Noninvasive nerve regulation and control method and system based on transcranial ultrasonic stimulation

Abstract

The invention discloses a noninvasive nerve regulation and control method and system based on transcranial ultrasonic stimulation. The method comprises the following steps: calibrating the focal length of an ultrasonic transducer through acoustic simulation; obtaining T1 weighted structure image data of a user, and converting the T1 weighted structure image data into a pseudo CT image; on the basis of the T1 weighted structure image data of the user, the hippocampus head mask in the standard template is matched, and the head skin of the user is reconstructed; based on the head skin of the user, determining the position where the ultrasonic transducer is most attached to the head skin of the user so as to establish the trajectory of the target spot; based on the trajectory of the target spot, correcting the focus position of the ultrasonic transducer based on the trajectory of the target spot by simulating an ultrasonic path so as to form a trajectory of a focus; and based on the track of the focus, controlling the ultrasonic transducer to operate according to preset parameters so as to implement transcranial ultrasonic stimulation. Therefore, the deep brain area can be accurately stimulated in a transcranial ultrasonic stimulation mode, craniotomy is not needed, and the method is more suitable for being developed on a large scale in common tested groups.

Description

TECHNICAL FIELD

[0001] The present application relates to a non-invasive neuromodulation method based on transcranial ultrasound stimulation, and also relates to a corresponding non-invasive neuromodulation system, and belongs to the technical field of neuromodulation. BACKGROUND

[0002] Ultrasound, i.e. sound waves with a frequency higher than 20 kHz, has the ability to focus through solid structures, can propagate long distances in soft biological tissues with minimal power loss, which makes it one of the most widely used technologies in biomedical imaging. When ultrasound is at different intensities, it will show different biological effects, among which low-intensity focused ultrasound gradually becomes the mainstream form of non-invasive neuromodulation technology due to its precise neuromodulation effect.

[0003] Neuromodulation technology is a technology that enhances or inhibits neural activity through physical stimulation (such as electricity, magnetism, ultrasound, etc.) or chemical means in a way of invasive or non-invasive, so as to treat diseases. Invasive neuromodulation technology, such as deep brain stimulation (DBS) and epidural cortical stimulation (EpCS), although has good spatial selectivity in stimulating specific brain areas in clinical application, is limited in scope of application due to the need for surgical operation, and is only suitable for patients with specific diseases. Traditional non-invasive neuromodulation methods, such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), although have been applied in clinical practice, have the disadvantages of limited spatial resolution (only centimeter level) and stimulation depth.

[0004] In this context, the potential clinical value of focused ultrasound as a neuromodulation method has gradually emerged. Research has started as early as half a century ago, and in the past decade, the research has risen sharply. Studies have shown that tFUS can regulate the neural activity of the brain of animals and humans, and can regulate the brain activity indicated by various means such as sensory or motor behavior, functional magnetic resonance imaging (fMRI), electroencephalogram (EEG) and near-infrared spectroscopy (NIRS). Compared with other non-invasive neural control technologies, low-intensity transcranial focused ultrasound (tFUS) has high spatial resolution and deep brain stimulation capability, and can non-invasively activate or inhibit the neural activity of specific brain regions. Transcranial ultrasound stimulation can precisely stimulate the deep brain while ensuring safety, and different parameters will cause activation or inhibition effect. For example, stimulating the right amygdala can inhibit its activity and reduce anxiety in patients; stimulating the posterior cingulate cortex (PCC) / dorsal anterior cingulate cortex (dACC) with theta burst can improve the functional connectivity of PCC / dACC with other brain regions and inhibit GABA levels in PCC. However, the existing research lacks attention to cognitive changes after stimulation, lacks causal exploration directly linking neural system changes to cognition and behavior (such as memory, decision-making under stress, etc.), and there is no precedent for precise stimulation of the hippocampal head, and the regulation of transcranial ultrasound stimulation on memory, decoding and inference, and the combination of hippocampal head activation changes and cognitive changes. There is also a blank in the research on amygdala stimulation in decision-making in an anxiety environment. In summary, there is an urgent need for a non-invasive neural control technology that can combine deep brain neural system activity with external behavioral changes to fill the gaps in existing research and applications. SUMMARY

[0005] The primary technical problem to be solved by the present application is to provide a non-invasive neural control method based on transcranial ultrasound stimulation.

[0006] Another technical problem to be solved by the present application is to provide a non-invasive neural control system based on transcranial ultrasound stimulation.

[0007] To achieve the above technical purposes, the present application adopts the following technical solutions:

[0008] According to a first aspect of an embodiment of the present application, a non-invasive neural control method based on transcranial ultrasound stimulation is provided, comprising the following steps:

[0009] Calibrate the focal length of the ultrasound transducer through acoustic simulation, so that the focal length of the transducer matches the average pulse intensity of the transcranial ultrasound stimulation;

[0010] Obtain T1-weighted structural image data of the user and convert it into a pseudo-CT image;

[0011] reconstructing the skin of the head of the user based on the T1-weighted structural image data of the user, in cooperation with a mask of a to-be-stimulated part in a standard template;

[0012] determining a position where the ultrasound transducer is most fitted to the skin of the head of the user based on the skin of the head of the user, so as to establish a trajectory of the target point;

[0013] based on the pseudo-CT image of the user and the trajectory of the target point, correcting the focal point position of the ultrasound transducer according to the trajectory of the target point by simulating an ultrasound path, so as to form a trajectory of the focal point;

[0014] controlling the ultrasound transducer to operate according to preset parameters based on the trajectory of the focal point, so as to implement transcranial ultrasound stimulation.

