WO2023108876A1 - 全息超声跨颅与神经环路调控系统及其设计方法 - Google Patents

全息超声跨颅与神经环路调控系统及其设计方法 Download PDF

Info

Publication number
WO2023108876A1
WO2023108876A1 PCT/CN2022/076195 CN2022076195W WO2023108876A1 WO 2023108876 A1 WO2023108876 A1 WO 2023108876A1 CN 2022076195 W CN2022076195 W CN 2022076195W WO 2023108876 A1 WO2023108876 A1 WO 2023108876A1
Authority
WO
WIPO (PCT)
Prior art keywords
holographic
ultrasonic
sound field
control system
stimulation
Prior art date
Application number
PCT/CN2022/076195
Other languages
English (en)
French (fr)
Inventor
牛丽丽
林争荣
李飞
郑海荣
孟龙
孟文
Original Assignee
中国科学院深圳先进技术研究院
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国科学院深圳先进技术研究院 filed Critical 中国科学院深圳先进技术研究院
Publication of WO2023108876A1 publication Critical patent/WO2023108876A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N7/02—Localised ultrasound hyperthermia
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H40/00—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices
    • G16H40/60—ICT specially adapted for the management or administration of healthcare resources or facilities; ICT specially adapted for the management or operation of medical equipment or devices for the operation of medical equipment or devices
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/50—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for simulation or modelling of medical disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0004—Applications of ultrasound therapy
    • A61N2007/0021—Neural system treatment
    • A61N2007/0026—Stimulation of nerve tissue

Definitions

  • the invention relates to the technical field of holographic ultrasound control, in particular to a holographic ultrasound transcranial and nerve loop control system and a design method thereof.
  • neuropsychiatric diseases is closely related to the abnormal function of deep brain nuclei, and the damage of synaptic connections between neural circuits promotes the pathological process of diseases. Reversing disease-associated nuclei and their functional connections in neural circuits with physical stimulation can alleviate or cure symptoms.
  • the complexity of the pathogenesis of different neuropsychiatric diseases indicates that the treatment strategy should focus on the selection of "loop synergistic intervention", and the stimulation of different targets in the intracranial neural loop will help to improve the clinical efficacy of neuromodulation technology .
  • Physical neuromodulation technology is an important means of neuroscience research and neurological disease intervention using implantable and non-implantable technologies. Combining basic principles of electricity, magnetism, and light with neuroscience, neurostimulation and regulation technologies such as deep electrical stimulation, transcranial magnetic stimulation, and optogenetic regulation have been produced. Deep brain stimulation is to implant electrodes into specific nerve nuclei in the brain, through controllable high-frequency current stimulation to inhibit the abnormal nerve function of nuclei cells, and achieve the purpose of effective intervention and treatment of diseases. This technology provides an effective new intervention method for many intractable brain diseases such as depression, Parkinson's, intractable epilepsy, dystonia, and intractable pain.
  • Transcranial magnetic stimulation technology is a non-invasive detection and treatment technology, which is used to evaluate nerve electrophysiological conduction pathways, as well as neurological rehabilitation for depression, epilepsy, stroke, schizophrenia, autism and other diseases.
  • Neuromodulation of light-sensing genes integrates the knowledge of optics and genetic engineering to achieve neuromodulation and potential disease intervention.
  • the interaction between medical ultrasound and human tissue mainly uses the wave effect of the interaction between sound waves and matter.
  • ultrasound also has three basic acoustic effects: mechanical effect, thermal effect and cavitation effect.
  • Objects or biological tissues in the sound field absorb, scatter, and reflect sound waves, and convert the energy of sound waves into physical momentum, and are affected by force, which is defined as ultrasonic radiation force in acoustics.
  • neuropsychiatric diseases is often not limited to the dysfunction of neurons in a single nucleus, and is often directly related to the abnormality of multi-nuclei in the brain functional network.
  • dysfunction of multifunctional circuits plays a crucial role in the pathogenesis of epilepsy, which mainly includes the hippocampal amygdala circuit, cortical-subcortical circuit, basal ganglia circuit and so on.
  • Deep brain electrical stimulation technology uses surgical orientation to implant multiple stimulating electrodes into different nuclei in the brain, and realizes the stimulation of nuclei and vagus nerves by giving safe and controllable currents, providing a safe way for many clinically intractable epilepsy. effective treatment.
