; Figure 5 is a schematic diagram of a dose-effect curve under each gear provided by another embodiment of the present application; Figure 6 is a body weight change graph of an animal model at a key time node provided by an embodiment of the present application; Figure 7 is a comparison graph of serum hormone levels between each experimental group provided by an embodiment of the present application; Figure 8 is a schematic block diagram of a kit provided by an embodiment of the present application. DETAILED DESCRIPTION

[0015] In order to make the purpose, technical solutions and advantages of the embodiments of the present application more clear, the following will combine the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are some embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by those skilled in the art without creative labor are within the protection scope of the present application.

[0016] The flow chart shown in the drawings is only an example description, not necessarily including all the contents and operations / steps, and not necessarily executed in the described order. For example, some operations / steps can also be decomposed, combined or partially combined, so that the actual execution order can be changed according to the actual situation.

[0017] Herein, the suffix used for an element such as "module", "part" or "unit" is merely intended for ease of description and does not have a specific meaning unless otherwise specifically stated. Thus, "module", "part", or "unit" can be mixedly used.

[0018] Herein, the terms "upper", "lower", "inner", "outer", "front", "rear", "one side", "the other side", and the like indicate the orientation or positional relationship based on the orientation or positional relationship shown in the drawings, and are merely for convenience of description of the present application and simplification of the description, and do not indicate or imply that the device or element referred to must have a particular orientation, be constructed and operated in a particular orientation, and thus cannot be construed as limiting the present application. In addition, the terms "first", "second" are used only for descriptive purposes and cannot be construed as indicating or implying relative importance.

[0019] Herein, unless otherwise specifically stated and limited, the terms "mount", "provided with", "connected", and the like should be broadly understood, for example, "connected" can be fixedly connected, can be detachably connected, or integrally connected; can be mechanically connected, can be directly connected, or indirectly connected through an intermediate medium, can be internal communication of two elements. For those skilled in the art, the specific meaning of the above terms in the present application can be understood according to the specific circumstances.

[0020] Herein, the term "and / or" includes any and all combinations of one or more of the listed related items.

[0021] Herein, the term "a plurality of" means two or more, that is, it includes two, three, four, five, etc.

[0022] It should be noted that in this text, the term "includes", "comprises" or any other variant thereof is intended to cover non-exclusive inclusion, so that the process, method, article or device including a series of elements not only includes those elements, but also includes other elements not explicitly listed or inherent to such process, method, article or device. Without more limitations, the element defined by the statement "includes a" does not exclude the presence of another identical element in the process, method, article or device that includes the element.

[0023] As used in the present specification, the term "about" typically means + / - 5% of the stated value, more typically + / - 4% of the stated value, more typically + / - 3% of the stated value, more typically + / - 2% of the stated value, even more typically + / - 1% of the stated value, and even more typically + / - 0.5% of the stated value. 5%, more typically + / - 4% of the stated value, more typically + / - 3% of the stated value, more typically + / - 2% of the stated value, even more typically + / - 1% of the stated value, and even more typically + / - 0.5% of the stated value. 5%, more typically + / - 4% of the stated value, more typically + / - 3% of the stated value, more typically + / - 2% of the stated value, even more typically + / - 1% of the stated value, and even more typically + / - 0.5% of the stated value. 5%, more typically + / - 4% of the stated value, more typically + / - 3% of the stated value, more typically + / - 2% of the stated value, even more typically + / - 1% of the stated value, and even more typically + / - 0.5% of the stated value. 5%, more typically + / - 4% of the stated value, more typically + / - 3% of the stated value, more typically + / - 2% of the stated value, even more typically + / - 1% of the stated value, and even more typically + / - 0.5% of the stated value. 5%, more typically + / - 4% of the stated value, more typically + / - 3% of the stated value, more typically + / - 2% of the stated value, even more typically + / - 1% of the stated value, and even more typically + / - 0.5% of the stated value. 0.5%.

[0024] 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 the range should be considered as having specifically disclosed all possible subranges and independent numerical values ​​within those ranges. For example, range 1... The description of 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., as well as individual numbers within this range, such as 1, 2, 3, 4, 5, and 6. The above rules apply regardless of the breadth of the range.

[0025] As a non-invasive physical modulation method, the therapeutic effect of focused ultrasound highly depends on the precise coordination of several key parameters, including power, duty cycle, stimulation duration, frequency, and simulated focal plane distance.

[0026] Among these, power, also known as acoustic power, is the output intensity of the ultrasonic emission; duty cycle is the ratio of the ultrasonic pulse being on and off, such as a duty cycle of 10%, which means that 10 milliseconds are emitted every 100 milliseconds; stimulation duration is the duration of a single ultrasonic treatment (e.g., 30 seconds, 60 seconds, etc.) and / or the total duration of multiple ultrasonic treatments. Stimulation duration, power, and duty cycle together determine the total energy input (also known as dose).

[0027] Among these parameters, frequency refers to the acoustic frequency of ultrasound waves. Higher frequencies result in more precise focusing and reduced penetration depth; lower frequencies allow for deeper penetration but decrease focusing accuracy. The simulated focal plane distance is the preset depth position of the ultrasound focus within the body. Frequency and simulated focal plane distance need to be individually set based on individual anatomical structures (such as the depth of the ovary from the body surface) to ensure that energy is precisely focused on a specific area and to avoid accidental damage to surrounding tissues.

[0028] In this embodiment, power, duty cycle, and stimulation duration are used as adjustable variables. Effective parameter combinations are explored through changes in energy. Meanwhile, frequency and simulated focal plane distance are used as basic parameters and are not included in the variable exploration scope of each experiment. Instead, they are pre-set based on the group characteristics of the target population (such as the average ovarian depth corresponding to different races, body types, and animal models) and the specific symptoms of PCOS (such as ovarian volume, hormone levels, etc.), forming the basic framework for personalized treatment.

