Closed-loop ultrasonic regulation and control system for targeting deep brain region and assembly manufacturing method of closed-loop ultrasonic regulation and control system

Abstract

The invention discloses a closed-loop ultrasonic regulation and control system for a targeted deep brain area. A bio-electricity signal collector collects bio-electricity signals of a detection target and uploads the bio-electricity signals to a main control unit. The main control unit identifies the bio-electricity signal and outputs an excitation signal to the signal generator after identifying a characteristic electric signal. The signal generator generates an ultrasonic waveform signal according to the ultrasonic parameter. Signals are amplified by a power amplifier and then input to an ultrasonic transducer, corresponding mechanical waveforms are output under voltage excitation, then bioelectricity signals are collected in real time for neural activity reaction after ultrasonic stimulation, and closed-loop ultrasonic regulation and control are achieved. According to the invention, electric signals are recorded at the same time, ultrasonic stimulation parameters are fed back in real time, a remarkable inhibition effect is generated on mouse epilepsy electroencephalogram, ultrasonic output energy is automatically adjusted, and the possibility of adverse reaction is reduced. The ultrasonic transducer is firmly fixed on the head of the mouse by the adaptive device, so that ultrasonic regulation and control on the freely moving mouse are realized, and the mouse is not limited by anesthesia stimulation.

Description

Technical Field

[0001] The present invention belongs to the field of medical devices, and in particular relates to a closed-loop ultrasound control system targeting deep brain regions and a method for manufacturing its components. Background Art

[0002] Epilepsy is a chronic neurological disease and one of the most common and serious brain diseases worldwide, affecting approximately 70 million people. Its onset is due to abnormal electrical activity in the central nervous system, which disrupts normal nerve signal conduction. This abnormal electrical activity manifests as abnormal discharges in groups of brain cells during an epileptic seizure, causing temporary involuntary spasms in parts of the patient's body or throughout the body, sometimes accompanied by loss of consciousness and uncontrolled excretion. These symptoms not only seriously affect the quality of life of patients, but also impose a heavy burden on society. Therefore, it is particularly urgent to find more effective treatment and rehabilitation methods.

[0003] In this context, neuromodulation technology, as an emerging treatment method, has shown broad application prospects. Neuromodulation effectively controls the frequency and severity of epileptic seizures by precisely delivering specific regulatory factors to specific areas of the body to change neural activity. With the continuous integration and progress of multiple disciplines such as computational science, materials science, biology, neuroscience, and medicine, neuromodulation technology has developed rapidly. Various methods such as electrical stimulation, sound waves, magnetic fields, and chemical regulation have gradually shown great potential in managing neurological and psychiatric diseases such as epilepsy. This series of advances not only brings new hope to patients, but also opens up new paths for the further development of neuroscience.

[0004] Deep brain stimulation (DBS) is a precise neuromodulatory technology that can directly act on specific neural circuits and has been widely used in the treatment of movement disorders such as Parkinson's disease, tremor and dystonia. The significant advantage of DBS is that it can target structures deep in the brain, which are usually difficult to effectively regulate with traditional treatments. By implanting electrodes in specific deep areas of the patient's brain, DBS can apply precise electrical stimulation to regulate neural activity to achieve precise control of deep neural networks. This unique ability gives DBS unparalleled potential in the treatment of neurological diseases involving deep brain circuits, especially intractable epilepsy.

[0005] Specifically, the existing public technologies include the following:

[0006] Transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS) are non-invasive neuromodulation methods that use a device fixed to the scalp to transmit electromagnetic stimulation to the brain to change neuronal activity. However, this type of stimulation is only applicable to superficial nuclei such as the cortex, and it is difficult to transmit stimulation to deep brain regions.

[0007] Deep brain stimulation (DBS) is a neuromodulatory method that allows targeted circuits and has been approved for the treatment of movement disorders such as Parkinson's disease, tremor and dystonia. By implanting electrodes in specific areas of the patient's brain, designated electrical stimulation is applied to regulate neural activity. Since the first implantation of electrodes in the human brain in 1948, DBS has been developed for decades, including hardware upgrades such as implanted electrodes and power supply equipment, as well as improvements based on clinical and preclinical evidence such as stimulation modes and stimulation waveforms, making DBS technology more mature.

[0008] Although the above-mentioned neuromodulation methods have made significant progress, they still have many limitations and challenges. Although transcranial electromagnetic stimulation can non-invasively regulate neural activity, due to technical limitations, it can only act on the surface areas of the brain and cannot effectively target deep brain structures. Although deep brain stimulation can accurately act deep in the brain, its surgical techniques are high, the equipment is expensive, and the invasive implantation of electrodes will cause surgical trauma to patients and may cause adverse consequences such as infection. These limitations not only limit the widespread application of these technologies, but also pose challenges to patients' treatment experience and safety, requiring further technological innovation and optimization.

