System for blind state maintenance in a neuromodulation randomized double-blind trial

Abstract

The embodiment of the specification provides a system for blind state maintenance in neuromodulation randomized double-blind test, and relates to the field of intelligent medical treatment. The system comprises: an information acquisition module configured to acquire grouping information of a plurality of detection objects including a stimulation group and a pseudo-stimulation group; an execution receiving module configured to receive an execution operation for a target detection object by using an experimental device; a first pre-stimulation module and a second pre-stimulation module configured to, in response to the execution operation, control an execution mechanism to execute a first action and a second action on the target detection object based on the execution operation regardless of whether the target detection object is the stimulation group or the pseudo-stimulation group; and a test stimulation module configured to, when the target detection object is the stimulation group, control the execution mechanism to execute an action of maintaining a rated stimulation intensity on the target detection object based on the execution operation, and when the target detection object is the pseudo-stimulation group, control the execution mechanism to execute an action of 0 stimulation intensity on the target detection object based on the execution operation.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of intelligent medical treatment, and more particularly, to a system for maintaining blind state in a neural regulation randomized double-blind test. BACKGROUND

[0002] A double-blind experiment refers to an experiment in which neither the tester nor the testee knows the group (experimental group or control group) to which the testee belongs, and the analyzer usually does not know which group the analyzed data belongs to. The double-blind experiment aims to eliminate subjective bias and personal preferences that may exist in the consciousness of the experimenter and the participants. In most cases, a double-blind experiment requires a very high degree of scientific rigor.

[0003] Although theoretically, a double-blind experiment can be achieved in clinical practice, the group information of the test drug may be inferred or known, for example, through differences in the operation modes of dispensing, administering, and sample collection corresponding to different groups of subjects, or based on the specificity of the group of subjects in terms of blood drug concentration, test results, or adverse drug reactions (ADRs), the subject's group information can be inferred. For example, in the treatment of refractory epilepsy, Parkinson's disease, and other neurological diseases, vagus nerve electrical stimulation (VNS) and deep brain electrical stimulation (DBS) are two different neural regulation techniques that have a significant effect on the treatment of diseases, but the double-blind test in the implementation process is relatively complex, and the risk of breaking the blind state is relatively high. SUMMARY

[0004] The present application aims to at least solve one of the technical problems existing in the prior art. To this end, the present application provides a system for maintaining blind state in a neural regulation randomized double-blind test; the method of the present application adds a pre-stimulation step before the actual test stimulation to avoid breaking the blind state during the implementation process.

[0005] The first aspect of the present application discloses a system for maintaining blind state in a neural regulation randomized double-blind test, the system comprising:

[0006] An information acquisition module for acquiring grouping information of a plurality of detection objects; the grouping information includes a stimulation group and a pseudo-stimulation group;

[0007] An execution receiving module for receiving an execution operation for a target detection object using an experimental device, the target detection object being one of the plurality of detection objects, the execution operation being used to indicate an identifier and a parameter value of an execution parameter;

[0008] A first pre-stimulation module for controlling an execution mechanism to execute a first action on the target detection object based on the execution operation in response to the execution operation, regardless of whether the target detection object is in the stimulation group or the pseudo-stimulation group;

[0009] The second pre-stimulation module is used to respond to the execution operation and control the execution mechanism to perform a second action on the target detection object based on the execution operation, regardless of whether the target detection object is a stimulation group or a spurious stimulation group.

[0010] The experimental stimulus module is used to control the actuator to maintain the rated stimulus intensity on the target detection object when the target detection object is a stimulus group, and to control the actuator to perform an action with a stimulus intensity of 0 on the target detection object when the target detection object is a spurious stimulus group.

[0011] In some embodiments, the first action includes: increasing the stimulation intensity from 0 to a first stimulation intensity from an initial time point to a first time point, and maintaining the first stimulation intensity to a second time point;

[0012] The second action includes: from the second time point to the third time point, the stimulation intensity is increased from the first stimulation intensity to the second stimulation intensity as the rated stimulation intensity;

[0013] Optionally, the second stimulus intensity is the preset maximum stimulus intensity;

[0014] Optionally, between the second pre-stimulation module and the trial stimulation module, the system further includes:

[0015] The adverse reaction judgment module is used to receive the reaction message of the target detection object, determine whether an adverse reaction has occurred based on the reaction message, and if so, execute the first action again for the target detection object that has an adverse reaction.

[0016] The tolerance assessment module is used to receive the duration of adverse reactions of the target detection object after the first stimulus intensity, and to determine whether the target detection object tolerates the reaction based on the duration. If the object does not tolerate the reaction, the first stimulus intensity is maintained as the rated stimulus intensity; if the object tolerates the reaction, the intensity is increased to the second stimulus intensity as the rated stimulus intensity.