[0029] It should be understood that the parameter positioning method for inhibiting PCOS complicated with epilepsy based on focused ultrasound and the matching kit provided in the embodiments of the present application have excellent generalization ability and clinical adaptability. On the one hand, after a parameter exploration is completed for a specific population (such as different races, body types) or a specific PCOS subtype, the dose-effect curve and the preferred parameter combination obtained can be repeatedly used in the same population, thereby improving the clinical implementation efficiency of the treatment scheme; on the other hand, when facing a new target population or a new ultrasound instrument, the dose-effect curve and the preferred parameter combination can be quickly determined under the existing framework through a simple experimental design, and the physiological characteristics of different populations and the gear parameter settings of different ultrasound instruments can be flexibly adapted. Therefore, under the premise of ensuring treatment accuracy and safety, the embodiments of the present application greatly simplify the experimental process, shorten the research and development cycle, and reduce the amount of animal use and resource consumption, thereby providing a fast, reliable and easy-to-promote implementation path for the personalized clinical application of focused ultrasound in the complex scenario of PCOS complicated with epilepsy.

[0030] Some embodiments of the present application will be described in detail below with reference to the accompanying drawings. The following embodiments and features in the embodiments can be combined with each other without conflict.

[0031] Please refer to Figure 1 , Figure 1 is a schematic flowchart of a parameter positioning method for inhibiting PCOS complicated with epilepsy based on focused ultrasound provided in the embodiments of the present application, as Figure 1 indicated, the embodiments of the present application provide a parameter positioning method for inhibiting PCOS complicated with epilepsy based on focused ultrasound.

[0032] In S101, a plurality of preset gears are obtained, each gear corresponding to a different power and duty cycle combination; according to prior experimental data and a biological heat model, a safe interval of the stimulation duration under different gears is predicted.

[0033] Specifically, a plurality of preset gears are obtained, wherein the preset gears refer to a plurality of pre-divided ultrasound output levels (such as first gear, second gear, third gear, etc.), each gear corresponding to a fixed power and duty cycle combination, and the product of the power and the duty cycle gradually increases as the gear increases, representing stronger energy output. The specific number of gears and parameters can be flexibly set according to the device performance and treatment needs.

[0034] The prior experimental data refers to pre-obtained experimental information, and the sources include animal models (such as rats, mice), computer simulation results or critical points of tissue thermal injury observed in human trials. In combination with a small amount of prior experimental data, such as the critical stimulation duration that causes thermal injury of the ovary or the surrounding tissue of a rat model under a certain gear, the biological heat model is used to estimate the maximum safe duration that does not cause burns or tissue damage under different gears, and the safe interval of the stimulation duration corresponding to each gear is determined.

[0035] In some embodiments, the prior experimental data comprises experimental data of at least one gear causing immediate tissue damage at the first stimulation duration. The immediate tissue damage refers to the clear tissue damage observed by naked eyes, images or simple pathology within a short time (e.g., within a few minutes) after the end of the ultrasound stimulation, such as skin redness, bleeding, etc. For example, when the gear 4 is the sound power 6.5 W and the duty cycle is 40%, the prior experimental data can include that the gear 4 causes skin burns at the stimulation duration of 30 s.

[0036] In some embodiments, the bio-thermal model is the Pennes model, and the expression is as follows: ; wherein, is the sound power; is the duty cycle; is the stimulation duration; is the volume of the affected tissue; is the tissue density; is the specific heat capacity of the tissue; is the blood perfusion rate; is the perfusion constant; and is the energy conversion rate.

[0037] The Pennes bio-thermal model describes the relationship between the tissue temperature rise and the sound power, the duty cycle, the stimulation duration, etc. The remaining model parameters, such as the perfusion constant, the volume of the affected tissue, the tissue density, the specific heat capacity of the tissue, the blood perfusion rate, and the energy conversion rate, can be reasonably set according to the physiological characteristics of the actual experimental object (e.g., the abdominal soft tissue of a rat), the literature data, or the previous measurement results. For example, the perfusion constant can be 200 s.

[0038] It should be understood that the bio-thermal model is a calculation model based on the thermodynamic characteristics of biological tissue, which is used to evaluate whether the temperature threshold causing burns or tissue damage is approached or exceeded under different parameter combinations, so as to determine the safe operation boundary. In subsequent embodiments, the Pennes bio-thermal model will be taken as an example for illustration, but in actual application, the bio-thermal model can also be other existing bio-thermal models, such as the Weinbaum-Jiji (WJ) bio-thermal model, the two-phase hysteresis model, the blood vessel scale explicit model, etc., which are not limited herein.

[0039] In some embodiments, the S101 further comprises: predicting a safe threshold of the stimulation duration under different gears according to the prior experimental data and the bio-thermal model; obtaining the effective stimulation duration of each gear, and determining an effective threshold of the stimulation duration under different gears according to the effective stimulation duration; and obtaining a safe interval of the stimulation duration under different gears according to the safe threshold and the effective threshold.

[0040] Specifically, according to prior experimental data and a mature biological heat model, the longest stimulation duration under each preset gear without causing thermal damage, i.e., a safety threshold, is calculated, and the shortest stimulation duration under a specific gear that can achieve a preliminary therapeutic effect, i.e., an effective threshold, is obtained. The safety threshold is taken as the upper limit, and the effective threshold is taken as the lower limit, to demarcate a stimulation duration safety interval corresponding to each gear. When focused ultrasound is performed in the corresponding safety interval of each gear, the risk of tissue damage can be avoided, and the effect of ultrasound intervention can be ensured.

[0041] In some embodiments, the prior experimental data and the effective stimulation duration of each gear can be derived from a simplified pre-experiment. For example, a test stimulation duration is applied to an animal model under a certain gear, and it is observed whether immediate thermal damage (such as obvious redness) of the ovary or surrounding tissue occurs. If it is confirmed that slight damage occurs, the combination of the gear and the duration is marked as an unsafe threshold, and then the safety threshold is calculated. In other embodiments, the prior experimental data and the effective stimulation duration of each gear can be derived from existing experimental data.

[0042] It should be understood that, in the initial stage, a small amount of easily accessible prior experimental data is combined with a mature biological heat model to quickly predict the safety interval of the stimulation duration under different gears, thereby avoiding the high animal cost investment brought by traditional large-scale pre-experiments and greatly shortening the early exploration period.

[0043] For example, it is assumed that the ultrasonic therapeutic instrument has 5 gears, and the power and duty cycle settings of each gear are shown in Table 1.