[0009] In recent years, low-intensity transcranial focused ultrasound (LITUS) is an emerging non-invasive neuromodulation technology. LITUS can precisely regulate neural activity by focusing low-intensity ultrasound waves on specific areas of the brain without the need for surgical implantation of any device. The unique advantage of this technology is that it can penetrate the skull in a non-invasive manner and precisely target brain areas, thereby inhibiting abnormal neural electrical activity. Compared with other neuromodulation methods, LITUS has fewer side effects and is more tolerable to patients. With the further development of technology and the advancement of clinical trials, LITUS is expected to provide a new and effective treatment option for patients with refractory epilepsy.

[0010] However, as an emerging non-invasive neuromodulation technology, low-intensity focused ultrasound (LIFUS) has shown great potential in the treatment of neurological diseases, but it still has some significant limitations and challenges. First, the mechanism of action of LIFUS has not been fully elucidated, which makes it difficult for traditional stimulation modes to fully consider individual differences between patients or the progression of the disease, which may lead to unstable treatment effects. Second, although LIFUS can non-invasively target deep brain structures, most current ultrasound probes are cylindrical or conical and large in size, resulting in limited controllability of targeting accuracy and effect, especially in small animal experiments, where the operating space is small and more prone to targeting errors. In addition, due to the large size of the ultrasound probe, it becomes particularly difficult to evaluate the effect of ultrasound stimulation in freely moving mice, so only mice under anesthesia can be selected for experiments. However, the effect evaluation during anesthesia cannot completely exclude the influence of anesthetic drugs on neural activity, which may affect the accuracy of the experimental results. Finally, long-term ultrasound application may lead to the accumulation of thermal effects and potential adverse effects on the nervous system. Therefore, in the process of further exploring the therapeutic potential of LIFUS, it is necessary to pay attention to its limitations in precision control, equipment design, and safety to ensure the effectiveness and safety of its clinical application. Summary of the invention

[0011] The technical purpose of the present invention is to provide a closed-loop ultrasound control system targeting deep brain regions and a method for manufacturing its components, so as to solve the difficulties in transcranial ultrasound evaluation and detection of small animals.

[0012] To solve the above problems, the technical solution of the present invention is:

[0013] A closed-loop ultrasound control system targeting deep brain regions, comprising:

[0014] Ultrasonic components, signal generators, power amplifiers, bioelectric signal collectors and main control units;

[0015] The bioelectric signal collector is connected to the electrodes provided on the detection target, and is configured to collect the bioelectric signals of the detection target, and upload the collected bioelectric signals to the main control unit;

[0016] The main control unit is connected to the signal generator signal and is configured to receive and identify the bioelectric signal from the bioelectric signal collector, and output an excitation signal to the signal generator after identifying the characteristic electrical signal;

[0017] The signal generator is connected to the power amplifier signal and is configured to generate an ultrasonic waveform signal according to the ultrasonic parameters set by the main control unit after receiving the excitation signal from the main control unit;

[0018] The power amplifier is connected to the ultrasonic transducer of the ultrasonic component, and the ultrasonic waveform signal is amplified and input into the ultrasonic transducer. The ultrasonic transducer receives the amplified ultrasonic waveform signal and outputs the corresponding mechanical waveform. The bioelectric signal collector collects the bioelectric signals of the neural activity response after ultrasonic stimulation in real time to realize closed-loop ultrasonic control.

[0019] Further preferably, it is characterized in that the main control unit is also configured to pre-process the received bioelectric signal: the received bioelectric signal is filtered in a frequency band of 0.1-30 Hz, and a baseline correction is performed using a wavelet transform.

[0020] Further preferably, the main control unit is further configured to read the bioelectrical signal of the detection target in the past 0.5 seconds in real time at a frequency of 20 Hz, and when the characteristic electrical signal is identified, the ultrasonic parameters are adaptively adjusted according to the identification result, and an excitation signal is immediately sent to the signal generator;

[0021] Among them, the waveform in the bioelectric signal with an amplitude greater than twice the standard deviation of the baseline activity and lasting for more than 35ms is regarded as a characteristic electrical signal;

[0022] Among them, the ultrasonic parameters are adaptively adjusted: according to the amplitude of the identified characteristic electrical signal, it is mapped to 0.3-1vpp according to the following formula as the ultrasonic output voltage of the signal generator,

[0023] f(A)=0.3+0.7×(1―e ―0.05(A―m) )

[0024] Wherein, f(A) is the peak-to-peak value of the ultrasonic output voltage of the signal generator, A is the amplitude of the characteristic electrical signal, and m is the threshold value of the characteristic electrical signal.

[0025] Specifically, the ultrasonic assembly includes: an adapter, an ultrasonic transducer, a base and an optical fiber ceramic ferrule;

[0026] The base is located at the bottom of the ultrasonic component and is an epoxy resin glue configured to fix the adapter to the part of the skull to be stimulated and to weaken the power frequency interference of the electrical signal collection caused by the circuit formed by the transducer through the skull or the adapter and the dental cement.