  • Transcranial magnetic stimulation is a neuromodulation technology that uses pulsed magnetic fields to act on the central nervous system to change the membrane potential of neurons to generate induced currents, affect the metabolism in the brain and the electrical activity of neurons, thereby causing a series of physiological and biochemical reactions. .
  • This technology is mainly used in the treatment of refractory brain functional diseases.
  • transcranial magnetic stimulation is also performed through two stimulation targets, and the brain function network is focused to achieve the goal of regulating refractory epilepsy. application.
  • Optogenetic technology is a new type of neural regulation technology developed rapidly in recent years.
  • This technology first uses gene manipulation technology to express light-sensing genes (ChR2, Arch, etc.) in specific types of neurons in the nervous system, and uses light-sensing channels to Under the light stimulation of different wavelengths, the passage of ions is selectively achieved, and the purpose of selective regulation of neurons is achieved.
  • the expression of viruses in different regions combined with light stimulation is used to inhibit the abnormal discharge of epilepsy animal models.
  • Different physical neuromodulation technologies have different advantages and disadvantages: the application of deep brain stimulation technology needs to implant electrodes into the deep brain tissue through craniotomy, the stimulation target cannot be replaced, and the entire power supply equipment needs to be surgically implanted into the body.
  • Transcranial magnetic stimulation technology has bottlenecks such as insufficient stimulation depth, inability to focus, low stimulation resolution, and difficulty in determining the stimulation area.
  • Light-sensing gene regulation technology cannot be used in the clinical treatment of brain diseases due to the need for transfection of viral proteins.
  • the above technology has been applied to brain function network stimulation with multiple targets, the implantation of multiple electrodes in the brain or the space limitation of magnetic coil hardware greatly reduces the patient's acceptance.
  • the new ultrasonic neuromodulation technology has unique advantages such as non-invasive, deep brain stimulation, and dynamic adjustable focus.
  • ultrasound neuromodulation technology As a new type of physical nerve stimulation technology, ultrasound neuromodulation technology has its unique advantages of non-invasiveness, strong penetrability and high spatial-temporal resolution, etc. It has important clinical disease intervention value and broad application prospects. However, there are no related technologies and reports for the intervention of neural circuits in the pathological process of diseases, especially the ultrasonic intervention of circuit synaptic function. Moreover, the preclinical research of ultrasound neuromodulation technology and the clinical research of some people mainly use single focus stimulation.
  • One object of the present invention is to provide a holographic ultrasonic transcranial and neural loop regulation system and its design method, the system can realize holographic ultrasonic precise transcranial focusing stimulation and real-time regulation of the neural loop function, and adopts different structures
  • the unique holographic lens structure is used to modulate and form different forms of focused sound fields to meet the requirements of double-point or multi-point stimulation sites.
  • the present invention provides a holographic ultrasonic transcranial and neural loop control system, including:
  • a holographic ultrasonic focusing module includes at least two ultrasonic transducers and holographic lenses respectively coupled to the corresponding ultrasonic transducers, the holographic lenses are used to convert the corresponding ultrasonic transducers
  • the sound field modulation of the device forms a focused sound field
  • a sound field characterization and measurement system the sound field characterization and measurement system is used to measure the sound field of the holographic ultrasonic focusing module and the focused sound field formed after modulation, and analyze and compare numerical simulation results to optimize the holographic lens and the Structural design and processing of ultrasonic transducers;
  • An electronic cooperative control system is connected to the holographic ultrasound focusing module, and is used for real-time regulation of the ultrasonic stimulation parameters of the holographic ultrasound focusing module and the position of the holographic ultrasound focusing module;
  • the effectiveness recording and feedback system is connected to the electronic collaborative control system, and is used for real-time monitoring, recording and feedback of the effect of the focused sound field modulated by the holographic lens on the stimulation site of the target area Effective information, and transmit the effective information to the electronic cooperative control system, so as to regulate the ultrasonic stimulation parameters and position of the holographic ultrasonic focusing module in real time through the electronic cooperative control system, so as to realize the stimulation of the target area real-time control.
  • the holographic ultrasonic focusing module includes a first ultrasonic transducer, a first holographic lens coupled to the first ultrasonic transducer, a second ultrasonic transducer, and a The second holographic lens of the second ultrasonic transducer, wherein the first holographic lens and the second holographic lens adopt different structures, so as to enable the holographic ultrasonic focusing module to form a focused sound field for double-point paired stimulation.