[0015] Preferably, the focal length of the ultrasound transducer is calibrated by acoustic simulation, specifically including:

[0016] detecting a pressure wave generated by the sound wave emitted by the ultrasound transducer in water by means of a hydrophone;

[0017] converting the pressure wave into an electrical signal;

[0018] based on a preset average pulse intensity of transcranial ultrasound stimulation, adjusting the focal length of the ultrasound transducer so that the detected electrical signal is equal to the average pulse intensity, so as to complete the calibration of the focal length of the ultrasound transducer.

[0019] Preferably, the skin of the head of the user is reconstructed based on the pseudo-CT image of the user, in cooperation with a mask of a to-be-stimulated part in a standard template, specifically including:

[0020] based on the hippocampal head mask in the standard template, acquiring a personalized hippocampal head mask for the user in cooperation with the pseudo-CT image of the user;

[0021] segmenting each component of the brain based on a preset segmentation tool;

[0022] inputting the personalized hippocampal head mask of the user and the segmentation result of the brain into a preset neural navigation system, so as to reconstruct the skin of the head of the user.

[0023] Preferably, the trajectory of the target point is established by the following method:

[0024] selecting four marker positions of a nose root, a left ear, a right ear and a nose tip on the skin of the head of the user, so as to match the skin of the subject with the reconstructed skin of the head;

[0025] Select a target point in the personalized hippocampus head mask of the user, find the position where the ultrasound transducer is most fitted with the reconstructed head skin, and connect the target point and the midpoint of the transducer to form a stimulation track of the target point.

[0026] Preferably, based on the target point track, the focus position of the ultrasound transducer is corrected based on the position of the target point by simulating the ultrasound path, specifically including:

[0027] Simulate the brain structure image in the vertical direction of the target point to preliminarily judge the simulation result according to the generated skull thickness; wherein the vertical direction of the target point represents the direction perpendicular to the skull;

[0028] Based on the simulation result of the preliminary judgment, the X-axis and Y-axis are adjusted, and the distance between the outlet plane and the head skin is adjusted according to the angle between the ultrasound transducer and the head skin, so that the target point gradually approaches the focus point with the maximum average pulse intensity of the ultrasound transducer until a preset level is reached;

[0029] Preferably, the X-axis direction represents the horizontal direction of the transducer; the Y-axis direction represents the vertical direction of the transducer; and the preset level represents that the difference between the average pulse intensity of the target point and the focus point with the maximum average pulse intensity of the ultrasound transducer is less than a first threshold value, and the maximum temperature rise in the skin, skull and brain tissue does not exceed a second threshold value.

[0030] Preferably, the preset parameters include:

[0031] The stimulation parameters used in the stimulation of the hippocampus head are: a basic frequency of 500 kHz, a duty cycle of 10%, a pulse repetition frequency of 5 Hz, a pulse width of 20 ms, a pulse period of 200 ms, and a spatial peak pulse average intensity of 14.4 W / cm 2 , and an ultrasonic duration of 80 s;

[0032] The stimulation parameters used in the stimulation of the amygdala are: a basic frequency of 500 kHz, a duty cycle of 5%, a pulse repetition frequency of 10 Hz, a pulse width of 5 ms, a pulse period of 100 ms, and a spatial peak pulse average intensity of 14.4 W / cm 2 , an ultrasonic duration of 30 s, a stimulation interval of 30 s, and a repetition of 10 times.

[0033] Preferably, the non-invasive neural regulation method further includes:

[0034] The gel pad of a preset shape is attached to the ultrasound transducer to fill the gap between the ultrasound transducer and the head skin through the gel pad of the preset shape.

[0035] According to a second aspect of an embodiment of the present application, a non-invasive neural regulation method based on transcranial ultrasound stimulation is provided, including:

[0036] calibrate the focal length of the ultrasound transducer through acoustic simulation so that the focal length of the transducer matches the average pulse intensity of the transcranial ultrasound stimulation;

[0037] obtain T1-weighted structural image data of a user and convert the T1-weighted structural image data into pseudo-CT images;

[0038] reconstruct the user's head skin based on the T1-weighted structural image data of the user and in cooperation with a mask of a to-be-stimulated part in a standard template;

[0039] determine a position at which the ultrasound transducer best fits the user's head skin based on the user's head skin, thereby establishing a trajectory of a target point;

[0040] collect electroencephalogram data of the user's scalp in real time;

[0041] perform real-time sleep staging on the electroencephalogram data of the user's scalp by using a random forest algorithm;

[0042] extract all slow waves in a sleep N3 stage from the electroencephalogram data of the user's scalp and calculate lengths of all the slow waves according to a preset initial threshold value of the slow waves;

[0043] extract all spindle waves in a sleep N2 stage from the electroencephalogram data of the user's scalp and calculate lengths of all the spindle waves according to a preset initial threshold value of the spindle waves;

[0044] when a wave crest of the slow wave and a wave trough of the spindle wave are simultaneously detected, control the ultrasound transducer to operate once according to preset parameters.