[0017] In some embodiments, the time points are all calculated from the initial time point;

[0018] Optionally, the first time point is 2-3 days;

[0019] Optionally, the second time point is 4-5 days;

[0020] Optionally, the third time point is 1-2 weeks.

[0021] In some embodiments, the grouping information is obtained by randomly grouping the detection objects;

[0022] Optionally, the information acquisition module also includes a tool for acquiring stimulus types for multiple detection objects, including VNS and DBS.

[0023] In some embodiments, the system further includes a blindness assessment and correction module, which is used to assess the patient's blindness through a structured questionnaire (including questions such as "the probability of you receiving real treatment" and "the basis for your guess"). If the guess accuracy rate of a certain group exceeds 60%, dynamic parameter adjustment is initiated (such as fine-tuning the difference in current intensity between the treatment group and the control group).

[0024] In some embodiments, the system further includes:

[0025] The first pre-stimulation feedback module is used to receive feedback information sent by the execution structure as target feedback information when the first action is performed on the target detection object.

[0026] The second pre-stimulation feedback module is used to receive feedback information sent by the execution structure as target feedback information when the second action is performed on the target detection object.

[0027] The experimental stimulus feedback module is used to receive feedback information sent by the execution structure as target feedback information when the target detection object is a stimulus group or a spurious stimulus group.

[0028] A second aspect of this application discloses an electronic device, comprising: a memory and a processor; the memory is used to store a computer program; the processor executes the computer program to perform the following steps:

[0029] Obtain grouping information for multiple detection subjects; the grouping information includes stimulus groups and spurious stimulus groups.

[0030] The experimental equipment is used to receive the execution operation for the target detection object, which is one of multiple detection objects. The execution operation is used to indicate the identifier and parameter value of the execution parameters.

[0031] In response to the execution operation, regardless of whether the target detection object is a stimulus group or a spurious stimulus group, the control actuator performs the first action on the target detection object based on the execution operation.

[0032] In response to the execution operation, regardless of whether the target detection object is a stimulus group or a spurious stimulus group, the control actuator performs a second action on the target detection object based on the execution operation.

[0033] When the target detection object is a stimulus group, the control actuator performs an action to maintain the rated stimulus intensity on the target detection object based on the execution operation; when the target detection object is a spurious stimulus group, the control actuator performs an action to reduce the stimulus intensity to 0 on the target detection object based on the execution operation.

[0034] The third aspect of this application discloses a device for maintaining blindness in a randomized double-blind trial of neural modulation, characterized in that the device includes experimental equipment, an execution structure, and the electronic equipment disclosed in the second aspect of this application.

[0035] In some embodiments, the experimental device is a programmable device and the actuator is a stimulator disposed within the body of the target object; or, the experimental device is an electromagnetic wave control device and the actuator includes an electromagnetic wave generating device and an electromagnetic wave detecting device.

[0036] In some embodiments, the experimental equipment is a drug dispensing control device, and the actuators include a robotic arm and sensors.

[0037] This application has the following beneficial effects:

[0038] This application innovatively discloses a system for maintaining blinding in randomized double-blind trials of neuromodulation. For example, in a vagus nerve stimulation (VNS) experiment, the maximum VNS stimulation intensity, such as 0.8 mA, is first set before the experiment. For all patients in the control and sham stimulation groups, the intensity is gradually adjusted to the maximum within 2-3 days, allowing all patients to experience the relevant adverse reactions. Most of these adverse reactions are transient and generally do not recur when the same intensity is reached again. Afterwards, the corresponding programming settings are performed according to the group, with the sham stimulation group set to 0. Since the diseases being treated are mostly chronic and require long-term stimulation, this short-term pre-stimulation before the experiment will not significantly affect the treatment results. Therefore, it can effectively avoid unblinding and ensure the authenticity of the experimental results. Attached Figure Description

[0039] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0040] Figure 1 This is a schematic diagram of the system provided in the first aspect of the present invention;

[0041] Figure 2 This is a schematic diagram of a computer device provided in an embodiment of the present invention;

[0042] Figure 3 This is a schematic diagram of the architecture of an exemplary computing device provided in an embodiment of the present invention;

[0043] Figure 4 This is a schematic diagram of the storage medium provided in an embodiment of the present invention;

[0044] Figure 5 This is a comparison of the system process provided in this embodiment of the invention with previous methods. Detailed Implementation

[0045] To enable those skilled in the art to better understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0046] In some of the processes described in the specification, claims, and accompanying drawings of this invention, multiple operations appearing in a specific order are included. However, it should be clearly understood that these operations may not be executed in the order they appear herein, or may be executed in parallel. The operation numbers, such as 101, 102, etc., are merely used to distinguish different operations and do not represent any execution order. Furthermore, these processes may include more or fewer operations, and these operations may be executed sequentially or in parallel. It should be noted that the descriptions such as "first," "second," etc., in this document are used to distinguish different messages, devices, modules, etc., and do not represent a sequential order, nor do they limit "first" and "second" to different types.