  • the holographic lens is configured to be obtained by the following design method: based on the reciprocity principle of sound wave transmission-reception, the phase of the incident sound wave of the ultrasonic transducer is designed by a time-reversal method, Establish a theoretical model of holographic lens structure for different ultrasonic focused sound field requirements, and design a holographic lens structure for different target stimulation requirements.
  • the sound field characterization and measurement system includes a sound field measurement module and a sound field characterization module connected to the sound field measurement module.
  • the sound field of the transducer is measured, and the sound field characterization module is used to quantify the horizontal and vertical resolution, focus position, and sound pressure value parameters of the ultrasonic transducer modulated by the corresponding holographic lens, and analyze and compare numerical simulation results.
  • the electronic cooperative control system includes a plurality of electronic control systems, different ultrasonic transducers are controlled by independent electronic control systems, and the vibration elements of the ultrasonic transducers are controlled by The corresponding electronic control system is set to realize synchronous work, interval differential work or paired cooperative work.
  • the effectiveness recording and feedback system includes an effectiveness recording unit, a real-time effectiveness monitoring module connected to the effectiveness recording unit, and a feedback control module connected to the real-time effectiveness monitoring module.
  • the effectiveness recording unit is used to record in real time the stimulation position of the focused sound field formed by the modulation of the holographic lens on the target area;
  • the real-time effectiveness monitoring module is used to record the stimulation position based on the effectiveness recording unit
  • the consistency of the point and the target target point outputs real-time effectiveness monitoring information;
  • the feedback control unit is used to feed back the real-time effectiveness monitoring information output by the real-time effectiveness monitoring module to the electronic collaborative control system, so as to
  • the electronic coordinated control system regulates the position of the holographic ultrasound focusing module in real time, thereby realizing the real-time adjustment of the stimulation site.
  • the holographic ultrasound transcranial and nerve loop control system further includes a signal excitation module, the signal excitation module is connected to the holographic ultrasound focusing module and the electronic cooperative control system, and includes A parameter modulation unit and a start control unit, the parameter modulation unit is used to set the ultrasonic parameters of the ultrasonic transducer; the start control unit is used to control the operation of the ultrasonic transducer after the ultrasonic parameters are set, and is used for The ultrasonic transducer is shut down urgently when the ultrasonic parameter is set incorrectly.
  • the ultrasonic transducer is a single-element planar ultrasonic transducer
  • the single-element planar ultrasonic transducer includes a piezoelectric ceramic sheet, A bipolar lead, and an encapsulation shell for encapsulating the piezoelectric base and the bipolar lead.
  • the present invention also provides a design method of the holographic ultrasonic transcranial and neural loop control system, including steps:
  • the phase of the incident sound wave is designed by the time inversion method, and the theoretical model of the holographic lens structure is established for different ultrasonic focused sound field requirements, and based on the theoretical model of the holographic lens structure design for different targets
  • the step S1 includes the steps of:
  • the step S4 includes the steps of:
  • the present invention compensates for the phase distortion caused by the irregular geometric shape of the skull, non-uniform density, sound velocity, attenuation coefficient and other parameter distributions, and establishes a holographic ultrasonic precise cross-cranial focusing to carry out systematic and detailed theoretical model calculations and numerical values.
  • Simulation verification establishing a theoretical model of holographic ultrasound focusing for different ultrasonic focusing sound field requirements, the purpose is to achieve accurate and variable sound field modulation of ultrasound; at the same time, a holographic lens structure is designed for different target stimulation requirements to improve ultrasound deep brain focusing resolution and accuracy.
  • the present invention designs and prepares a low-cost, small-sized ultrasonic transducer according to the space and anatomical position of different stimulated brain regions.
  • the ultrasonic transducer has stable performance and can satisfy deep brain Stimulation needs, while meeting the needs of in-body wearable multi-point deep brain stimulation.
  • the holographic lens adopted in the present invention has less influence on the performance of the ultrasonic transducer, and can significantly improve the resolution of the focal spot of the sound field of the ultrasonic transducer, which is more conducive to the ultrasonic sound wave in the deep nuclei. focus.
  • the holographic ultrasonic transcranial and neural loop control system of the present invention integrates the holographic ultrasonic focusing module, the sound field characterization and measurement system, the electronic collaborative control system, the signal excitation module, and the effectiveness recording and feedback system.