[0045] According to a third aspect of an embodiment of the present application, a non-invasive neural modulation system based on transcranial ultrasound stimulation is provided, comprising:

[0046] an acoustic simulation device configured to calibrate the focal length of the ultrasound transducer through acoustic simulation so that the focal length of the transducer matches the average pulse intensity of the transcranial ultrasound stimulation;

[0047] a data acquisition unit configured to obtain T1-weighted structural image data of a user;

[0048] a skin reconstruction unit connected to the data acquisition unit and configured to convert the T1-weighted structural image data of the user into pseudo-CT images and reconstruct the user's head skin in cooperation with a hippocampal head mask in a standard template;

[0049] a target point positioning unit connected to the skin reconstruction unit and configured to determine a position at which the ultrasound transducer best fits the user's head skin based on the user's head skin, thereby establishing a trajectory of a target point;

[0050] a focus positioning unit, connected with the target positioning unit, for correcting the focus position of the ultrasound transducer based on the trajectory of the target, by simulating the ultrasound path, to form a trajectory of the focus based on the trajectory of the target;

[0051] an ultrasound transducer, connected with the focus positioning unit, for operating the ultrasound transducer according to preset parameters based on the trajectory of the focus, for implementing transcranial ultrasound stimulation.

[0052] According to a fourth aspect of the embodiments of the present application, a non-invasive neural modulation system based on transcranial ultrasound stimulation is provided, comprising a processor and a memory, the processor reading the computer program in the memory for executing the non-invasive neural modulation method described above.

[0053] Compared with the prior art, the present application has the following technical effects:

[0054] (1) It can precisely stimulate deep brain areas such as the head of the hippocampus and the amygdala. Compared with transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), transcranial ultrasound stimulation has higher spatial resolution and greater stimulation depth. Compared with invasive neural modulation methods such as DBS (Deep Brain Stimulation), transcranial ultrasound stimulation does not require craniotomy and is more suitable for large-scale implementation in ordinary subject groups.

[0055] (2) For stimulation of the head of the hippocampus, theta burst stimulation is used. Theta burst adjusts brain activity by simulating the natural theta rhythm pattern of the brain. Transcranial ultrasound stimulation in theta-burst mode stimulates the brain with continuous ultrasound pulses at a frequency of 5Hz, which matches the theta rhythm frequency of the hippocampus related to learning and memory processes.

[0056] (3) The brainsight navigation system is used in combination with babelbrain software to calculate the path and deviation of ultrasound waves after entering the skull, so that a more precise focus stimulation position can be obtained without changing the target position.

[0057] (4) By customizing a gel pad of a specific shape, the cavity between the ultrasound transducer and the skin is eliminated, the situation where the transducer cannot be attached to the skin is addressed, the effective propagation of ultrasound waves is ensured, ultrasound attenuation is reduced, and signal quality is improved. In addition, for the air bubbles originally contained in the gel, a centrifuge is used to centrifuge the gel to minimize air bubbles in the gel. Furthermore, the use of air-free gel and shaped gel pads can also protect the ultrasound transducer from damage caused by energy reflection.

[0058] (5) The non-invasive neuromodulation method can analyze the immediate changes in nervous system activity during ultrasonic stimulation, allowing for a deeper understanding of the functional mechanisms of specific neural networks and their responses to external stimuli. In addition, the online mode of the non-invasive neuromodulation method can also be used for neural modulation during sleep. BRIEF DESCRIPTION OF DRAWINGS

[0059] Figure 1 A flowchart of a non-invasive neuromodulation method based on transcranial ultrasonic stimulation according to the first embodiment of the present application is provided.

[0060] Figure 2 A schematic diagram of calibrating the focal length of the ultrasonic transducer through acoustic simulation in the first embodiment of the present application is provided.

[0061] Figure 3 A working principle diagram of transcranial ultrasonic stimulation in offline mode in the first embodiment of the present application is provided.

[0062] Figure 4 A flowchart of a non-invasive neuromodulation method based on transcranial ultrasonic stimulation according to the second embodiment of the present application is provided.

[0063] Figure 5 A schematic diagram of neural modulation during sleep in the second embodiment of the present application is provided.

[0064] Figure 6 A structural diagram of a non-invasive neuromodulation system based on transcranial ultrasonic stimulation according to the third embodiment of the present application is provided.

[0065] Figure 7 A structural diagram of a non-invasive neuromodulation system based on transcranial ultrasonic stimulation according to the fourth embodiment of the present application is provided. DETAILED DESCRIPTION

[0066] The technical content of the present application will be described in detail below in combination with the drawings and specific embodiments.

[0067] This invention provides a non-invasive neuromodulation method and system based on transcranial ultrasound stimulation (TUS). First, the user's MRI structural image is imported into a pre-set neuronavigation system to reconstruct the user's skull and brain tissue. Then, based on the reconstructed skull and brain tissue, target points are selected in the neuronavigation system to obtain the focal position. Finally, the ultrasound transducer is held stably on the user's head using a handheld device or a support, and ultrasound stimulation is performed on the hippocampus and amygdala under different parameters. Furthermore, in this embodiment, TUS is combined with MRI (BOLD, MRS) and EEG to obtain changes in the nervous system and neurotransmitter levels before and after stimulation or during TUS stimulation, either offline or online.