[0027] The adapter is connected to the upper end surface of the base, and a first cylindrical hole is opened through the top and bottom of the adapter with the axis of the adapter as the center. The ultrasonic transducer is arranged in the first cylindrical hole, and the lower bottom surface of the ultrasonic transducer is arranged higher than the lower bottom surface of the outer wall of the adapter;

[0028] With the axis of the ultrasonic transducer as the center, a second cylindrical hole is opened that runs through the top and bottom of the ultrasonic transducer. The optical fiber ceramic ferrule passes through the second cylindrical hole. The optical fiber ceramic ferrule cooperates with the ultrasonic transducer and is configured so that the optical fiber ceramic ferrule points to the position of the nucleus mapped on the brain surface, so that the ultrasonic transducer and the adapter are accurately positioned.

[0029] Specifically, the adapter includes an adapter body and several auxiliary fixing rings arranged on the circumference of the adapter body. When the ultrasonic transducer is inserted into the adapter body, the several auxiliary fixing rings are deformed to fix the ultrasonic transducer; the first cylindrical hole is opened in the adapter body, the inner diameter of the adapter body is 5.1mm, and the outer diameter is 6.1mm; the inner diameter of the auxiliary fixing ring is 0.8mm, the outer diameter is 2mm, and the shortest distance from the center of the adapter body is 2.3mm.

[0030] Further preferably, the ultrasonic component also includes a torus model, which is consistent with the structural size of the ultrasonic transducer. When the ultrasonic component is installed or not implemented, the torus model is placed in the adapter; when the ultrasonic component is in the implementation state, the ultrasonic transducer is placed in the adapter; the outer diameter of the torus model is 5 mm, the inner diameter is 1.5 mm, and the height is 6 mm; the inner diameter of the torus model matches the diameter of the optical fiber ceramic ferrule.

[0031] The surface of the adapter body is marked with scales from bottom to top, and the ultrasonic transducer is fixed at a predetermined position in the first cylindrical hole according to the scales so that the ultrasonic transducer can accurately target the brain area.

[0032] Preferably, a Faraday cage is placed around the ultrasonic transducer to shield the electromagnetic interference generated during the ultrasonic stimulation, thereby weakening the stimulation interference generated during the ultrasonic stimulation;

[0033] Polymethyl methacrylate is also applied around the electrodes on the detection target and at the connection between the adapter and the surface of the skull to eliminate the ability of dental cement and skull to act as resistors or capacitors, thereby reducing power frequency interference;

[0034] The contact area between the ultrasound transducer and the skull surface is also filled with polydimethylsiloxane or epoxy resin.

[0035] A method for manufacturing an ultrasonic component comprises the following steps:

[0036] Place the fiber optic ceramic ferrule in a holder and fix it on a stereotaxic instrument to accurately locate the brain area that requires ultrasonic stimulation, and then lift the fiber optic ceramic ferrule;

[0037] Apply vaseline on the surface of the torus model and insert it into the adapter to obtain an assembly;

[0038] Insert the assembly into the optical fiber ceramic ferrule from bottom to top, so that the optical fiber ceramic ferrule is located in the middle hole of the torus model;

[0039] Operate the stereotaxic body to slowly lower the fiber optic ceramic ferrule until the adapter of the assembly reaches the surface of the skull, and use epoxy resin glue to fix the adapter around and fill the surrounding pores;

[0040] After the epoxy glue has hardened, secure the adapter with dental cement.

[0041] Due to the adoption of the above technical solution, the present invention has the following advantages and positive effects compared with the prior art:

[0042] The present invention uses transcranial focused ultrasound to precisely regulate the deep brain nuclei of awake mice, realizes simultaneous recording of electrical signals, and provides real-time feedback on ultrasonic stimulation parameters, which has a significant inhibitory effect on mouse epileptic EEG, can autonomously adjust the ultrasonic output energy, and reduces the possibility of adverse reactions. Based on this, an ultrasonic component is designed, which can fix the electrode to the skull of the detection target, and install an ultrasonic transducer when ultrasonic stimulation is required, so that the detection target does not have to be limited to anesthetic stimulation. When the experiment is not carried out, the ultrasonic transducer can be replaced with a transducer model to meet the needs of repeated experiments. By simultaneously recording electrical signals, ultrasonic stimulation parameters are fed back in real time. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Various other advantages and benefits will become apparent to those of ordinary skill in the art by reading the following detailed description of the preferred embodiment.The drawings are only for the purpose of illustrating the preferred embodiments and are not to be construed as limiting the invention.