[0044] Table 1. Power and duty cycle settings of each gear A pre-experiment was performed on the abdominal region of a rat. After shaving, 3rd, 4th, and 5th gears were used to apply 30-second ultrasonic stimulation to different abdominal regions of the same rat. The results showed that the 4th and 5th gears could cause skin burns within 30 seconds, while the 3rd gear did not observe damage under the same time, indicating that it was near the safety boundary. It is known that the normal skin temperature of a rat is about 34°C, and when the tissue temperature rises to 48-50°C and lasts for several minutes, and the tissue temperature reaches 55°C and maintains about 30 seconds, obvious thermal damage (such as second-degree burns) can be caused. Therefore, it can be inferred that the temperature rises by about 20°C when burns occur.

[0045] Based on this, the ratio formula can be simplified as: ; Taking the estimation of the safety threshold of the 3rd gear based on the prior experimental data of the 4th gear as an example, at this time, is the temperature rise when the 4th gear causes burns, corresponding to the temperature rise when a burn occurs at the 3rd gear, a duty cycle (e.g., 40%) for the 4th gear, a sound power (e.g., 6.5W) for the 4th gear, a stimulation duration when a burn occurs at the 4th gear (e.g., 30s); a duty cycle (e.g., 30%) for the 3rd gear, a sound power (e.g., 6.5W) for the 3rd gear, a stimulation duration when a burn occurs at the 3rd gear, i.e., the quantity to be estimated.

[0046] Suppose the temperature of both the 4th and 3rd gears increases by 20°C when a burn occurs, then Substitute the data into the ratio formula: ; Thus, t2 is estimated to be about 41 seconds, i.e., if the 3rd gear is executed for 41 seconds of focused ultrasound, the theoretical tissue damage risk is equivalent to that of the 4th gear executed for 30 seconds of focused ultrasound.

[0047] For the sake of safety, the safety threshold of the 3rd gear is set to 30 seconds. Similarly, further calculation shows that the safety threshold of the 2nd gear should be less than 72 seconds, and the safety threshold of the 1st gear should be less than 120 seconds. In some embodiments, when multiple safety thresholds are estimated according to different prior experimental data, the smallest safety threshold or the mean of multiple safety thresholds can be selected to avoid the risk of burns.

[0048] In some embodiments, the safety threshold estimated based on the Pennes bio-heat model can also be verified by experiments. For example, for the 3rd gear, the bio-heat model estimates that it should reach a burn risk equivalent to that of the 4th gear at 30 seconds when it is about 41 seconds; in an independent animal experiment, if a stimulus close to or slightly higher than this duration (e.g., 40-45 seconds) is applied to the 3rd gear, and if thermal damage to the skin or subcutaneous tissue is indeed observed, it indicates that the model prediction is consistent with the actual biological effect. Such verification can be used to confirm the applicability of the Pennes bio-heat model and the rationality of the parameters used in this experiment (e.g., the perfusion constant is 200s).

[0049] S102, according to the safety interval of the stimulation duration of each gear, a plurality of experimental parameter combinations of different preset doses are set, and the dose is the product of power, duty cycle and stimulation duration.

[0050] Specifically, the product of the power, the duty cycle and the stimulation duration is defined as a unified dose, so as to integrate different gear parameters, and according to the preset dose level, a suitable stimulation duration is selected in the safety interval of each gear, so that the dose calculated by the parameter combination is as close as possible to the preset dose level. For example, to achieve a target preset dose of about 75, 30 seconds can be selected at gear 3 (6.5W, 30%), about 70 seconds can be selected at gear 2 (4W, 30%), and about 100 seconds can be selected at gear 1 (2W, 40%), and these stimulation durations all fall within the safety interval of the respective gears.

[0051] The multiple parameter combinations formed thereby, although from different gears, have similar dose values, thereby covering diversified operating conditions through limited experiments under the premise of safety, and providing data support for subsequent construction and analysis of dose-effect relationship.

[0052] In some embodiments, S102 further includes: calculating a target stimulation duration of the current gear according to the preset dose and the power and the duty cycle corresponding to each gear; and if the target stimulation duration exceeds the safety interval of the stimulation duration of the current gear, not setting the experimental parameter combination of the current gear within the preset dose.

[0053] Specifically, for each preset dose, the theoretical stimulation duration required to achieve the dose is first back-calculated according to the power and the duty cycle of the current gear, and the calculation formula is "target stimulation duration ≈ dose / (power × duty cycle)", when the target stimulation duration exceeds the safety interval of the corresponding gear, the use of the gear at the dose is actively excluded, to avoid the risk of tissue damage caused by too high stimulation duration, and invalid or unstable experimental results caused by too low stimulation duration.

[0054] For example, to achieve a target preset dose of about 34, about 30 seconds can be selected at gear 2 (4W, 30%), and about 40 seconds can be selected at gear 1 (2W, 40%), and these stimulation durations all fall within the safety interval of the respective gears. The target stimulation duration of gear 3 (6.5W, 30%) is calculated to be about 17 seconds, but this duration is lower than its effective threshold (such as 20 seconds), so this combination is considered to be unstable or invalid due to too low duration, and therefore the parameter combination of gear 3 at this dose level is not set. Through this screening mechanism, all parameter combinations used meet dose consistency, safety and effectiveness constraints.

[0055] In some embodiments, the preset dose can be set based on a high limit dose and a preset division parameter (such as 1, 1 / 2, 1 / 4, 3 / 2, 1 / 3, etc.), wherein the high limit dose refers to the maximum effective dose that can be achieved in each gear under the premise of ensuring safety, for example, the dose that does not cause burns in prior experimental data, or the dose that does not cause burns after conversion by a biological heat model, and the high limit doses of different gears are close to each other. A series of preset doses satisfying the proportion can be generated according to the preset division parameter, for example, the high limit dose, 1 / 2 high limit dose, 1 / 4 high limit dose, and for example, the high limit dose, 3 / 2 high limit dose, 1 / 3 high limit dose, for covering the potential effective range from low to high.

[0056] In some embodiments, a high dose group of the high limit dose and a medium dose group of the 1 / 2 high limit dose are set for each gear. For example, the high limit dose is about 75, and the high dose group can include combinations of 3 gears for 30 seconds, 2 gears for 70 seconds, and 1 gear for 100 seconds; the dose of the medium dose group is about 34, and can include 2 gears for 30 seconds and 1 gear for 40 seconds.