[0068] Understandably, compared to traditional transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS), TUS offers higher spatial resolution and greater stimulation depth, enabling precise stimulation of deep brain regions such as the hippocampus and amygdala. Furthermore, compared to invasive neuromodulation techniques like deep brain stimulation (DBS), TUS does not require craniotomy, making it more suitable for large-scale implementation in general populations.

[0069] First Embodiment

[0070] like Figure 1 As shown, the first embodiment of the present invention provides a non-invasive neuromodulation method based on transcranial ultrasound stimulation, specifically including the following steps:

[0071] S1: The focal length of the ultrasonic transducer is calibrated through acoustic simulation.

[0072] In this embodiment, before using the ultrasound transducer for ultrasound stimulation, the focal length of the ultrasound transducer needs to be calibrated so that the focal length of the calibrated ultrasound transducer matches the average pulse intensity of the transcranial ultrasound stimulation.

[0073] Specifically, such as Figure 2 As shown, the TUS drive system 1 drives the ultrasonic transducer 2 to emit sound waves, which generate pressure waves as they propagate in water. The probe 3 of the hydrophone detects these pressure waves and converts them into electrical signals. The signal acquisition unit 4 collects these electrical signals. Therefore, based on a pre-set average pulse intensity, for example: I... SPPA 30W / cm 2 By adjusting the focal length of the ultrasonic transducer 2, the average pulse intensity after the detected electrical signal is converted is made equal to the preset average pulse intensity, thereby completing the focal length calibration of the ultrasonic transducer 2.

[0074] S2: Obtain T1-weighted structural image data of the user and convert it into a pseudo-CT image.

[0075] Specifically, the T1-weighted structural image data of the user is collected through MRI examination, which is a conventional technical means in the art and will not be described in detail here.

[0076] When the T1-weighted structural image data of the user is collected, the T1-weighted structural image data can be converted into a pseudo-CT image through an open source tool (for example, the open source tool kit mr-to-pct). It can be understood that this step can be adaptively adjusted as needed to achieve data conversion processing through different open source tools.

[0077] It can be understood that the steps S1 and S2 in the embodiment have no priority, and both can be performed simultaneously or separately. However, when step S2 is completed, step S3 of reconstructing the user's head skin is entered.

[0078] S3: Based on the T1-weighted structural image data of the user, cooperate with the hippocampal head mask in the standard template to reconstruct the user's head skin.

[0079] Specifically, in this embodiment, first, the hippocampal head mask in the Montreal Neurological Institute standard template (in this embodiment, the hippocampal head is taken as an example for illustration, and in other embodiments, the amygdala can also be replaced) is used to make a personalized hippocampal head mask for the user in FMRIB Software Library (FSL) in cooperation with the T1-weighted structural image data of the user.

[0080] Then, each component of the brain is segmented by simNIBS, which is an open source non-invasive brain stimulation simulation software. It can be understood that in other embodiments, other tools can also be used to segment each component of the brain.

[0081] Finally, the results of simNIBS segmentation and the personalized hippocampal head mask of the user are imported into the preset neuro-navigation system (in this embodiment, the Brainsight navigation system is used) to reconstruct the head skin of the user. The reconstruction process is generated by the navigation system, and the threshold of the reconstruction needs to be adjusted manually to make the reconstructed skin neither have serious defects (threshold is too high) nor have noise (threshold is too low). The judgment method of serious defects is that it will affect the registration of the subject's head and the navigation reconstructed head.

[0082] S4: Based on the head skin of the user, determine the position where the ultrasonic transducer best fits the head skin of the user, and establish the trajectory of the target point.

[0083] Specifically, when the user's head skin is reconstructed based on step S3, first, four mark positions of the nose root, the left ear, the right ear and the nose tip are selected on the user's head skin to match the subject skin (i.e., the actual head skin of the user) with the reconstructed head skin. Then, a target point is selected in the user's personalized hippocampus head mask to find the position where the ultrasound transducer is most fitted to the reconstructed head skin, and a stimulation track of the target point is formed by connecting the target point and the midpoint of the transducer.

[0084] S5: Based on the track of the target point, the focal point position of the ultrasound transducer is corrected based on the track of the target point by simulating the ultrasound path to form the track of the focal point.

[0085] Specifically, when the track of the target point is formed based on step S4, first, the pseudo-CT generated in step S2 is imported into the Brainsight navigation system, and the HU value (Hounsfield Unit, the density of the tissue calculated based on the density of water and air, the HU value of the brain tissue is generally 20-40, and the HU value of the skull is generally between 700 and 3000) adopts 300.

[0086] Then, the brain structure image in the vertical direction of the target point is simulated to preliminarily judge the simulation result according to the generated skull thickness; wherein the vertical direction of the target point represents the direction perpendicular to the skull. The approximate focal length and the offset (human experience judgment) are preliminarily judged.

[0087] Subsequently, the uncorrected sound field image is simulated, and the X-axis and the Y-axis are adjusted based on the uncorrected sound field simulation result.

[0088] Finally, based on the simulation result of the preliminary judgment, the X-axis and the Y-axis are adjusted, and the distance between the outlet plane and the head skin (i.e., the Z-axis) is adjusted according to the angle between the ultrasound transducer and the head skin, so that the target point gradually approaches the focal point with the maximum average pulse intensity of the ultrasound transducer until a preset level is reached.