[0044] Figure 1 It is the design diagram and installation diagram of the adapter of the present invention;

[0045] Figure 2 It is a schematic diagram of the installation of the transducer of the present invention;

[0046] Figure 3 A structural diagram of a closed-loop ultrasound control system targeting deep brain regions according to the present invention;

[0047] Figure 4 It is a schematic diagram of the signal processing flow of the main control unit of the present invention;

[0048] Figure 5 The flowchart and result diagram of the closed-loop regulation of epilepsy mice experiment of the present invention;

[0049] Figure 6 This is a diagram of the ultrasonic stimulation combined with in vivo electrophysiological deep brain electrode recording of the present invention. DETAILED DESCRIPTION

[0050] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the specific implementation methods of the present invention will be described below with reference to the accompanying drawings. Obviously, the accompanying drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings and other implementation methods can be obtained based on these drawings without creative work.

[0051] In order to simplify the drawings, only the parts related to the present invention are schematically shown in each figure, and they do not represent the actual structure of the product. In addition, in order to simplify the drawings and facilitate understanding, in some figures, only one of the parts with the same structure or function is schematically drawn or marked. In this article, "one" not only means "only one", but also means "more than one".

[0052] The following is a further detailed description of a closed-loop ultrasound control system targeting deep brain regions and a method for manufacturing the components thereof proposed by the present invention in conjunction with the accompanying drawings and specific embodiments. The advantages and features of the present invention will become more apparent from the following description and claims.

[0053] Example

[0054] See also Figures 1 to 6 This embodiment provides a closed-loop ultrasound control system targeting deep brain regions. First, Figure 3 For example, the system includes: an ultrasonic component, a signal generator, a power amplifier, a bioelectric signal collector and a main control unit.

[0055] The bioelectric signal collector is connected to electrodes arranged on the detection target (mouse), can collect the bioelectric signals of the mouse, and upload the collected bioelectric signals to the main control unit.

[0056] The main control unit is connected to the signal generator signal, which receives and identifies the bioelectric signal from the bioelectric signal collector. When the characteristic electrical signal is identified (the characteristic electrical signal is the characteristic EEG of mice during epileptic seizures), it outputs an excitation signal to the signal generator.

[0057] The signal generator is connected to the power amplifier signal. When it receives the excitation signal from the main control unit, it generates an ultrasonic waveform signal according to the ultrasonic parameters set by the main control unit. The signal generator can be a general-purpose signal generator available on the market. The model used in this embodiment is Rigol DG822. Ultrasonic stimulation parameters include: fundamental frequency, pulse length, pulse repetition frequency, burst length, burst interval, and total stimulation duration, which can be combined arbitrarily. Among them, the fundamental frequency (FF) is the resonant frequency of the probe. The parameters that can be directly set by the signal generator are often slightly different from the above-mentioned ultrasonic stimulation parameters. Most of them can be calculated by simple formulas through ultrasonic stimulation parameters, or designed by computer language (mat lab).

[0058] The power amplifier is connected to the ultrasonic transducer of the ultrasonic component. Its function is to amplify the ultrasonic waveform signal and input it into the ultrasonic transducer. The ultrasonic transducer receives the amplified ultrasonic waveform signal and outputs the corresponding mechanical waveform, which affects the brain of the experimental mouse. At the same time, the bioelectric signal collector collects the bioelectric signals of the neural activity response after ultrasonic stimulation in real time to achieve closed-loop ultrasonic control. There is no excessive restriction on the selection of the power amplifier.

[0059] See also Figure 4 Preferably, the main control unit will also pre-process the received bioelectric signals: that is, after filtering the bioelectric signals in the 0.1-30Hz frequency band, the wavelet transform is used to perform baseline correction. After the pre-processing is completed, the main control unit reads the bioelectric signals of the mouse for the past 0.5 seconds in real time at a frequency of 20Hz. When the characteristic electrical signals are identified, the ultrasonic parameters are adaptively adjusted according to the identification results, and an excitation signal is immediately sent to the signal generator. The waveform in the bioelectric signal with an amplitude greater than twice the standard deviation of the baseline activity and lasting more than 35ms is identified as a characteristic electrical signal. Then, the ultrasonic parameters are adaptively adjusted, and according to the amplitude of the identified characteristic electrical signal, it is mapped to 0.3-1vpp according to the following formula as the ultrasonic output voltage of the signal generator,

[0060] f(A)=0.3+0.7×(1―e ―0.05(A―m) )

[0061] Wherein, f(A) is the peak-to-peak value of the ultrasonic output voltage of the signal generator, A is the amplitude of the characteristic electrical signal, and m is the threshold of the characteristic electrical signal, i.e., the EEG mean value of the mouse in the baseline state + 2*standard deviation.

[0062] See also Figure 1 and Figure 2The ultrasonic assembly of this embodiment is now described: Specifically, the ultrasonic assembly includes: an adapter, an ultrasonic transducer, a base and an optical fiber ceramic ferrule. The base is located at the bottom of the ultrasonic assembly and is used to fix the adapter.