  • the characterization and measurement system measures, analyzes and compares the numerical simulation results of the sound field of the holographic ultrasonic focusing module and the modulated focused sound field to optimize the structural design and processing of the holographic lens and the ultrasonic transducer;
  • the real-time effectiveness monitoring module of the effectiveness record and feedback system monitors the effectiveness of the ultrasound on the stimulation site regulation of the target area under different focus stimulations, and determines the multi-target ultrasound according to the feedback control unit of the effectiveness record and feedback system. Stimulation can accurately and effectively act on the target; and according to the collaborative work of multiple modules, real-time accurate multi-target and multi-modal ultrasonic stimulation.
  • the holographic ultrasonic transcranial and nerve loop control system of the present invention utilizes the electronic cooperative control system to electronically control the vibrators in the ultrasonic transducer, and each vibrator is controlled by an independent signal excitation module and an electronic system .
  • various stimulation methods such as synchronous work, interval differential work, and paired cooperative work are realized for each vibration element by the setting of the corresponding electronic control system.
  • Fig. 1 is a structural block diagram of the holographic ultrasound transcranial and nerve loop control system according to a preferred embodiment of the present invention.
  • FIG. 2 , FIG. 3 and FIG. 4 are flow charts of the design method of the holographic ultrasound transcranial and nerve loop control system in the preferred embodiment of the present invention.
  • Fig. 5 is a simulation diagram of the structure of the holographic lens and the focused sound field formed by modulation of the holographic ultrasound transcranial and nerve loop control system according to the preferred embodiment of the present invention.
  • Fig. 6 is a schematic diagram of the 3D printing structure corresponding to the first holographic lens designed in the present invention.
  • Fig. 7 is a schematic diagram of the 3D printing structure corresponding to the second holographic lens designed in the present invention.
  • Fig. 8 is a schematic structural diagram of the holographic ultrasound focusing module of the holographic ultrasound transcranial and nerve loop control system according to the preferred embodiment of the present invention.
  • Fig. 9 is a characterization diagram of the acoustic characteristics of the ultrasonic transducer of the holographic ultrasonic transcranial and neural loop control system according to the preferred embodiment of the present invention.
  • Fig. 10 is a sound field characterization diagram of the holographic ultrasonic transcranial and nerve loop control system of the above-mentioned preferred embodiment of the present invention under the conditions of no holographic lens, first holographic lens, and second holographic lens.
  • Fig. 11 is a schematic diagram of paired stimulation of ultrasound parameter setting and electronic collaborative control system of the holographic ultrasound transcranial and nerve loop regulation system according to the preferred embodiment of the present invention.
  • Fig. 12 is a schematic diagram of the holographic ultrasound transcranial and neural circuit regulation system of the above-mentioned preferred embodiment of the present invention using immunohistochemical staining to mark c-Fos (immediate early gene), thereby realizing the localization of the stimulation site.
  • holographic ultrasonic focusing module 10 ultrasonic transducer 11; piezoelectric ceramic sheet 113; bipolar lead 114; packaging shell 115; first ultrasonic transducer 111; second ultrasonic transducer 112; holographic lens 12; first holographic lens 121; second holographic lens 122; sound field characterization and measurement system 20; sound field measurement module 21; sound field characterization module 22; electronic collaborative control system 30; effectiveness recording and feedback system 40; effectiveness recording unit 41 ; Real-time validity monitoring module 42 ; Feedback control unit 43 ; Signal excitation module 50 ; Parameter modulation unit 51 ;
  • the term “a” should be understood as “at least one” or “one or more”, that is, in one embodiment, the number of an element can be one, while in another embodiment, the number of the element
  • the quantity can be multiple, and the term “a” cannot be understood as a limitation on the quantity.
  • connection should be understood in a broad sense, for example, it can be a fixed connection or a detachable connection. Connected, or integrally connected; it can be mechanically connected, or electrically connected, or can communicate with each other; it can be directly connected, or indirectly connected through an intermediary, and it can be the internal communication of two components or the interaction of two components relation.
  • installation connection
  • connection connection
  • connection should be understood in a broad sense, for example, it can be a fixed connection or a detachable connection. Connected, or integrally connected; it can be mechanically connected, or electrically connected, or can communicate with each other; it can be directly connected, or indirectly connected through an intermediary, and it can be the internal communication of two components or the interaction of two components relation.