[0089] In this embodiment, the X-axis direction represents the horizontal direction of the transducer; the Y-axis direction represents the vertical direction of the transducer; the preset level represents that the difference between the average pulse intensity of the target point and the average pulse intensity of the focal point with the maximum average pulse intensity of the ultrasound transducer is less than a first threshold value (0.5 in this embodiment) and the maximum temperature rise in the skin, the skull and the brain tissue does not exceed a second threshold value (2℃ in this embodiment).

[0090] Based on the skull thickness and the angle of the transducer, the track of the target point is corrected to generate a new target point (or target point) and track. When stimulating, navigate to the target point, and the emitted ultrasound will reach the original target point after refraction.

[0091] S6: Based on the trajectory of the focal point, control the ultrasonic transducer to operate according to the preset parameters for implementing transcranial ultrasound stimulation.

[0092] In this embodiment, the preset parameters are set as follows:

[0093] The stimulation parameters used in the stimulation of the hippocampus head are: a basic frequency of 500 kHz, a duty cycle of 10%, a pulse repetition frequency of 5 Hz, a pulse width of 20 ms, a pulse period of 200 ms, and a spatial peak pulse average intensity of 14.4 W / cm 2 , an ultrasonic duration of 80 s;

[0094] The stimulation parameters used in the stimulation of the amygdala are: a basic frequency of 500 kHz, a duty cycle of 5%, a pulse repetition frequency of 10 Hz, a pulse width of 5 ms, a pulse period of 100 ms, and a spatial peak pulse average intensity of 14.4 W / cm 2 , an ultrasonic duration of 30 s, a stimulation interval of 30 s, and repeated 10 times.

[0095] After the trajectory of the focal point of the ultrasonic transducer is determined based on step S5, the ultrasonic transducer needs to be controlled to operate according to the preset parameters for implementing transcranial ultrasound stimulation on the user. The specific operation steps are as follows:

[0096] (1) After the user is comfortably seated, use the registration tool pointer to position the four marker positions of the nose root, left ear, right ear and nose tip set in front of the user's head, and assist the camera to position the user's head. The standard for good positioning is that the pointer passes through the ultrasonic transducer placement area of the user's head, and the error between the display and the skin of the head is less than 3 mm.

[0097] (2) Apply the centrifuged gel to the ultrasonic transducer placement site. The gel is water-based and forms a gel pad of a predetermined shape. Centrifugation can effectively remove air bubbles in the gel, reduce errors, and protect the subject's head and the transducer of the TUS.

[0098] (3) The ultrasonic transducer is attached to the skin with the specific shape of the gel pad pointed by the focal point trajectory, so that the specific shape of the gel pad eliminates the gap between the ultrasonic transducer and the skin of the head, to cope with the situation that the ultrasonic transducer cannot be attached to the skin, to ensure the effective propagation of ultrasonic waves, reduce ultrasonic attenuation, and improve signal quality. In addition, the use of bubble-free gel and a gel pad of a specific shape can also protect the ultrasonic transducer from damage caused by energy reflection. In this embodiment, the standard for good placement of the ultrasonic transducer is that the Brainsight navigation system displays a position with an error of less than 3 mm from the focal point.

[0099] (4) Control the ultrasonic transducer to start according to the preset parameters and begin ultrasonic stimulation.

[0100] Reference Figure 3 As shown, this embodiment adopts an offline approach. Before performing ultrasound stimulation, the user first acquires T1-weighted structural image data using a 32-channel coil on an MRI scanner, and then... (The sentence is incomplete and requires more context to translate accurately.) 3 The hippocampus was selected under the voxel and MRS data were acquired. Subsequently, the user completed a cognitive task on the MRI, and task-state functional imaging (t-fMRI) data were acquired. Finally, a set of resting-state functional imaging (rs-fMRI) data was acquired before the subject left the MRI machine.

[0101] After 80 seconds of tbTUS stimulation of the hippocampus under navigation guidance, the user returned to the MRI and first underwent a set of rs-fMRI scans. Then, the second part of the cognitive task was completed in the MRI and t-fMRI data was acquired. Subsequently, MRS of the hippocampus was acquired with the same parameters, and finally a set of rs-fMRI was acquired to determine the effect of ultrasound stimulation.

[0102] Understandably, in this embodiment, magnetic resonance spectroscopy (MRS) is used to quantify the levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurotransmitter glutamate (Glu) after hippocampal head stimulation. This allows for a deeper understanding of the GABAergic and Gluergic mechanisms of TUS-induced hippocampal brain region neural plasticity, thereby elucidating the neurochemical basis of TUS-mediated hippocampal head neural regulation. Furthermore, long-duration resting MRI can provide the duration of the TUS stimulation effect, offering important reference for non-invasive neuromodulation therapy in patients with AD and other conditions.

[0103] Second Embodiment

[0104] like Figure 4 and Figure 5 As shown, the second embodiment of the present invention provides another non-invasive neuromodulation method based on transcranial ultrasound stimulation. The difference between this embodiment and the first embodiment is that the non-invasive neuromodulation method in this embodiment uses an online approach to perform neuromodulation of sleep.