[0063] The adapter is connected to the upper end surface of the base, and a first cylindrical hole is opened through the top and bottom of the adapter with the axis of the adapter as the center. The ultrasonic transducer is arranged in the first cylindrical hole, and the lower bottom surface of the ultrasonic transducer is arranged higher than the lower bottom surface of the outer wall of the adapter.

[0064] With the axis of the ultrasonic transducer as the center, a second cylindrical hole is opened that runs through the top and bottom of the ultrasonic transducer. The optical fiber ceramic ferrule passes through the second cylindrical hole. The optical fiber ceramic ferrule cooperates with the ultrasonic transducer and is configured so that the optical fiber ceramic ferrule points to the position of the nucleus mapped on the brain surface, so that the ultrasonic transducer and the adapter are accurately positioned.

[0065] by Figure 1 Taking (a, b, c, d, e) as an example, this embodiment is designed with an adapter for fixing and positioning the transducer, and the adapter is made by 3D printing. The adapter consists of an adapter body that can wrap the ultrasonic transducer, and three auxiliary fixing rings arranged around the adapter body. The auxiliary fixing ring can produce deformation when the transducer is inserted ( Figure 1 c) to firmly fix the transducer without affecting the flexible loading and unloading of the transducer. The adapter body is provided with a first cylindrical hole, and the function of the first cylindrical hole is to wrap the ultrasonic transducer. The inner diameter of the adapter body is 5.1mm and the outer diameter is 6.1mm; the inner diameter of the auxiliary fixing ring is 0.8mm and the outer diameter is 2mm, and the shortest distance from the center of the adapter body is 2.3mm (this size can just make the transducer firmly fixed without affecting the flexible loading and unloading of the transducer). It is worth mentioning that the surface of the adapter body is marked with scales from bottom to top, and the ultrasonic transducer is fixed to a predetermined position in the first cylindrical hole according to the scale, so that the ultrasonic transducer can accurately target the brain area.

[0066] Preferably, the closed-loop ultrasonic control device also includes a torus model, which is a 3D printed model and is consistent with the structural dimensions of the ultrasonic transducer, with an outer diameter of 5 mm and a height of 6 mm. When the closed-loop ultrasonic control device is installed, the torus model is placed in the adapter to avoid deformation of the adapter during the glue fixation process. When in an unexperimental state, the torus model is placed in the adapter to avoid deformation of the adapter and protect the mouse skull. When the closed-loop ultrasonic control device is in an implementation state, the ultrasonic transducer is placed in the adapter. The center of the torus model is also provided with a through hole consistent with the second cylindrical hole, and a fiber optic ceramic ferrule can be inserted into the through hole to facilitate positioning of the brain area, and the inner diameter of the torus model matches the diameter of the fiber optic ceramic ferrule.

[0067] Preferably, this embodiment also provides a method for manufacturing and installing an ultrasonic component, comprising the following steps:

[0068] First, use isoflurane to anesthetize the mouse, and then proceed to the next step after the mouse is deeply anesthetized. According to the rodent stereotaxic surgery operation process, the cranial window is cleaned and the skull is leveled, etc., which will not be described in detail here.

[0069] Place the fiber optic ceramic ferrule into the holder and fix it on the stereotaxic instrument to accurately locate the brain area that requires ultrasonic stimulation of the detection target, and then slowly lift the fiber optic ceramic ferrule.

[0070] Apply a layer of vaseline on the surface of the prepared torus model and insert it into the adapter to obtain an assembly. Vaseline can lubricate the torus model and prevent the torus model from sticking to the epoxy resin glue. Figure 1 , e).

[0071] Insert the assembly into the fiber optic ceramic ferrule from bottom to top, so that the fiber optic ceramic ferrule is located in the second cylindrical hole in the middle of the torus model. Thus, we can accurately locate the position and angle of the adapter through the fiber optic ceramic ferrule needle ( Figure 1 , h).

[0072] Operate the stereotaxic body to slowly lower the fiber optic ceramic ferrule and the assembly until the adapter reaches the skull surface. At this point, we can obtain the position on the mouse skull where the electrode can be embedded ( Figure 1 , a). Electrodes for recording the neural electrical signals of mice are placed in a certain range of locations ( Figure 1 ,f). In this embodiment, the ground wire and the reference electrode are placed on the cerebellum, and the signal electrode is placed above one side of the hippocampus or above the prefrontal cortex.

[0073] After the adapter reaches the skull surface, use epoxy glue to fix the adapter around and fill the surrounding pores. After the epoxy glue hardens, use dental cement to fix the adapter ( Figure 1 , g, i). After the dental cement hardens, remove the fiber optic ceramic ferrule and put the mouse back into the cage. After the mouse recovers for a week, stimulation and signal recording can be performed. When ultrasonic stimulation is required, the torus model is replaced with an ultrasonic transducer. When replacing, apply coupling agent to the emitting surface of the transducer, and then insert the adapter. During this process, calculate the position where the transducer should stay (i.e., stay at the corresponding scale position) according to the depth of the nucleus targeted by the experiment, so as to accurately target the brain area. During the insertion process, if Figure 2 As shown, the coupling agent will overflow from the hole in the middle of the transducer, reducing resistance and facilitating transducer insertion.