[0057] In this way, the dose gradient is reasonable, a small amount of experiments can cover a wide range of parameter space, and blind selection of parameters beyond the safe or ineffective region is avoided, so that all experimental parameter combinations are within the safe and potentially effective range, and the experimental efficiency is improved.

[0058] S103, based on a plurality of experimental parameter combinations, respectively performing ultrasonic stimulation on the experimental model to obtain corresponding biological response results.

[0059] Specifically, the abdominal ovary region of the experimental model (such as a rat with PCOS and epilepsy) is irradiated once according to the experimental parameter combination. For example, about 60 adult female rats are prepared, and are divided into three stages, each stage independently performing daily gavage of letrozole 1 mg / kg (1% carboxymethylcellulose sodium assisted) for 3 consecutive weeks to establish a PCOS model. After verifying the success of the modeling by vaginal smear, the ovary position is determined and marked using an ultrasonic diagnostic instrument. After the rats are anesthetized using isoflurane, focused ultrasound is performed on the ovary region by using an ultrasonic treatment instrument for multiple stimulations.

[0060] After the experimental model is stimulated by a specific ultrasonic parameter, a measurable physiological or behavioral change (such as susceptibility to epilepsy) exhibited by the experimental model is detected as a biological response result, such as seizure time and seizure frequency. For example, the detection method can be intraperitoneal injection of 30 mg / kg of pentylenetetrazole (PTZ) to induce epilepsy, and the seizure condition is recorded as a biological response result.

[0061] In some embodiments, the biological response results include: seizure time obtained based on an epilepsy susceptibility test; the ultrasound stimulation is applied every other day in step S103, alternating with the epilepsy susceptibility test. It should be understood that ovarian function recovery and ovulation in experimental models (such as rats) require time, and the anesthetic isoflurane used during ultrasound stimulation can interfere with the epilepsy susceptibility test. Therefore, for the accuracy of the results, the ultrasound stimulation is scheduled every other day, spaced apart from the epilepsy susceptibility test.

[0062] For example, on day 1, a single ultrasound stimulation is applied to a PCOS epilepsy model rat; on day 2, an epilepsy susceptibility test is performed; on day 3, ultrasound stimulation is repeated; on day 4, another epilepsy susceptibility test is performed, and so on. The experimental process does not require surgical exposure of the ovary, tissue sectioning, or ex vivo manipulation; it only involves non-invasive ultrasound irradiation through surface localization, directly reflecting the therapeutic effect. The entire process is short, simple to operate, and provides intuitive data.

[0063] Please see Figure 2 , Figure 2 This application provides an embodiment of an epileptic seizure trend graph during ultrasound stimulation. For example... Figure 2 As shown, during the first 2-3 sessions of ultrasound stimulation, there was no significant improvement in seizure frequency. After 4 sessions, the high-dose group showed that level 3 (30s) (orange line) exacerbated seizure severity, while level 2 (30s) (blue line) had a certain inhibitory effect on seizures. Correspondingly, in four consecutive epilepsy susceptibility tests on the rat model, the seizure duration at level 3 (30s) was 181%, 184.8%, 93.5%, and 250% of that in the control group, while the seizure duration at level 2 (30s) was 92.59%, 21.21%, 13.85%, and 26.79% of that in the control group.

[0064] It should be understood that, during the experimental design phase, by introducing dosage as a unified metric, a limited number of representative dosage groups are set up. Each group contains parameter combinations with different levels but similar dosages, covering a wide parameter space with a small number of experiments, thus reducing the number of experimental operations and resource consumption. Furthermore, the experimental procedure is simple and efficient: ultrasound stimulation is performed every other day, alternating with seizure time testing, eliminating the need for complex pathological sections, ex vivo organ manipulation, or invasive testing, allowing for rapid and intuitive data acquisition, further shortening the experimental cycle and lowering the technical threshold and cost.

[0065] S104, based on the preset dose-response relationship, fits the dose-response curves for each level according to the biological response results of each experimental parameter combination at each level.

[0066] Specifically, based on a pre-assumed dose-effect relationship form (such as a unimodal curve, etc.), the dose values corresponding to different parameter combinations at each gear and their biological response results are correlated and fitted. For example, according to the significant and moderate seizure delays obtained at 30 seconds and 70 seconds under gear 2, a fast interpolation is made to conclude that the effect peak under this gear is likely to be located in the 34-75 dose interval, combined with the preset unimodal trend.

[0067] It should be understood that although the fitting curve has some sacrifice in absolute accuracy due to limited experimental data, it can effectively reflect the overall trend and quickly determine the potential high-efficiency dose range, providing a decision basis for whether to add a verification group in this interval later.

[0068] In some embodiments, the preset dose-effect relationship comprises one or more of the following: a. The dose-effect curve is unimodally distributed within the safety parameter interval; b. The peak dose of the dose-effect curve is inversely related to the values of power and duty cycle in the gear; c. The absolute value of the slope of the dose-effect curve is positively related to the values of power and duty cycle in the gear; d. The maximum curvature change rate of the dose-effect curve is less than a preset change rate threshold.

[0069] The preset dose-effect relationship a is set according to the Hormesis theory. It should be understood that biological systems generally exhibit a biphasic dose-response relationship to external stimuli, i.e., lower doses produce stimulating / beneficial effects, and high doses produce inhibitory / harmful effects, thereby forming a unimodal dose-effect curve in the shape of an inverted U. This biphasic dose-response curve is widely observed, and most drugs conform to this phenomenon (i.e., only one recommended dose), which is applied to ultrasound treatment.

[0070] The preset dose-effect relationships b and c are set according to the basic rules combined with the biological effects of ultrasound. The effects of ultrasound can be divided into thermal effects and mechanical effects. Within the common parameter range, thermal effects and mechanical effects increase approximately exponentially with the increase of ultrasound intensity (defined as the product of power and duty cycle), while the dose (defined as the product of power, duty cycle, and stimulation time) increases linearly with the ultrasound intensity. It should be understood that at the same dose, high gears have higher energy utilization rates due to high ultrasound intensity, and are more likely to reach peak response; while low gears need longer time (i.e., higher dose) to accumulate sufficient effects.