[0047] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0048] Figure 1 This is a schematic diagram of a system for maintaining blindness in a randomized double-blind trial of neural modulation, provided by an embodiment of the present invention. Specifically, the system includes the following steps:

[0049] Information acquisition module 101 is used to acquire grouping information of multiple detection objects; the grouping information includes stimulus group and spurious stimulus group;

[0050] In some embodiments, the term “subject of testing” as used herein refers to any animal (e.g., a mammal), including but not limited to humans, non-human primates, rodents, etc., that will become the recipient of a particular treatment. Generally, the terms “subject” and “patient” are used interchangeably herein when referring to human subjects. Preferably, the subject of testing is a human.

[0051] In some embodiments, the grouping information is obtained by randomly grouping the detection objects.

[0052] In some embodiments, the information acquisition module further includes methods for acquiring stimulation types for multiple detection subjects, including VNS and DBS. Vagus nerve stimulation (VNS) is an important neuromodulation technique that delivers electrical pulses to the vagus nerve to achieve therapeutic effects. It can be used to treat various diseases, such as epilepsy, depression, cognitive impairment, and post-stroke limb dysfunction. Deep brain stimulation (DBS) is a neuromodulation technique that modulates nerve function by implanting electrodes in specific brain nuclei and applying controllable electrical pulses. It falls under the category of "minimally invasive surgery" (without removing brain tissue). Its core principle is similar to a "brain pacemaker," intervening in abnormal neural circuit activity through electrical signals to improve symptoms caused by neurological dysfunction. It has become an important treatment for many intractable neurological diseases.

[0053] The execution receiving module 102 is used to receive execution operations for a target detection object using experimental equipment. The target detection object is one of multiple detection objects, and the execution operation is used to indicate the identifier and parameter value of the execution parameters.

[0054] The first pre-stimulation module 103 is used to respond to the execution operation, regardless of whether the target detection object is a stimulation group or a spurious stimulation group, to control the execution mechanism to perform a first action on the target detection object based on the execution operation.

[0055] In some embodiments, the first action includes: increasing the stimulation intensity from 0 to a first stimulation intensity from an initial time point to a first time point, and maintaining the first stimulation intensity to a second time point;

[0056] The second action includes: from the second time point to the third time point, the stimulation intensity is increased from the first stimulation intensity to the second stimulation intensity as the rated stimulation intensity;

[0057] In some embodiments, the second stimulation intensity is a preset maximum stimulation intensity.

[0058] The second pre-stimulation module 104 is used to respond to the execution operation, regardless of whether the target detection object is a stimulation group or a spurious stimulation group, to control the execution mechanism to perform a second action on the target detection object based on the execution operation.

[0059] In some embodiments, between the second pre-stimulation module and the trial stimulation module, the system further includes:

[0060] The adverse reaction judgment module is used to receive the reaction message of the target detection object, determine whether an adverse reaction has occurred based on the reaction message, and if so, execute the first action again for the target detection object that has an adverse reaction.

[0061] The tolerance assessment module is used to receive the duration of adverse reactions of the target detection object after the first stimulus intensity, and to determine whether the target detection object tolerates the reaction based on the duration. If the object does not tolerate the reaction, the first stimulus intensity is maintained as the rated stimulus intensity; if the object tolerates the reaction, the intensity is increased to the second stimulus intensity as the rated stimulus intensity.

[0062] In some embodiments, all time points are calculated from the initial time point; the first time point is 2-3 days; the second time point is 4-5 days; and the third time point is 1-2 weeks.

[0063] The experimental stimulus module 105 is used to control the actuator to perform an action to maintain the rated stimulus intensity on the target detection object when the target detection object is a stimulus group, and to control the actuator to perform an action to reduce the stimulus intensity to 0 on the target detection object when the target detection object is a spurious stimulus group.

[0064] In some embodiments, the system further includes a blindness assessment and correction module, used to assess the patient's blindness through a structured questionnaire (including questions such as "What is the probability of you receiving real treatment?" and "Based on your guesses"). If the correct guessing rate of a certain group exceeds 60%, dynamic parameter adjustment is initiated (such as fine-tuning the difference in current intensity between the treatment group and the control group). The relevant side effects or therapeutic effects of stimulation, high-frequency stimulation, etc., have been listed above and can be retrieved by the patient. Patients can make predictions based on these symptoms.

[0065] In some embodiments, the system further includes:

[0066] The first pre-stimulation feedback module is used to receive feedback information sent by the execution structure as target feedback information when the first action is performed on the target detection object.

[0067] The second pre-stimulation feedback module is used to receive feedback information sent by the execution structure as target feedback information when the second action is performed on the target detection object.

[0068] The experimental stimulus feedback module is used to receive feedback information sent by the execution structure as target feedback information when the target detection object is a stimulus group or a spurious stimulus group.