[0074] Preferably, in this embodiment, since the overall system has a large power and a complex circuit, it may interfere with the in vivo electrophysiological recording, including power frequency interference and / or stimulation interference. In order to eliminate the influence of the ultrasonic transducer or other electrical equipment on the in vivo electrophysiological recording as much as possible, the following measures are taken:

[0075] 1) A Faraday cage is placed around the ultrasonic transducer to shield the electromagnetic interference generated during ultrasonic stimulation, thereby weakening the stimulation interference generated during ultrasonic stimulation.

[0076] 2) Polymethyl methacrylate (PMMA) is applied around the electrophysiological recording electrodes (including silver wires, skull pins, pin pins, etc. that may come into contact with the skull and dental cement) and at the connection between the adapter and the brain to minimize the ability of dental cement and skull to act as resistors or capacitors, thereby reducing power frequency interference ( Figure 2 e,f). The specific operation process is to mix PMMA powder with ethanol or acetone in a ratio of 1:1 to dissolve PMMA into a paste, then apply PMMA to the surface of the object to be blocked, and wait for a while for the ethanol or acetone to evaporate. Of course, multiple layers of filling can be performed, but it should be noted that before each filling, the solvent of the previous filling must be completely evaporated.

[0077] 3) Use polydimethylsiloxane (PDMS) or epoxy resin to fill the surface of the skull where the ultrasonic transducer needs to contact.

[0078] by Figure 2 g and Figure 2 The comparison of the electrical signal quality before and after h shows that after adopting the above shielding measures ( Figure 2 h) The signal quality of electrophysiological recordings is significantly improved.

[0079] See also Figure 4 , the control process of the closed-loop ultrasound control system targeting deep brain regions is now described:

[0080] First, the electrodes on the mouse's head were connected to the EEG recording system, and the EEG baseline was measured for 10 minutes to determine the mean and standard deviation of the EEG signal in the mouse's baseline state ( Figure 5 , a).

[0081] Then, epilepsy model was established: mice were intraperitoneally injected with 30 mg / kg PTZ.

[0082] After modeling, the EEG signals of mice were continuously measured for 30 minutes ( Figure 5 , a).

[0083] After 30 minutes, an ultrasonic transducer was installed on the mouse head and the mouse was stimulated continuously for 30 minutes using a closed-loop stimulation strategy ( Figure 5, a).

[0084] After the stimulation, the ultrasonic transducer was removed and the EEG signal was measured for another 30 minutes ( Figure 5 , a).

[0085] EEG signal preprocessing process: After the received EEG signal is filtered in the 0.1-30Hz frequency band, wavelet transform is used for baseline correction. Closed-loop stimulation strategy: The bioelectric signals of the mouse in the past 0.5 seconds are read in real time at a frequency of 20Hz. After identifying the characteristic EEG (spike) during an epileptic seizure, the ultrasonic stimulation parameters are adjusted, and the ultrasonic stimulation signal is immediately output to the function generator. Identification of characteristic EEG (spike) of epilepsy: The EEG signal of the mouse before modeling is taken as the baseline. After modeling and drug administration, the waveform with an amplitude greater than twice the standard deviation of the baseline EEG activity and lasting for more than 35ms is taken as a spike. Adaptive adjustment of ultrasonic stimulation parameters: According to the previous step, the amplitude of the identified spike can be obtained according to the following formula: f(A) = 0.3 + 0.7 × (1-e ―0.05(A―m) ) is mapped to 0.3-1vpp as the signal generator output voltage.

[0086] See also Figure 5 The results of using this embodiment to achieve closed-loop ultrasound control of epileptic mice are now described to verify the feasibility of this embodiment: After the experiment, the collected EEG signals of the mice are analyzed. Figure 5 a) The experimental process has been described in the above content. Figure 5 b is the baseline, filtered and baseline-corrected signals before and after ultrasound stimulation. Figure 5 c is the density of spikes detected by the above algorithm before and after ultrasound stimulation. The horizontal axis is time, the vertical axis is amplitude, and each point represents a spike detected. It can be seen that the density of spikes is significantly reduced after ultrasound stimulation. Figure 5 d is the 3D contour result of the phase amplitude coupling size before and after the baseline and ultrasound stimulation. It can be seen that the alpha-gamma phase amplitude coupling of mice increased significantly after epilepsy administration, while ultrasound stimulation inhibited this increase. The third picture from left to right shows the immediate effect after ultrasound stimulation. Figure 5 e is the alpha-gamma phase amplitude coupling diagram of the baseline and before and after ultrasound stimulation. It can be seen that the alpha-gamma phase amplitude coupling of mice increased significantly after epilepsy administration, while ultrasound stimulation inhibited this increase. The third figure from left to right shows the immediate effect after ultrasound stimulation.