[0071] Therefore, the dose-effect curve of high gear usually reaches the peak at lower dose, and the rising / falling section is steeper (larger absolute value of slope); on the contrary, the peak of low gear curve appears at higher dose, and the change is more gentle (smaller absolute value of slope). For example, gear 2 may reach the optimal antiepileptic effect at dose 34, while gear 1 needs a dose of 70 or more to approach the same effect.

[0072] The preset dose-effect relationship d is set according to the constraint of curve smoothness to avoid unreasonable fluctuations caused by sparse experimental data or noise interference. Among them, the maximum curvature change rate refers to the maximum value of the curvature (i.e. the change rate of the degree of curve bending) on the dose-effect curve, and the corresponding preset change rate threshold is set based on the reasonable dynamic range in actual application, to ensure that the fitting curve presents a gradual and continuous trend change.

[0073] In some embodiments, please refer to Figure 3 , Figure 3 is a schematic diagram of the dose-effect curve of each gear provided by the embodiment of the present application, as shown in Figure 3 , the coordinate system of the dose-effect curve has an ultrasound dose as the horizontal axis and a treatment effect as the vertical axis, wherein the treatment effect can be the average value of the result of each epilepsy susceptibility test, and the treatment effect can be quantified as the average value of the results of multiple epilepsy susceptibility tests, for example, the average value of the seizure time of each epilepsy susceptibility test of the rat model in each experimental group; other physiological indicators such as the severity of seizures and the number of seizures per unit time can also be used.

[0074] In some embodiments, the treatment effect is defined as the average value of the difference between the seizure time of the control group and the test group in all rounds. For example, one epilepsy susceptibility test is required after each ultrasound stimulation, and the number of epilepsy susceptibility tests is , each test includes a PCOS control group and a plurality of test groups receiving specific ultrasound parameters, the average value of the seizure time of the plurality of test groups is , and the average value of the seizure time of the PCOS control group is . For each epilepsy susceptibility test, the calculation formula of the treatment effect is .

[0075] Taking 2 gears 70s as an example, the treatment effect can be quantitatively calculated by four test data: .

[0076] Therefore, the treatment effect of different gears at different dose levels is quantitatively obtained, and the biological response data points (such as Figure 3(The solid dots in the data) represent the therapeutic effect of a specific dose at a certain level. Based on these limited data points, curve fitting is performed in combination with the preset dose-effect relationship to deduce the dose-effect trend of each level.

[0077] In some embodiments, based on a preset dose-effect relationship and the obtained biological response data points for each gear level, the predicted region of the peak dose for each gear level can be determined according to the therapeutic effect trend corresponding to the data points. When a gear level has missing data points due to burn risk, unreliable parameters, or experimental abnormalities, making it impossible to directly fit its peak position, the peak dose of the gear level with missing data points can be reasonably inferred based on the preset dose-effect relationship b (i.e., the peak dose of the dose-effect curve is inversely correlated with the power and duty cycle values ​​in the gear level) and the predicted regions of the peak doses of other gear levels. For example, if the predicted peak dose of the high gear level is located in a lower dose range, while the predicted peak dose of the low gear level is located in a higher dose range, the peak dose of the intermediate gear level can be interpolated accordingly.

[0078] In some embodiments, when constructing the dose-response curve, c (i.e., the absolute value of the slope of the dose-response curve is positively correlated with the values ​​of power and duty cycle in the gear) can be used to optimize the curve shape in the prediction area. For example, the high gear curve shows a steeper rising / falling trend, while the low gear curve shows a gentler trend.

[0079] like Figure 3 As shown, level 2 contains two valid data points: medium and high doses. The therapeutic effect at the high dose is not significantly better than at the medium dose, indicating that its dose-response curve may have approached or exceeded the peak value. Therefore, it is reasonable to infer that the peak value is near the medium dose. Similarly, it can be determined that the peak dose of level 1 is greater than or equal to the high dose. For level 3, which has only one valid data point due to missing data, we can infer that the peak dose of level 3 may be lower than the medium dose based on the inverse correlation between the peak dose and the power and duty cycle values ​​of the level. Combined with the fact that the absolute value of the slope of the level 3 curve is greater than that of levels 1 and 2, we can finally plot the possible dose-response curve for level 3.

[0080] Therefore, even with sparse or partially missing data, reasonable dose-response curves that conform to physical mechanisms and biological response laws can be generated, providing a reliable basis for subsequent parameter optimization.

[0081] S105, Based on the dose-effect curve, determine the preferred dose range for each level, and conduct a feasibility assessment of the preferred dose range for each level to determine the preferred parameter combination for focused ultrasound.

[0082] From the dose-effect curve of each gear, the preferred dose range is identified, and then the actual feasibility of each gear is comprehensively screened. The feasibility evaluation can include the following dimensions: whether the preferred dose range has an immediate or delayed tissue heat damage risk; whether the preferred dose range is within the output capacity of the existing ultrasound instrument; whether the preferred dose range has promotion potential, for example, a medium intensity gear is more promotional than an extremely high or extremely low gear, which can be determined in advance by research and experiments to determine the priority of gear promotion. For example, gear 1 is effective in the high dose interval, but the required stimulation duration is close to or exceeds its safety threshold, with a risk of scalding. The preferred dose of gear 3 is in the low dose interval, but because the power and duty cycle are too high, there is still a risk of scalding in actual application. In contrast, the preferred dose range of gear 2 falls completely within its safety interval, and the experimental data is stable and reproducible, so gear 2 and its corresponding parameters (such as gear 2 for 30 seconds) are finally selected as the preferred parameter combination.

[0083] It should be understood that the preferred parameter combination is not theoretically optimal, but a feasible solution that has been experimentally verified to be suitable and effective, and can be used for subsequent animal repeated verification, adaptation to different PCOS subtypes, or as an initial parameter template for clinical conversion.

[0084] In some embodiments, the preferred parameter combination is retested to verify the stability of the parameters. For example, an additional repeated test of a group (such as 5 rat models) of 2 gears for 30 seconds shows that the treatment effect of 2 gears for 30 seconds is about 35% of the average duration of the PCOS control group, and the parameters have stability.