[0069] A second aspect of this application discloses an electronic device, comprising: a memory and a processor; the memory is used to store a computer program; the processor executes the computer program to perform the following steps:

[0070] Obtain grouping information for multiple detection subjects; the grouping information includes stimulus groups and spurious stimulus groups.

[0071] The experimental equipment is used to receive the execution operation for the target detection object, which is one of multiple detection objects. The execution operation is used to indicate the identifier and parameter value of the execution parameters.

[0072] In response to the execution operation, regardless of whether the target detection object is a stimulus group or a spurious stimulus group, the control actuator performs the first action on the target detection object based on the execution operation.

[0073] In response to the execution operation, regardless of whether the target detection object is a stimulus group or a spurious stimulus group, the control actuator performs a second action on the target detection object based on the execution operation.

[0074] When the target detection object is a stimulus group, the control actuator performs an action to maintain the rated stimulus intensity on the target detection object based on the execution operation; when the target detection object is a spurious stimulus group, the control actuator performs an action to reduce the stimulus intensity to 0 on the target detection object based on the execution operation.

[0075] The third aspect of this application discloses a device for maintaining blindness in a randomized double-blind trial of neural modulation, characterized in that the device includes experimental equipment, an execution structure, and the electronic equipment disclosed in the second aspect of this application.

[0076] In some embodiments, the experimental device is a programmable device and the actuator is a stimulator disposed within the body of the target object; or, the experimental device is an electromagnetic wave control device and the actuator includes an electromagnetic wave generating device and an electromagnetic wave detecting device.

[0077] In some embodiments, the experimental equipment is a drug dispensing control device, and the actuators include a robotic arm and sensors.

[0078] Figure 2 This is a schematic diagram of a computer device provided in an embodiment of the present invention, such as... Figure 2 As shown, the device 2000 may include: one or more processors 2010 and one or more memories 2020; wherein the memories store computer-readable code that, when run by the one or more processors, can perform the methods described above.

[0079] The processor in this embodiment can be an integrated circuit chip with signal processing capabilities. The processor can be a general-purpose processor, a digital signal processor (DSP), an application-specific integrated circuit (ASIC), an off-the-shelf programmable gate array (FPGA), or other programmable logic devices, discrete gate or transistor logic devices, or discrete hardware components. It can implement or execute the methods, operations, and logic block diagrams disclosed in this embodiment. The general-purpose processor can be a microprocessor or any conventional processor, and can be based on an x86 or ARM architecture.

[0080] In general, the various exemplary embodiments of this disclosure can be implemented in hardware or dedicated circuitry, software, firmware, logic, or any combination thereof. Some aspects can be implemented in hardware, while others can be implemented in firmware or software that can be executed by a controller, microprocessor, or other computing device. When aspects of embodiments of this disclosure are illustrated or described as block diagrams, flowcharts, or using some other graphical representation, it will be understood that the blocks, apparatuses, systems, techniques, or methods described herein can be implemented as non-limiting examples in hardware, software, firmware, dedicated circuitry or logic, general-purpose hardware or controllers or other computing devices, or some combination thereof.

[0081] For example, the method or apparatus according to embodiments of this disclosure can also be used by means of Figure 3 The architecture of the computing device 3000 shown is used for implementation. For example... Figure 3 As shown, the computing device 3000 may include a bus 3010, one or more CPUs 3020, a read-only memory (ROM) 3030, a random access memory (RAM) 3040, a communication port 3050 connected to a network, an input / output component 3060, a hard disk 3070, etc. The storage devices in the computing device 3000, such as the ROM 3030 or the hard disk 3070, may store various data or files used for processing and / or communication of the methods provided in this disclosure, as well as program instructions executed by the CPU. The computing device 3000 may also include a user interface 3080. Of course, Figure 3 The architecture shown is merely exemplary and can be omitted as needed when implementing different devices. Figure 3 One or more components in the computing device shown.

[0082] This invention also includes a computer-readable storage medium, such as... Figure 4The diagram illustrates a storage medium 4000 provided in an embodiment of the present invention. The computer storage medium 4020 stores computer-readable instructions 4010. When the computer-readable instructions 4010 are executed by a processor, the method described above according to embodiments of the present disclosure can be performed. The computer-readable storage medium in the embodiments of the present disclosure may be volatile memory or non-volatile memory, or may include both volatile and non-volatile memory. Non-volatile memory may be read-only memory (ROM), programmable read-only memory (PROM), erasable programmable read-only memory (EPROM), electrically erasable programmable read-only memory (EEPROM), or flash memory. Volatile memory may be random access memory (RAM), which is used as an external cache. By way of example, but not limitation, many forms of RAM are available, such as Static Random Access Memory (SRAM), Dynamic Random Access Memory (DRAM), Synchronous Dynamic Random Access Memory (SDRAM), Double Data Rate Synchronous Dynamic Random Access Memory (DDRSDRAM), Enhanced Synchronous Dynamic Random Access Memory (ESDRAM), Synchronous Link Dynamic Random Access Memory (SLDRAM), and Direct Memory Bus Random Access Memory (DRRAM). It should be noted that the memory used in the methods described herein is intended to include, but is not limited to, these and any other suitable types of memory.