[0087] See also Figure 6 A deep electrode ( Figure 6a, b, electrodes such as tetrode electrodes and microwire electrode arrays) are used to achieve ultrasonic stimulation combined with in situ deep electrode electrophysiological recording. The installation process is as follows: place the adapter as described above. When burying the deep electrode, first locate the position where the deep electrode needs to be buried on the surface of the skull, set the Z value of the stereotaxic instrument with the tip of the electrode touching the surface of the dura mater to 0, and then lift the electrode. Following the above positioning steps, put the transducer on the outside of the deep electrode and slowly lower the electrode and transducer. When the transducer contacts the adapter, carefully put the transducer into the adapter, and then continue to lower the electrode and transducer. When the Z value on the stereotaxic instrument is 0, it means that the tip of the electrode contacts the dura mater again. At this time, the descent speed is slowed down until the depth of the desired target site is reached. Mice can choose to be stimulated and recorded under anesthesia or fix the above device with dental cement and then stimulate and record in an awake state ( Figure 5 , f). Record the electrical signals before and after the ultrasonic stimulation. Analyze the changes in the electrical signals. In this embodiment, after the electrical signals are baseline corrected, the spontaneous discharge spike time points are extracted using the empirical threshold, and the data 0.6ms before and 1ms after each spike time point are extracted for cluster analysis ( Figure 6 , d). Cluster analysis: After standardizing several spike signals, self-organizing map clustering (SOM) was used ( Figure 6 , e). The numbers in the figure represent the proportion of different spike categories before and after ultrasound stimulation ( Figure 6 , g, h), in Figure 6 In h, red represents an increase in proportion, and blue represents a decrease in proportion. It can be seen that ultrasonic stimulation has an impact on the spike category.

[0088] In summary, this embodiment provides a promising solution to the technical problems of LI FUS by improving the ultrasound stimulation mode and optimizing the ultrasound stimulation mouse experimental method. First, unlike the traditional open-loop ultrasound, this embodiment uses a closed-loop ultrasound control system to dynamically adjust the stimulation parameters by real-time monitoring of neural activity, thereby determining the optimal ultrasound stimulation time and performing feedback adjustment. This system can automatically adjust the intensity of ultrasound according to the individual differences and real-time status of the detection target, thereby improving the personalization and effect of treatment. Secondly, this embodiment can reduce unnecessary stimulation, effectively control the thermal effect of ultrasound, and reduce potential adverse effects on the nervous system by optimizing the time and intensity of stimulation. In addition, a small ring column probe is innovatively used, and an adapter for probe positioning and fixing is correspondingly designed, so that closed-loop ultrasound can more accurately locate the target brain area and reduce the uncertainty of treatment caused by positioning errors. Therefore, this embodiment not only improves the accuracy of ultrasound stimulation effect evaluation in freely moving mice, but also allows the mice to be put back into the cage for feeding after the experiment, so as to repeat the experiment, thereby extending the time range allowed by the experimental design.

[0089] The embodiments of the present invention are described in detail above in conjunction with the accompanying drawings, but the present invention is not limited to the above embodiments. Even if various changes are made to the present invention, if these changes fall within the scope of the claims of the present invention and their equivalents, they still fall within the protection scope of the present invention.

Claims

1. A closed-loop ultrasound control system targeting deep brain regions, characterized in that: include: Ultrasonic components, signal generators, power amplifiers, bioelectric signal collectors and main control units; The bioelectric signal collector is connected to the electrodes provided on the detection target, and is configured to collect the bioelectric signals of the detection target, and upload the collected bioelectric signals to the main control unit; The main control unit is connected to the signal generator signal, and is configured to receive and identify the bioelectric signal from the bioelectric signal collector, and output an excitation signal to the signal generator after identifying the characteristic electrical signal; The signal generator is signal-connected to the power amplifier and is configured to generate an ultrasonic waveform signal according to ultrasonic parameters set by the main control unit after receiving an excitation signal from the main control unit; The power amplifier is connected to the ultrasonic transducer of the ultrasonic component, and the ultrasonic waveform signal is amplified and input into the ultrasonic transducer. The ultrasonic transducer receives the amplified ultrasonic waveform signal and outputs a corresponding mechanical waveform. The bioelectric signal collector collects the bioelectric signals of the neural activity response after ultrasonic stimulation in real time to realize closed-loop ultrasonic control.

2. The closed-loop ultrasound control system targeting deep brain regions according to claim 1, characterized in that: The main control unit is also configured to pre-process the received bioelectric signal: filter the received bioelectric signal in a frequency band of 0.1-30 Hz, and perform baseline correction using wavelet transform.