[0085] In some embodiments, the number of ultrasound stimulations is 8 to 10 times. The treatment effect of 2 gears for 30 seconds is significant and relatively stable after two weeks of treatment, so the stimulation duration can be 10 times.

[0086] In some embodiments, the method further comprises: monitoring whether delayed tissue damage occurs during the execution of step S103; if so, updating the safety interval of the corresponding gear according to the experimental data of the delayed tissue damage and the biological heat model.

[0087] Specifically, during the ultrasound stimulation process, whether the experimental animals have delayed tissue damage is observed synchronously. For example, after the first 2-3 times of high-dose group ultrasound stimulation every other day, no abnormalities are found on the skin surface, but after the fourth stimulation, gradually, burns begin to appear, and subsequent sampling also finds subcutaneous or abdominal organ burn marks, indicating that there is a delayed damage caused by cumulative thermal effect. At this time, the total number of stimulations at which the damage occurs in this gear is combined with the single time length, which is regarded as a new critical condition, and the aforementioned biological heat model (such as the ratio formula based on the Pennes model) is used for estimation. For example, if the damage occurs after 4 times of stimulation and 30 seconds of single stimulation at gear 3, it can be equivalent to estimate that the similar delayed risk may be triggered when the stimulation time is 50 seconds at gear 2, so the upper limit of the safety interval of gear 2 is adjusted from the original 72 seconds to 50 seconds. The updated safety interval can be used to guide the parameter adjustment or secondary fine exploration of subsequent experiments, and the safety of the experiment is improved.

[0088] In some embodiments, the biological response size and change trend of 1 / 2 high-dose and high-dose meet the following typical mode, and a reasonable dose-effect curve can be directly constructed based on limited data: the low-gear group monotonically increases within the high-dose, the higher-gear group begins to decrease before 1 / 2 high-dose, and the optimal value of the relatively intermediate-dose group is located between the upper and lower gears. If the number of gears is large (such as more than 5 gears), the curve shape of adjacent gears can quickly converge to a relatively narrow optimal dose range; on the contrary, if the number of gears is small (such as only 3 gears), the possible optimal peak range needs to be inferred in combination with the existing curve shape, and the parameter is supplemented in the possible peak range for secondary verification.

[0089] For example, the preferred dose range includes the peak position of the dose-effect curve, and S105 includes: when the dose-effect curve has multiple candidate peaks and / or the preferred dose range is greater than a preset range threshold, obtaining a target experimental parameter combination located in the preferred dose range; setting at least two verification parameter combinations under the same gear of the target experimental parameter combination; wherein one verification parameter combination has a dose greater than that of the target experimental parameter combination, and the other verification parameter combination has a dose smaller than that of the target experimental parameter combination; performing steps S103-S105 to update the dose-effect curve based on the data of the verification parameter combination.

[0090] Specifically, if the dose-effect curve of a certain gear has multiple candidate peaks or the preferred dose range is too wide due to sparse data, a fine verification process is started, for example, in the foregoing example, it is inferred that the peak dose of gear 2 is near the medium dose, but it cannot be determined whether the peak dose of gear 2 is located at the medium dose, lower than the medium dose, or higher than the medium dose, at this time, there may be multiple candidate peaks, which makes the estimation of the dose curve inaccurate or needs to divide a large preferred dose range.

[0091] The target experimental parameter combination (e.g., 2nd gear 30 seconds, dose 36) in the preferred dose range is taken as a reference, and two sets of verification parameter combinations are added under the same gear: one set of slightly higher dose (e.g., 2nd gear 40 seconds, dose 48), and the other set of slightly lower dose (e.g., 2nd gear 20 seconds, dose 24), and all fall within the safe interval of gear 2. Then, S103 to S105 are repeatedly executed to obtain the new response data of the biological sample, and the dose-effect curve is refitted.

[0092] Please refer to Figure 4 to Figure 5 , Figure 4 is a schematic diagram of the dose-effect curve of each gear provided by an embodiment of the present application, Figure 5 is another schematic diagram of the dose-effect curve of each gear provided by an embodiment of the present application. In some cases, as shown in Figure 4 , the blue hollow points represent the newly added verification data points, and the curve trend indicates that the peak value is biased to the high-dose side, and accordingly the preferred dose range of the 2nd gear can be corrected, and the verification parameter combination with a higher dose (e.g., 2nd gear 40 seconds) is updated as the new preferred parameter combination. In other cases, as shown in Figure 5 , the yellow hollow points represent the newly added verification data points, and the curve trend indicates that the peak value is biased to the low-dose side, Figure 3 the initial speculation of the peak position is wrong, at this time, the preferred dose range should be adjusted to the low-dose side, and the verification parameter combination with a lower dose (e.g., 2nd gear 20 seconds) should be adopted as a better choice. In this way, the fine exploration of the parameters can be quickly and simply realized, and a better parameter range basis can be provided for subsequent personalized medical treatment.

[0093] In some embodiments, after the step of obtaining a plurality of preset gears, the method further comprises: adjusting a preset division parameter of the preset dose according to the number of the preset gears, to update the values and the number of the preset doses; wherein the fewer the number of the preset gears is, the more the number of the preset doses corresponding to the preset division parameter is.

[0094] For example, when the number of the preset gears is small, the preset division parameter of the preset dose is adjusted to be 3 equal parts, i.e., a high-limit dose, 3 / 2 high-limit dose, and 1 / 3 high-limit dose, to improve the discriminability of the initial dose-effect curve, so as to more clearly predict the dose-effect trend under each gear, and avoid misjudgment of the peak value due to insufficient dose coverage. For another example, when the number of the preset gears is large, the preset division parameter of the preset dose is adjusted to be 2 equal parts, i.e., a high-limit dose and 1 / 2 high-limit dose, at this time, although the data points of each gear are small, the dose-effect curve under each gear can be predicted in combination with the preset dose-effect relationship and the curve shape of multiple gears.