[0105] Specifically, in the second embodiment of the present invention, steps S1-S4 are the same as in the first embodiment, and will not be described again here. The difference from the first embodiment is that after the trajectory of the target point is obtained based on step S4, step S5' is executed.

[0106] S5': Neuromodulation of sleep.

[0107] Specifically, in the present embodiment, first, the scalp electroencephalogram data of the patient is subjected to real-time sleep staging by using the random forest algorithm, and the A-class random undersampling is used to solve the problem that the N3 stage and the N1 stage are relatively short compared with the wake period. The real-time decoding algorithm uses the data of the first 30 seconds to output a sleep stage label to predict the sleep stage of the next 3 seconds.

[0108] Based on the neocortical sleep data of the patient of the previous night, all slow waves in the sleep N3 stage are extracted, and the 75% of the rising state and the falling state of the slow wave is defined as the initial threshold value of the system, and the length of all slow waves is calculated. Real-time detection is performed on the rising state and the falling state by using the threshold value, and when both the threshold values are satisfied, the length of the selected slow wave is detected to ensure that it meets the frequency of the slow wave. In addition, the system also updates the threshold values of the rising state and the falling state based on all slow wave events in the N3 sleep data of the previous 400 seconds.

[0109] Based on the neocortical sleep data of the patient of the previous night, all slow waves in the sleep N3 stage are extracted, and the 75% of the rising state and the falling state of the slow wave is defined as the initial threshold value of the system, and the length of all slow waves is calculated. Real-time detection is performed on the rising state and the falling state by using the threshold value, and when both the threshold values are satisfied, the length of the selected slow wave is detected to ensure that it meets the frequency of the slow wave. In addition, the system also updates the threshold values of the rising state and the falling state based on all slow wave events in the N3 sleep data of the previous 400 seconds.

[0110] When the slow wave rising state and the spindle wave trough are detected at the same time, an ultrasonic stimulation is performed on the hippocampus head of the user.

[0111] Third embodiment

[0112] As Figure 6 shown, on the basis of the above-mentioned first embodiment, the third embodiment of the present application provides a non-invasive neural regulation system based on transcranial ultrasound stimulation, which comprises an acoustic simulation device 10, a data acquisition unit 20, a skin reconstruction unit 30, a target positioning unit 40, a focal point positioning unit 50 and an ultrasonic transducer 60. Specifically,

[0113] The acoustic simulation device 10 is used to calibrate the focal length of the ultrasound transducer through acoustic simulation, so that the focal length of the transducer matches the average pulse intensity of transcranial ultrasound stimulation. The data acquisition unit 20 is used to acquire the user's T1-weighted structural image data. The skin reconstruction unit 30 is connected to the data acquisition unit 20 to convert the user's T1-weighted structural image data into a pseudo-CT image and, in conjunction with the hippocampus mask in the standard template, reconstruct the user's scalp skin. The target localization unit 40 is connected to the skin reconstruction unit 30 to determine the position where the ultrasound transducer best fits the user's scalp skin, thereby establishing the target trajectory. The focus localization unit 50 is connected to the target localization unit 40 to correct the focus position of the ultrasound transducer based on the target trajectory by simulating the ultrasound path, thus forming the focus trajectory. The ultrasound transducer 60 is connected to the focus localization unit 50 to operate according to preset parameters based on the focus trajectory for transcranial ultrasound stimulation.

[0114] It is understood that each of the above units is a functional module for implementing the steps in the first embodiment, but is not limited to this module form. In other embodiments, other module structures can also be used to implement the non-invasive neuromodulation method in the first embodiment.

[0115] Fourth embodiment

[0116] like Figure 7 As shown, based on the above-described non-invasive neuromodulation method based on transcranial ultrasound stimulation, this invention further provides a non-invasive neuromodulation system based on transcranial ultrasound stimulation. This non-invasive neuromodulation system includes one or more processors and a memory. The memory is coupled to the processors and is used to store one or more programs. When the one or more programs are executed by the one or more processors, the processors implement the non-invasive neuromodulation method based on transcranial ultrasound stimulation as described in the above embodiments.

[0117] The processor is configured to control the overall operation of the non-invasive neuromodulation system to complete all or part of the steps of the transcranial ultrasound stimulation based non-invasive neuromodulation method described above. The processor can be a central processing unit (CPU), a graphics processing unit (GPU), a field-programmable gate array (FPGA), an application-specific integrated circuit (ASIC), a digital signal processing (DSP) chip, or the like. The memory is configured to store various types of data to support the operation of the non-invasive neuromodulation system, which can include, for example, instructions for operating any application or method on the non-invasive neuromodulation system, and application-related data. The memory can be implemented by any type of volatile or non-volatile storage device or a combination thereof, such as static random access memory (SRAM), electrically erasable programmable read-only memory (EEPROM), erasable programmable read-only memory (EPROM), programmable read-only memory (PROM), read-only memory (ROM), magnetic memory, flash memory, and the like.

[0118] In an exemplary embodiment, the non-invasive neuromodulation system can be implemented by a computer chip or entity, or by a product having certain functions, for executing the transcranial ultrasound stimulation based non-invasive neuromodulation method described above, and achieving the technical effects consistent with the above method. A typical embodiment is a computer. Specifically, the computer can be, for example, a personal computer, a laptop computer, an in-vehicle human-machine interaction device, a cellular phone, a camera phone, a smart phone, a personal digital assistant, a media player, a navigation device, an email device, a game console, a tablet computer, a wearable device, or a combination of any of these devices.