[0083] This disclosure also provides a computer program product or system, including a computer program that, when executed by a processor, implements the following method steps:

[0084] Obtain grouping information for multiple detection subjects; the grouping information includes stimulus groups and spurious stimulus groups.

[0085] The experimental equipment is used to receive the execution operation for the target detection object, which is one of multiple detection objects. The execution operation is used to indicate the identifier and parameter value of the execution parameters.

[0086] In response to the execution operation, regardless of whether the target detection object is a stimulus group or a spurious stimulus group, the control actuator performs the first action on the target detection object based on the execution operation.

[0087] In response to the execution operation, regardless of whether the target detection object is a stimulus group or a spurious stimulus group, the control actuator performs a second action on the target detection object based on the execution operation.

[0088] When the target detection object is a stimulus group, the control actuator performs an action to maintain the rated stimulus intensity on the target detection object based on the execution operation; when the target detection object is a spurious stimulus group, the control actuator performs an action to reduce the stimulus intensity to 0 on the target detection object based on the execution operation.

[0089] The process in specific applications is as follows:

[0090] I. Programming protocol for a randomized, double-blind, controlled trial of vagal nerve electrical stimulation (on vs. off):

[0091] Vagus nerve stimulation (VNS) is an important neuromodulation technique that delivers electrical impulses to the vagus nerve to treat various diseases, such as epilepsy, depression, cognitive impairment, and post-stroke limb dysfunction. However, its clinical research is severely limited. Different patients respond significantly to VNS stimulation, and many experience adverse reactions such as hoarseness and choking when drinking, even on the first programmed session with low stimulation parameters. These adverse reactions can lead to blindness and ultimately, clinical trials fail.

[0092] To avoid this phenomenon, we first set the maximum VNS stimulation intensity for this project before the experiment, such as 0.8 mA. For all patients in the control group and sham stimulation group, the stimulation intensity was adjusted to the maximum intensity over 2-3 days, gradually increasing the intensity to allow all patients to experience the relevant adverse reactions. Most of these adverse reactions are transient and generally will not recur once the same intensity is reached again. Afterwards, the appropriate programming settings were made according to the group, with the sham stimulation group set to 0 mA.

[0093] step:

[0094] 1. Based on the random number, all patients were grouped into a stimulation group and a sham stimulation group;

[0095] 2. All patients (stimulation group and sham stimulation group) were given stimulation starting from 0 mA (pulse width and frequency were set according to the experimental design) and gradually increased to a certain intensity (called low-intensity stimulation, such as 0.5 mA) over 2-3 days. Patients may experience hoarseness and difficulty swallowing. In most cases, these symptoms subsided within a certain period of time (approximately 4-5 days).

[0096] 3. Over a certain period of time (e.g., 1-2 weeks), gradually adjust the intensity to the rated stimulus intensity (e.g., 0.8mA 1.0mA). If adverse reactions occur again (e.g., hoarseness, difficulty swallowing, etc.), repeat step 2, wait for relief, and then increase the stimulus intensity again. (If adverse reactions do not subside after about a week, if tolerated, continue to increase to the rated intensity; if not tolerated, maintain this stimulus intensity (whether in the stimulation group or the sham stimulation group; the stimulation group will use this stimulus intensity as a long-term stimulation parameter, and the sham stimulation group will maintain this stimulus intensity temporarily until it is reduced to 0mA later)).

[0097] 4. After reaching the rated stimulation intensity, the true stimulation group maintains the same intensity, while the sham stimulation group adjusts the stimulation intensity to 0 mA.

[0098] Note: In most cases, VNS uses constant current stimulation (i.e., using rated current, usually measured in mA), and in a few cases, constant voltage stimulation (i.e., using rated voltage, usually measured in V) may also be used.

[0099] II. Procedural design for a randomized, double-blind, controlled trial of deep brain stimulation (power on vs. power off):

[0100] Deep brain stimulation (DBS) is also a neuromodulation therapy. DBS is a neuromodulation technique that modulates nerve function by implanting electrodes in specific brain nuclei and applying controllable electrical pulses. It falls under the category of "minimally invasive surgery" (without removing brain tissue). Its core principle is similar to a "brain pacemaker," intervening in abnormal neural circuit activity through electrical signals to improve symptoms caused by neurological dysfunction. It has become an important treatment for many intractable neurological diseases.

[0101] It faces a similar situation to VNS. It may also produce certain adverse reactions, such as abnormal limb sensation and visual disturbances. Similar methods can be used.

[0102] step:

[0103] 1. Based on the random number, all patients were divided into a stimulation group and a sham stimulation group.