[0095] In some embodiments, during the experiment, the weight change of the animal model is detected. Please refer to Figure 6 ,Figure 6 This is a graph showing the weight changes of the animal model provided in this application at key time points, such as... Figure 6 As shown, the experiment included a PCOS control group and three dosage experimental groups: a high-dose group, a medium-dose group, and a low-dose group. After letrozole administration, the body weight of the experimental models (e.g., rats) began to increase. After the ultrasound was initiated, the body weight decreased, and then gradually recovered after the ultrasound ended. Rapid weight gain is a characteristic of PCOS. The slower rate of weight gain after ultrasound may indicate a therapeutic effect of ultrasound stimulation, but other factors such as inflammation, reduced food intake, or gastrointestinal irritation cannot be ruled out.

[0096] In some embodiments, after the test is completed, perfusion sampling is performed, serum is subjected to mass spectrometry hormone detection, and brain tissue is subjected to immunofluorescence staining and mass spectrometry analysis, etc. Please refer to Figure 7 , Figure 7 This is a comparison chart of serum hormone levels between different experimental groups provided in the embodiments of this application, such as... Figure 7 As shown, mass spectrometry analysis was performed on the hormones in each group. The results showed that all parameters could increase the estrogen level in PCOS rats. The estrogen level in ordinary PCOS rats was about 20% of the normal level. The estrogen level in the medium-dose group (e.g., level 2 for 30 seconds) could increase to 3.5 times that of the PCOS group, which is close to 80% of the normal rat level. The other parameters could also be increased to about 50% of the normal rat level. The androgen level in the medium-dose group was about 20% lower than that in the PCOS group. The other parameters could not reduce the androgen level, but instead showed an increasing trend.

[0097] In some embodiments, when the experimental model is a rat, the preferred parameter combination includes: acoustic power of 4W, duty cycle of 30%, stimulation duration of 30s, frequency of 1.028MHz, and simulated focal plane distance of 11.5mm. Rats stimulated with these parameters experienced approximately 30% of the duration of grade 5 seizures in the PCOS control group, suggesting a significant reduction in the burden of severe seizures.

[0098] This application also provides a reagent kit 200, please refer to... Figure 8 , Figure 8 This is a schematic block diagram of a reagent kit provided in an embodiment of this application. The reagent kit 200 can be applied to an experimental setup to implement the aforementioned parameter localization method for suppressing PCOS-related epilepsy based on focused ultrasound.

[0099] like Figure 8 As shown, the kit 200 includes: The safe interval testing module 201 is used to acquire multiple preset levels, each level corresponding to different combinations of power and duty cycle; based on prior experimental data and biothermal models, it predicts the safe interval of stimulation duration at different levels. The experimental parameter setting module 202 is configured to set a plurality of experimental parameter combinations of different preset doses according to a safety interval of the stimulation duration of each gear, wherein the dose is the product of the power, the duty cycle and the stimulation duration. The ultrasound stimulation execution module 203 is configured to perform ultrasound stimulation on the experimental model based on the plurality of experimental parameter combinations to obtain corresponding biological response results. The dose-effect curve module 204 is configured to fit a dose-effect curve of each gear based on a preset dose-effect relationship and the biological response results of each experimental parameter combination under each gear, wherein the preset dose-effect relationship includes: a. the dose-effect curve is unimodal distributed within a safety parameter interval; and b. the peak dose of the dose-effect curve is inversely related to the values of the power and the duty cycle in the gear. The preferred dose range module 205 is configured to determine a preferred dose range of each gear based on the dose-effect curve, and to perform a feasibility evaluation on the preferred dose range of each gear to determine a preferred parameter combination of the focused ultrasound.

[0100] For example, the prior experimental data includes experimental data of at least one gear causing immediate tissue damage at a first stimulation duration. The expression of the biological heat model is: ; wherein, is the acoustic power; is the duty cycle; is the stimulation duration; is the volume of the affected tissue; is the tissue density; is the specific heat capacity of the tissue; is the blood perfusion rate; is the perfusion constant; and is the energy conversion rate.

[0101] For example, the safety interval test module 201 further includes a safety threshold sub-module, an effective threshold sub-module and a safety interval sub-module. The safety threshold sub-module is configured to predict a safety threshold of the stimulation duration under different gears according to the prior experimental data and the biological heat model. The effective threshold sub-module is configured to obtain an effective stimulation duration of each gear, and to determine an effective threshold of the stimulation duration under different gears according to the effective stimulation duration. The safety interval sub-module is configured to obtain a safety interval of the stimulation duration under different gears according to the safety threshold and the effective threshold.

[0102] For example, the experimental parameter setting module 202 further includes a target duration sub-module and a parameter combination sub-module. a target duration submodule configured to calculate a target stimulation duration of the current gear according to the preset dose and the power and duty cycle corresponding to each gear; a parameter combination submodule configured to, if the target stimulation duration exceeds a safe interval of the stimulation duration of the current gear, not set an experimental parameter combination of the current gear within the preset dose.

[0103] In an example, the kit 200 further comprises a delayed injury detection module configured to monitor whether a delayed tissue injury occurs, and, if so, update a safe interval of the corresponding gear according to experimental data of the delayed tissue injury and the biological thermal model.

[0104] In an example, the preset dose-effect relationship further comprises: c. the absolute value of the slope of the dose-effect curve is positively correlated with the values of the power and duty cycle in the gear; and d. the maximum curvature change rate of the dose-effect curve is less than a preset change rate threshold.

[0105] In an example, the biological response result comprises: a seizure time obtained based on a seizure susceptibility test; and the ultrasound stimulation is applied at a frequency of once every other day and is alternately performed with the seizure susceptibility test.

[0106] In an example, the preferred dose range includes a peak position of the dose-effect curve, and the kit 200 further comprises: a reference parameter module, a verification parameter module, and a data updating module. The reference parameter module is configured to, when the dose-effect curve has multiple candidate peaks or the preferred dose range is greater than a preset range threshold, obtain a target experimental parameter combination located in the preferred dose range. The verification parameter module is configured to set at least two sets of verification parameter combinations in the same gear as the target experimental parameter combination; wherein one set of verification parameter combinations has a dose greater than that of the target experimental parameter combination, and the other set of verification parameter combinations has a dose less than that of the target experimental parameter combination. The data updating module is configured to trigger the ultrasound stimulation execution module 203, the dose-effect curve module 204, and the preferred dose range module 205 to update the dose-effect curve based on data of the verification parameter combinations.