[0119] In another exemplary embodiment, the present application also provides a computer readable storage medium including program instructions, which, when executed by a processor, implement the steps of the transcranial ultrasound stimulation based non-invasive neuromodulation method in any one of the above embodiments. For example, the computer readable storage medium can be the memory described above including program instructions, which can be executed by the processor of the non-invasive neuromodulation system to complete the transcranial ultrasound stimulation based non-invasive neuromodulation method described above, and achieve the technical effects consistent with the above method.

[0120] In summary, the transcranial ultrasound stimulation based non-invasive neuromodulation method and system provided by the embodiments of the present application have the following beneficial effects:

[0121] (1) It can precisely stimulate deep brain regions, such as the head of the hippocampus and the amygdala. Compared with the previous TMS, tDCS and tACS, TUS has higher spatial resolution and greater stimulation depth. Compared with invasive neuromodulation methods such as DBS, TUS does not require craniotomy and is more suitable for large-scale development in ordinary subject groups.

[0122] (2) For the stimulation of the head of the hippocampus, theta burst stimulation is used, which modulates brain activity by simulating the natural theta rhythm pattern of the brain. tbTUS stimulates the brain with continuous uninterrupted ultrasound pulses at a frequency of 5 Hz, which matches the hippocampal theta rhythm frequency associated with learning and memory processes.

[0123] (3) The brainsight navigation system is used in combination with babel brain software to calculate the path and deviation of ultrasound after entering the skull, so that a more accurate focal stimulation position can be obtained without changing the target position.

[0124] (4) By customizing a gel pad of a specific shape, the cavity between the ultrasonic transducer and the skin is eliminated, the situation where the transducer cannot be attached to the skin is addressed, the effective propagation of ultrasound is ensured, the attenuation of ultrasound is reduced, and the signal quality is improved. In addition, for the air bubbles originally contained in the gel, a centrifuge is used to centrifuge the gel to minimize the air bubbles in the gel. In addition, the air-free gel and the shaped gel pad can also protect the ultrasonic transducer and prevent damage to the transducer caused by energy reflection.

[0125] (5) The non-invasive neural regulation method in this embodiment can analyze the immediate changes in neural activity during ultrasonic stimulation, and can deeply understand the functional mechanism of specific neural networks and their response to external stimuli. In addition, the online mode of the non-invasive neural regulation method can also regulate the sleep.

[0126] It should be noted that the above embodiments are only illustrative. The technical solutions of each embodiment can be combined, and all are within the protection scope of the present application.

[0127] In addition, the terms "first", "second" are only for descriptive purposes, and cannot be understood as indicating or implying relative importance or implicitly indicating the number of indicated technical features. Therefore, the features defined with "first", "second" can explicitly or implicitly include one or more of the features. In the description of the present application, the meaning of "multiple" is two or more, unless otherwise specifically limited.

[0128] The non-invasive neural regulation method and system based on transcranial ultrasound stimulation provided by the present application are described in detail above. Any obvious modification made by a person skilled in the art without departing from the essential content of the present application will constitute an infringement of the patent right of the present application and will bear the corresponding legal responsibility.

Claims

1. A method of non-invasive neuromodulation based on transcranial ultrasound stimulation, characterized in that The method comprises the following steps: Calibrate the focal length of the ultrasonic transducer through acoustic simulation, so as to match the focal length of the transducer with the average pulse intensity of transcranial ultrasound stimulation; Obtain T1-weighted structural image data of a user and convert it into a pseudo-CT image; Based on the T1-weighted structural image data of the user, cooperate with the mask of the stimulation site in the standard template, and reconstruct the skin of the head of the user; Based on the skin of the head of the user, determine the position where the ultrasonic transducer is most fitted to the skin of the head of the user, so as to establish the trajectory of the target point; Based on the pseudo-CT image of the user and the trajectory of the target point, simulate the ultrasonic path, so as to correct the focal point position of the ultrasonic transducer according to the trajectory of the target point, thereby forming the trajectory of the focal point; Based on the trajectory of the focal point, control the ultrasonic transducer to operate according to the preset parameters, so as to implement transcranial ultrasound stimulation.

2. The non-invasive neuromodulation method of claim 1, wherein The method for calibrating the focal length of the ultrasonic transducer through acoustic simulation comprises the following steps: Detect the pressure wave generated by the sound wave emitted by the ultrasonic transducer in water through a hydrophone; Convert the pressure wave into an electrical signal; Based on the pre-set average pulse intensity of transcranial ultrasound stimulation, adjust the focal length of the ultrasonic transducer, so that the detected electrical signal is equal to the average pulse intensity, thereby completing the calibration of the focal length of the ultrasonic transducer.

3. The non-invasive neuromodulation method of claim 1, wherein Based on the pseudo-CT image of the user, cooperate with the mask of the stimulation site in the standard template, and reconstruct the skin of the head of the user, which comprises the following steps: Based on the hippocampal head mask in the standard template, cooperate with the pseudo-CT image of the user, and obtain the personalized hippocampal head mask for the user; Segment each component of the brain based on a pre-set segmentation tool; Input the personalized hippocampal head mask of the user and the segmentation result of the brain into a pre-set neural navigation system, so as to reconstruct the skin of the head of the user.