[0104] 2. All patients (in the stimulation group and the sham stimulation group) were given a stimulation intensity increased from 0V (pulse width and frequency set according to the experimental design) to a certain level (called low-intensity stimulation, such as 1.0V) over 2-3 days. Depending on the target, patients may experience visual disturbances, sensory disturbances in the limbs, or autonomic nervous system dysfunction (such as sweating, facial flushing, etc.). In most cases, these symptoms subsided within a certain period of time (approximately 4-5 days).

[0105] 3. Over a certain period of time (e.g., 1-2 weeks), gradually adjust the intensity to the rated stimulus intensity (e.g., 2.0-3.0V). If adverse reactions occur again (e.g., visual disturbances, limb sensory disturbances, autonomic nervous system dysfunction, etc.), repeat step 2 and wait for the symptoms to subside before increasing the stimulus intensity again. (If adverse reactions do not subside after about a week, if tolerated, continue to increase to the rated intensity; if not tolerated, maintain this stimulus intensity (whether in the stimulation group or the sham stimulation group; the stimulation group will use this stimulus intensity as a long-term stimulation parameter, and the sham stimulation group will maintain this stimulus intensity temporarily until it is reduced to 0V later)).

[0106] 4. After reaching the rated stimulation intensity, the true stimulation group maintains the same intensity, while the sham stimulation group adjusts the stimulation intensity to 0 mA.

[0107] Note: In most cases, DBS uses constant voltage stimulation (i.e., using the rated voltage, the conventional unit is V), and in a few cases, constant current stimulation (i.e., using the rated current, the conventional unit is mA) can also be used.

[0108] III. Procedural design for randomized double-blind controlled trials of deep brain stimulation (comparison of different frequencies, such as low frequency (<100 Hz) vs. high frequency stimulation (>100 Hz)).

[0109] The mechanisms of action and clinical effects of deep brain stimulation (DBS) vary depending on the frequency. DBS is generally categorized into high-frequency and low-frequency stimulation, as detailed below:

[0110] Taking STN-DBS (subthalamic nucleus deep brain stimulation, a target-specific deep brain stimulation technique) as an example, this technique involves implanting electrodes in the deep subthalamic nucleus (STN) region of the brain to deliver high-frequency, weak electrical pulses to provide long-term stimulation to target nuclei in the brain, thereby regulating abnormal neural activity. Other targets may also exhibit differences in their mechanisms of action and therapeutic effects due to varying frequencies, as follows:

[0111] High-frequency stimulation:

[0112] Frequency range: usually above 100Hz, with commonly used frequencies between 130-185Hz.

[0113] Mechanism of action: High-frequency deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) can significantly inhibit the synchronicity of neural network electrical activity. Studies have found that high-frequency electrical stimulation (e.g., 130 Hz) can induce a strong asynchronous release of the neurotransmitter γ-aminobutyric acid (GABA), desynchronizing the electrical activity of STN neurons and thus alleviating motor dysfunction in a mouse model of Parkinson's disease.

[0114] Clinical Applications: High-frequency deep brain stimulation (DBS) is an effective treatment for mid-to-late stage Parkinson's disease, and can provide long-term improvement in the main symptoms of Parkinson's disease, such as bradykinesia, tremor, and rigidity. Furthermore, high-frequency electrical stimulation of the globus pallidus can also significantly improve conditions such as essential tremor and dystonia.

[0115] Low-frequency stimulation:

[0116] Frequency range: generally 60-80Hz.

[0117] Mechanism of action: Low-frequency stimulation (e.g., 20 Hz) induces weak asynchronous release of GABA, which has little effect on the electrical activity of STN neurons. However, by specifically knocking down the expression of the calcium receptor protein Synaptotagmin-1 in PV neurons in GPe through RNA interference technology, the intensity of asynchronous release induced by low-frequency stimulation can be enhanced, so that low-frequency DBS can also improve motor function.

[0118] Clinical application: High-frequency stimulation routinely used in DBS is not very effective for midline symptoms (such as balance, gait disorders, speech disorders and swallowing disorders), while low-frequency stimulation has a certain effect on improving midline symptoms such as frozen gait in Parkinson's disease patients. However, it is only effective for some patients, the effect is short-lived, and it may also aggravate symptoms such as bradykinesia, tremor and rigidity.

[0119] Therefore, it is crucial to study the differences in the efficacy of different frequencies of DBS. However, different frequencies of DBS may lead to different adverse reactions and clinical outcomes.

[0120] High-frequency stimulation (>100Hz) may trigger gait freezing and speech disorders; for example, 130Hz stimulation may cause dysarthria in 23% of patients. In addition, high-frequency stimulation is also significantly associated with depression (incidence 18%) and cognitive decline, and may also cause a decrease in walking speed.