3. The closed-loop ultrasound control system targeting deep brain regions according to claim 2, characterized in that: The main control unit is also configured to read the bioelectrical signal of the detection target in the past 0.5 seconds in real time at a frequency of 20 Hz, and when a characteristic electrical signal is identified, the ultrasonic parameters are adaptively adjusted according to the identification result, and an excitation signal is immediately sent to the signal generator; Among them, the waveform in the bioelectric signal with an amplitude greater than twice the standard deviation of the baseline activity and lasting for more than 35ms is regarded as a characteristic electrical signal; The ultrasonic parameters are adaptively adjusted: according to the amplitude of the identified characteristic electrical signal, it is mapped to 0.3-1vpp according to the following formula as the ultrasonic output voltage of the signal generator, f(A)=0.3+0.7×(1―e ―0.05(A―m) ) Wherein, f(A) is the peak-to-peak value of the ultrasonic output voltage of the signal generator, A is the amplitude of the characteristic electrical signal, and m is the threshold value of the characteristic electrical signal.

4. The closed-loop ultrasound control system targeting deep brain regions according to claim 1, characterized in that: The ultrasonic assembly comprises: an adapter, an ultrasonic transducer, a base and an optical fiber ceramic ferrule; The base is located at the bottom of the ultrasonic component and is epoxy resin glue, configured to fix the adapter to the part of the skull to be stimulated and weaken the power frequency interference of the electrical signal collection caused by the circuit formed by the transducer through the skull or the adapter and the dental cement; The adapter is connected to the upper end surface of the base, and a first cylindrical hole is provided through the top and bottom of the adapter with the axis of the adapter as the center, the ultrasonic transducer is arranged in the first cylindrical hole, and the lower bottom surface of the ultrasonic transducer is arranged higher than the lower bottom surface of the outer wall of the adapter; A second cylindrical hole is provided through the top and bottom of the ultrasonic transducer with the axis of the ultrasonic transducer as the center, and the optical fiber ceramic ferrule passes through the second cylindrical hole. The optical fiber ceramic ferrule cooperates with the ultrasonic transducer and is configured so that the optical fiber ceramic ferrule points to the position of the nucleus mapped on the brain surface, so that the ultrasonic transducer and the adapter are accurately positioned.

5. The closed-loop ultrasound control system targeting deep brain regions according to claim 4, characterized in that: The adapter includes an adapter body and a plurality of auxiliary fixing rings arranged on the circumference of the adapter body. When the ultrasonic transducer is inserted into the adapter body, the plurality of auxiliary fixing rings are deformed to fix the ultrasonic transducer. The first cylindrical hole is opened in the adapter body, the inner diameter of the adapter body is 5.1 mm, and the outer diameter is 6.1 mm. The inner diameter of the auxiliary fixing ring is 0.8 mm, the outer diameter is 2 mm, and the shortest distance from the center of the adapter body is 2.3 mm.

6. The closed-loop ultrasound control system targeting deep brain regions according to claim 5, characterized in that: The ultrasonic component also includes a torus model, which is consistent with the structural size of the ultrasonic transducer. When the ultrasonic component is installed or not implemented, the torus model is placed in the adapter; when the ultrasonic component is in the implementation state, the ultrasonic transducer is placed in the adapter; the outer diameter of the torus model is 5 mm, the inner diameter is 1.5 mm, and the height is 6 mm; the inner diameter of the torus model matches the diameter of the optical fiber ceramic ferrule.

7. The closed-loop ultrasound control system targeting deep brain regions according to claim 6, characterized in that: The surface of the adapter body is marked with scales from bottom to top, and the ultrasonic transducer is fixed at a predetermined position in the first cylindrical hole according to the scales so that the ultrasonic transducer can accurately target the brain area.

8. The closed-loop ultrasound control system targeting deep brain regions according to claim 6, characterized in that: A Faraday cage is also placed around the ultrasonic transducer to shield the electromagnetic interference generated during the ultrasonic stimulation, thereby weakening the stimulation interference generated during the ultrasonic stimulation; Polymethyl methacrylate is also coated around the electrodes on the detection target and at the connection between the adapter and the surface of the skull to eliminate the ability of dental cement and skull to act as resistors or capacitors, thereby reducing power frequency interference; The contact area between the ultrasonic transducer and the skull surface is filled with a surface layer using polydimethylsiloxane or epoxy resin.

9. A method for manufacturing an ultrasonic component, characterized in that: The steps include: Place the fiber optic ceramic ferrule in a holder and fix it on a stereotaxic instrument to accurately locate the brain area that requires ultrasonic stimulation, and then lift the fiber optic ceramic ferrule; Apply vaseline on the surface of the torus model and insert it into the adapter to obtain an assembly; Insert the assembly into the optical fiber ceramic ferrule from bottom to top, so that the optical fiber ceramic ferrule is located in the middle hole of the torus model; Operate the stereotaxic body to slowly lower the fiber optic ceramic ferrule until the adapter of the assembly reaches the surface of the skull, and use epoxy resin glue to fix the adapter around and fill the surrounding pores; After the epoxy glue has hardened, secure the adapter with dental cement.

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