4. The non-invasive neuromodulation method of claim 3, wherein The trajectory of the target point is established by the following method: Select four marker positions of the nose root, the left ear, the right ear and the nose tip on the skin of the head of the user, so as to match the skin of the subject with the reconstructed skin of the head; Select a target point in the personalized hippocampal head mask of the user, find the position where the ultrasonic transducer is most fitted to the reconstructed skin of the head, and connect the target point and the midpoint of the transducer to form the stimulation trajectory of the target point.

5. The non-invasive neuromodulation method of claim 1, wherein Based on the trajectory of the target point, simulate the ultrasonic path, so as to correct the focal point position of the ultrasonic transducer based on the position of the target point, which comprises the following steps: Simulate the brain structure image in the vertical direction of the target point, so as to preliminarily judge the simulation result according to the generated skull thickness; wherein the vertical direction of the target point represents the direction perpendicular to the skull; Based on the preliminary judgment of the simulation result, adjust the X-axis and the Y-axis, and adjust the distance between the outlet plane and the skin of the head according to the angle between the ultrasonic transducer and the skin of the head, so that the target point gradually approaches the focal point with the maximum average pulse intensity of the ultrasonic transducer, until a pre-set level is reached. The X-axis direction represents the horizontal direction of the transducer; the Y-axis direction represents the vertical direction of the transducer; the preset horizontal direction represents that the difference between the average pulse intensity of the target point and the average pulse intensity of the focus point of the ultrasonic transducer is less than a first threshold value, and the maximum temperature rise in the skin, skull and brain tissue does not exceed a second threshold value.

6. The non-invasive neuromodulation method of claim 1, wherein The preset parameters include: The stimulation parameters used in the stimulation of the hippocampal head were: base frequency 500 kHz, duty cycle 10%, pulse repetition frequency 5 Hz, pulse width 20 ms, pulse period 200 ms, spatial peak pulse average intensity 14.4 W / CM 2 , ultrasound duration 80 s; The stimulation parameters used in the stimulation of the amygdala were: base frequency 500 kHz, duty cycle 5%, pulse repetition frequency 10 Hz, pulse width 5 ms, pulse period 100 ms, spatial peak pulse average intensity 14.4 W / cm 2 , ultrasound duration 30 s, stimulation interval 30 s and repeated 10 times.

7. The non-invasive neuromodulation method of claim 1, wherein Further comprising: The gel pad of the preset shape is attached to the ultrasonic transducer to fill the gap between the ultrasonic transducer and the head skin through the gel pad of the preset shape.

8. A method of non-invasive neuromodulation based on transcranial ultrasound stimulation, characterized in that The method comprises the following steps: The focal length of the ultrasonic transducer is calibrated through acoustic simulation to match the average pulse intensity of the transcranial ultrasonic stimulation; T1-weighted structural image data of the user is acquired and converted into pseudo-CT images; Based on the T1-weighted structural image data of the user, the head skin of the user is reconstructed in cooperation with the mask of the to-be-stimulated part in the standard template; Based on the head skin of the user, the position of the ultrasonic transducer most fitted to the head skin of the user is determined to establish the trajectory of the target point; The scalp EEG data of the user is collected in real time; The scalp EEG data of the user is sleep staged in real time by using a random forest algorithm; According to the scalp EEG data of the user, all slow waves in the sleep N3 stage are extracted, and the lengths of all slow waves are calculated according to the preset initial threshold value of the slow wave; According to the scalp EEG data of the user, all spindle waves in the sleep N2 stage are extracted, and the lengths of all spindle waves are calculated according to the preset initial threshold value of the spindle wave; When the wave crest of the slow wave and the wave trough of the spindle wave are detected at the same time, the ultrasonic transducer is controlled to run once according to the preset parameters.

9. A non-invasive neuromodulation system based on transcranial ultrasound stimulation, characterized in that The method comprises: An acoustic simulation device is used to calibrate the focal length of the ultrasonic transducer through acoustic simulation to match the average pulse intensity of the transcranial ultrasonic stimulation; A data acquisition unit is used to acquire T1-weighted structural image data of the user; A skin reconstruction unit is connected to the data acquisition unit to convert the T1-weighted structural image data of the user into pseudo-CT images, and reconstruct the head skin of the user in cooperation with the hippocampal head mask in the standard template; A target point positioning unit is connected to the skin reconstruction unit to determine the position of the ultrasonic transducer most fitted to the head skin of the user based on the head skin of the user, thereby establishing the trajectory of the target point; A focus point positioning unit is connected to the target point positioning unit to correct the focus point position of the ultrasonic transducer based on the trajectory of the target point through simulated ultrasonic paths to form the trajectory of the focus point based on the trajectory of the target point; An ultrasonic transducer is connected to the focus point positioning unit to run the ultrasonic transducer according to the preset parameters based on the trajectory of the focus point to implement transcranial ultrasonic stimulation.

10. A non-invasive neuromodulation system based on transcranial ultrasound stimulation, characterized in that The method comprises a processor and a memory, and the processor reads a computer program in the memory to execute the non-invasive neuromodulation method in any one of claims 1-7.

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