[0121] Low-frequency stimulation (≤100Hz): While 60Hz stimulation can reduce the incidence of dysphagia, low-frequency stimulation is only effective in improving midline symptoms such as frozen gait in Parkinson's disease patients, and the effect is short-lived. It may also worsen symptoms such as bradykinesia, tremor, and rigidity. Studies have shown that 50Hz stimulation is likely to cause fatigue, and 80Hz may cause abnormal eye movements.

[0122] Therefore, in randomized double-blind controlled trials (RCTs), if the differences in the effects of different frequencies on a certain symptom are to be investigated, it may lead to patients being aware of the risks and potentially causing a breach of confidentiality.

[0123] The high-frequency and low-frequency crossover approach is commonly used in clinical trials, with single-round crossover being more practical. Multiple-round crossovers, however, require a longer timeframe. We designed the following clinical trial procedure, assuming a high-frequency group and a low-frequency group:

[0124] 1. All patients were randomly assigned to a high-frequency group and a low-frequency group;

[0125] 2. High-frequency group patients: Start with low-frequency stimulation. If adverse reactions occur, observe for a period (usually one week). During this observation period, most adverse reactions will disappear. If they persist, reduce the stimulation intensity (voltage), and most will disappear. After two weeks (or adjust the time according to experimental requirements), gradually adjust the stimulation frequency to the rated frequency (i.e., change from low-frequency stimulation to high-frequency stimulation). It is important to note that the change should be gradual, such as increasing by 10 Hz daily. Low-frequency group: Start with high-frequency stimulation, then gradually adjust to low frequency, using the same method as the high-frequency group patients.

[0126] 3. Set the final stimulation frequency to high frequency for the high-frequency group and to low frequency for the low-frequency group. Set the stimulation voltage and pulse width according to the experimental protocol.

[0127] In this material, by comparing the process of this system with previous methods, it is found that the results of this system are better, specifically as follows: Figure 5 As shown, in clinical practice, the blinding maintenance system of this application was compared with previous methods. It was found that when using previous methods, up to 79% (78.95% precisely) of patients could accurately perceive their group, while with this approach, only 55% of patients could accurately perceive (i.e., their perception matched their actual group). This significant reduction in accuracy indicates that the double-blind trial of this application has achieved very good results. Furthermore, the 55% figure is close to the accuracy rate of randomized perception (50%). This demonstrates that the proposed approach can significantly reduce the possibility of blinding, reduce psychogenic influences, and improve the accuracy of randomized double-blind trials.

[0128] It should be noted that the flowcharts and block diagrams in the accompanying drawings illustrate the architecture, functionality, and operation of possible implementations of systems, methods, and computer program products according to various embodiments of this disclosure. In this regard, each block in a flowchart or block diagram may represent a module, segment, or portion of code containing one or more executable instructions for implementing a specified logical function. It should also be noted that in some alternative implementations, the functions indicated in the blocks may occur in a different order than those indicated in the drawings. For example, two consecutively indicated blocks may actually be executed substantially in parallel, and they may sometimes be executed in reverse order, depending on the functions involved. It should also be noted that each block in the block diagrams and / or flowcharts, and combinations of blocks in the block diagrams and / or flowcharts, can be implemented using a dedicated hardware-based system that performs the specified function or operation, or using a combination of dedicated hardware and computer instructions.

[0129] Those skilled in the art will clearly understand that, for the sake of convenience and brevity, the specific working processes of the systems, devices, and units described above can be referred to the corresponding processes in the foregoing method embodiments, and will not be repeated here.

[0130] The exemplary embodiments of this disclosure described in detail above are merely illustrative and not restrictive. Those skilled in the art will understand that various modifications and combinations can be made to these embodiments or their features without departing from the principles and spirit of this disclosure, and such modifications should fall within the scope of this disclosure.

Claims

1. A system for maintaining blinding state in a randomized double-blind trial of neural modulation, characterized in that, The system includes: The information acquisition module is used to acquire grouping information for multiple detection objects; the grouping information includes stimulus groups and spurious stimulus groups. The execution receiving module is used to receive execution operations for the target detection object using experimental equipment. The target detection object is one of multiple detection objects, and the execution operation is used to indicate the identifier and parameter value of the execution parameters. The first pre-stimulation module is used to respond to the execution operation, regardless of whether the target detection object is a stimulation group or a sham stimulation group, to control the execution mechanism to perform a first action on the target detection object based on the execution operation; the first action includes: from the initial time point to the first time point, increasing the stimulation intensity from 0 to the first stimulation intensity, and maintaining the first stimulation intensity to the second time point; The second pre-stimulation module is used to respond to the execution operation, regardless of whether the target detection object is a stimulation group or a spurious stimulation group, to control the execution mechanism to perform a second action on the target detection object based on the execution operation; the second action includes: from the second time point to the third time point, the stimulation intensity is increased from the first stimulation intensity to the second stimulation intensity as the rated stimulation intensity, and the second stimulation intensity is the preset maximum stimulation intensity; The adverse reaction judgment module is used to receive the reaction message of the target detection object, determine whether an adverse reaction has occurred based on the reaction message, and if so, execute the first action again for the target detection object that has an adverse reaction. The tolerance assessment module is used to receive the duration of adverse reactions of the target detection object after the first stimulus intensity, and to determine whether the target detection object tolerates the reaction based on the duration. If the object does not tolerate the reaction, the first stimulus intensity is maintained as the rated stimulus intensity; if the object tolerates the reaction, the intensity is increased to the second stimulus intensity as the rated stimulus intensity. The experimental stimulus module is used to control the actuator to maintain the rated stimulus intensity on the target detection object when the target detection object is a stimulus group, based on the execution operation; and to control the actuator to perform an action with a stimulus intensity of 0 on the target detection object when the target detection object is a spurious stimulus group.