[0107] In an example, the parameters of the focused ultrasound further comprise a frequency and a simulated focal plane distance, and the frequency and the simulated focal plane distance are determined according to an average ovarian depth of a population and a polycystic ovary disease.

[0108] In an example, the kit 200 further comprises a division parameter adjustment module configured to adjust preset division parameters of a preset dose according to a number of preset gears to update a value and a number of the preset dose; wherein the fewer the number of preset gears, the greater the number of preset doses corresponding to the preset division parameters.

[0109] In some embodiments, the experimental model is a rat model of polycystic ovary syndrome; the experimental device can be used to perform ultrasound stimulation on the rat model of polycystic ovary syndrome.

[0110] It should be noted that, for the convenience and brevity of description, the specific working processes of the above-described kit and each module and unit can be referred to the corresponding processes in the foregoing method embodiments, which will not be described herein.

[0111] The above merely describes specific embodiments of the present application, but the protection scope of the present application is not limited thereto, and any person skilled in the art can easily think of various equivalent modifications or replacements within the technical scope disclosed by the present application, and these modifications or replacements shall be encompassed within the protection scope of the present application. Therefore, the protection scope of the present application shall be subject to the protection scope of the claims.

Claims

1. A parameter localization method for suppressing PCOS-related epilepsy based on focused ultrasound, characterized in that, The parameters of the focused ultrasound include power, duty cycle, and stimulation duration, and the method includes: S101: Acquire multiple preset power levels, each corresponding to a different combination of power and duty cycle; based on prior experimental data and biothermal models, predict the safe range of stimulation duration at different power levels. S102, based on the safe range of stimulation duration for each level, several combinations of experimental parameters with different preset doses are set, wherein the dose is the product of power, duty cycle and stimulation duration; S103, based on several combinations of the experimental parameters, the experimental model is subjected to ultrasonic stimulation to obtain the corresponding biological response results; S104, based on a preset dose-effect relationship, according to the biological response results of each combination of experimental parameters at each level, the dose-effect curves at each level are fitted respectively; the preset dose-effect relationship includes: a. the dose-effect curves exhibit a single-peak distribution within the safe parameter range; b. the peak dose of the dose-effect curves is inversely correlated with the values ​​of power and duty cycle at each level; S105, Based on the dose-effect curve, determine the preferred dose range for each level, and conduct a feasibility assessment of the preferred dose range for each level to determine the preferred parameter combination for focused ultrasound.

2. The method according to claim 1, characterized in that, The prior experimental data includes experimental data on immediate tissue damage caused by at least one setting at the first stimulation duration; The expression for the biothermal model is: ； in, Sound power; Duty cycle; For stimulation duration; For the volume of the tissue acting; Tissue density; For the specific heat capacity of the tissue; Blood perfusion rate; The infusion constant; This refers to the energy conversion rate.

3. The method according to claim 1 or 2, characterized in that, S101 further includes: Based on prior experimental data and biothermal models, predict the safe threshold for stimulation duration at different levels; Obtain the effective stimulation duration for each level, and determine the effective threshold for stimulation duration under different levels based on the effective stimulation duration; Based on the safety threshold and the effective threshold, a safe range for stimulation duration at different levels is obtained.

4. The method according to claim 1, characterized in that, S102 also includes: Calculate the target stimulation duration for the current level based on the preset dose and the power and duty cycle corresponding to each level. If the target stimulation duration exceeds the safe range for stimulation duration at the current level, then the experimental parameter combination for the current level will not be set within the preset dose range.

5. The method according to claim 1, characterized in that, The method further includes: During step S103, monitor for delayed tissue damage. If so, the safety range for the corresponding gear is updated based on the experimental data of delayed tissue damage and the biothermal model.

6. The method according to claim 1, characterized in that, The preset dose-response relationship also includes: c. The absolute value of the slope of the dose-response curve is positively correlated with the values ​​of power and duty cycle in the gear. d. The maximum rate of change of curvature of the dose-response curve is less than the preset rate of change threshold.

7. The method according to claim 1, characterized in that, The biological response results include: the duration of epileptic seizures obtained based on epilepsy susceptibility testing; The ultrasound stimulation is applied in step S103 at a frequency of once every other day and is performed alternately with the epilepsy susceptibility test.

8. The method according to claim 1, characterized in that, The preferred dose range includes the peak position of the dose-response curve, and S105 includes: When the dose-effect curve has multiple candidate peaks or the preferred dose range is greater than a preset range threshold, obtain the target experimental parameter combination within the preferred dose range; At the same level of the target experimental parameter combination, at least two sets of verification parameter combinations are set; wherein, the dose of one set of verification parameter combinations is greater than the dose of the target experimental parameter combination, and the dose of the other set of verification parameter combinations is less than the dose of the target experimental parameter combination. Perform steps S103 to S105 to update the dose-response curve based on the data from the combination of the verification parameters.

9. The method according to claim 1, characterized in that, The parameters of the focused ultrasound also include frequency and simulated focal plane distance, which are determined based on the average ovarian depth of the population and the symptoms of polycystic ovary syndrome.

10. A reagent kit, characterized in that, The kit includes: The safe zone testing module is used to acquire multiple preset power levels, each corresponding to a different combination of power and duty cycle; based on prior experimental data and biothermal models, it predicts the safe zone of stimulation duration at different power levels. The experimental parameter setting module is used to set several combinations of experimental parameters with different preset doses according to the safe range of stimulation duration for each level. The dose is the product of power, duty cycle and stimulation duration. An ultrasound stimulation execution module is used to perform ultrasound stimulation on the experimental model based on several combinations of the experimental parameters, and obtain the corresponding biological response results. The dose-response curve module is used to fit the dose-response curve for each level based on a preset dose-response relationship and the biological response results of each combination of experimental parameters at each level. The preset dose-response relationship includes: a. The dose-response curve exhibits a single-peak distribution within the safe parameter range; b. The peak dose of the dose-response curve is inversely correlated with the power and duty cycle values ​​at each level. The preferred dose range module is used to determine the preferred dose range for each level based on the dose-effect curve, and to conduct a feasibility assessment of the preferred dose range for each level in order to determine the preferred parameter combination for focused ultrasound.

Images