2. The system for maintaining blindness in a randomized double-blind trial of neural modulation according to claim 1, characterized in that, All time points are calculated from the initial time point; The first time point is 2-3 days; The second time point is 4-5 days; The third time point is 1-2 weeks.

3. The system for maintaining blindness in a randomized double-blind trial of neural modulation according to claim 1, characterized in that, The grouping information is obtained by randomly grouping the detected objects.

4. The system for maintaining blinding in a randomized double-blind trial of neural modulation according to claim 1, characterized in that, The information acquisition module also includes a tool for acquiring stimulus types for multiple detection objects, including VNS and DBS.

5. The system for maintaining blindness in a randomized double-blind trial of neural modulation according to claim 1, characterized in that, The system also includes a blindness assessment and correction module, which is used to assess the blindness of patients through a structured questionnaire. If the accuracy rate of a group's guesses exceeds 60%, dynamic parameter adjustment is initiated.

6. The system for maintaining blindness in a randomized double-blind trial of neural modulation according to claim 1, characterized in that, The system also includes: The first pre-stimulation feedback module is used to receive feedback information sent by the execution structure as target feedback information when the first action is performed on the target detection object. The second pre-stimulation feedback module is used to receive feedback information sent by the execution structure as target feedback information when the second action is performed on the target detection object. The experimental stimulus feedback module is used to receive feedback information sent by the execution structure as target feedback information when the target detection object is a stimulus group or a spurious stimulus group.

7. An electronic device, characterized in that, The device includes: a memory and a processor; the memory is used to store a computer program; the processor executes the computer program to perform the following steps: Obtain grouping information for multiple detection subjects; the grouping information includes stimulus groups and spurious stimulus groups. The experimental equipment is used to receive the execution operation for the target detection object, which is one of multiple detection objects. The execution operation is used to indicate the identifier and parameter value of the execution parameters. In response to the execution operation, regardless of whether the target detection object is a stimulus group or a spurious stimulus group, the control actuator performs a first action on the target detection object based on the execution operation; the first action includes: from the initial time point to the first time point, increasing the stimulus intensity from 0 to the first stimulus intensity, and maintaining the first stimulus intensity to the second time point; In response to the execution operation, regardless of whether the target detection object is a stimulus group or a spurious stimulus group, the control actuator performs a second action on the target detection object based on the execution operation; the second action includes: from a second time point to a third time point, the stimulus intensity is increased from a first stimulus intensity to a second stimulus intensity as a rated stimulus intensity, and the second stimulus intensity is a preset maximum stimulus intensity; The adverse reaction judgment module is used to receive the reaction message of the target detection object, determine whether an adverse reaction has occurred based on the reaction message, and if so, execute the first action again for the target detection object that has an adverse reaction. The tolerance assessment module is used to receive the duration of adverse reactions of the target detection object after the first stimulus intensity, and to determine whether the target detection object tolerates the reaction based on the duration. If the object does not tolerate the reaction, the first stimulus intensity is maintained as the rated stimulus intensity; if the object tolerates the reaction, the intensity is increased to the second stimulus intensity as the rated stimulus intensity. When the target detection object is a stimulus group, the control actuator performs an action to maintain the rated stimulus intensity on the target detection object based on the execution operation; when the target detection object is a spurious stimulus group, the control actuator performs an action to reduce the stimulus intensity to 0 on the target detection object based on the execution operation.

8. A device for maintaining blindness in a randomized double-blind trial of neural modulation, characterized in that, The device includes experimental equipment, an execution structure, and the electronic device as described in claim 7.

9. The device for maintaining blindness in a randomized double-blind trial of neural modulation according to claim 8, characterized in that, The experimental equipment is a programmable device, and the actuator is a stimulator installed inside the target object. Alternatively, the experimental equipment is an electromagnetic wave control device, and the actuator includes an electromagnetic wave generating device and an electromagnetic wave detection device.

10. The device for maintaining blindness in a randomized double-blind trial of neural modulation according to claim 8, characterized in that, The experimental equipment is a drug dispensing control device, and the actuator includes a robotic arm and sensors.

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