  • the present invention relates to a holographic ultrasonic transcranial and neural loop control system and its design method.
  • the present invention first compensates the non-uniform density of the skull, interface effects, sound velocity, attenuation coefficient and other parameters through the simulation design and processing of the holographic lens structure.
  • the resulting sound waves pass through the skull with phase distortion, enabling precise transcranial focusing and stimulation of the deep brain.
  • the space and anatomical position of different stimulating brain regions combined with the design of the aforementioned holographic lens structure layer and the design and processing of low-cost, small-sized adaptive ultrasonic transducers, and using two or more different holographic lens structures to realize neural Double-point or multi-point paired stimulation on the circuit aims to realize the regulation and intervention of synaptic function at the neural circuit level.
  • a precise transcranial neural loop regulation system based on holographic ultrasound was established.
  • the system not only includes new theories and technologies based on holographic precision transcranial, but also includes the ultrasonic regulation and intervention of neural circuits based on the STDP (Spike Timing Dependent Plasticity) learning rule.
  • STDP Spike Timing Dependent Plasticity
  • the holographic ultrasonic transcranial and neural circuit control system and its design method of the present invention are specifically clarified.
  • the holographic ultrasound transcranial and nerve loop control system includes a holographic ultrasound focusing module 10, a sound field characterization and measurement system 20, an electronic cooperative control system 30 connected to the holographic ultrasound focusing module 10, and a connected The effectiveness recording and feedback system 40 of the electronic cooperative control system 30; wherein the holographic ultrasonic focusing module 10 includes at least two ultrasonic transducers 11 and holographic A lens 12, the holographic lens 12 is used to modulate the sound field of the corresponding ultrasonic transducer 11 to form a focused sound field; wherein the sound field characterization and measurement system 20 is used to control the sound field and modulation Measure the focused sound field formed afterward, and analyze and compare the numerical simulation results to optimize the structural design and processing of the holographic lens 12 and the ultrasonic transducer 11; wherein the electronic cooperative control system 30 is used for real-time regulation of the The ultrasonic stimulation parameters of the holographic ultrasound focusing module 10 and the position of the holographic ultrasound focusing module 10; wherein the effectiveness recording and feedback
  • the target area is the deep nucleus of the brain
  • the stimulation site is the action point of ultrasound transcranial focusing.
  • the stimulation target can be a small animal, or it can be
  • the holographic ultrasound transcranial and neural loop control system is not limited to the specific application objects of non-human primate large animals and humans.
  • the holographic ultrasonic transcranial and neural circuit regulation system uses two different holographic lens structures to realize double-point paired stimulation on the neural circuit, aiming to achieve neural circuit level Synaptic function regulation and intervention.
  • the holographic ultrasonic focusing module 10 includes a first ultrasonic transducer 111, a first holographic lens 121 coupled to the first ultrasonic transducer 111, a second ultrasonic transducer 112, and a second ultrasonic transducer 112 coupled to the The second holographic lens 122 of the second ultrasonic transducer 112, wherein the first holographic lens 121 and the second holographic lens 122 adopt different structures, so as to enable the holographic ultrasonic focusing module 10 to form a dual-point paired stimulus. Focus the sound field.
  • the holographic ultrasound transcranial and nerve loop regulation system may also adopt various holographic lens structures to realize multi-point focusing stimulation, which is not limited in the present invention.
  • the present invention is based on the reciprocity principle of sound wave transmission-reception, and designs the phase of the incident sound wave of the ultrasonic transducer 11 through the time-reversal method, establishes a theoretical model of the holographic lens structure for different ultrasonic focused sound field requirements, and designs
  • the holographic lens structure for different target stimulation requirements enables the holographic ultrasound transcranial and neural loop control system to meet different target stimulation requirements.
  • the sound field characterization and measurement system 20 includes a sound field measurement module 21 and a sound field characterization module 22 connected to the sound field measurement module 21, and the sound field measurement module 21 is used for ultrasonic transducers coupled with different holographic lenses The sound field of the transducer is measured, and the sound field characterization module 22 is used to quantify the horizontal and vertical resolution, focus position, and sound pressure value parameters of the ultrasonic transducer modulated by the corresponding holographic lens 12, and analyze and compare numerical simulation results .
  • the present invention uses the sound field characterization and measurement system 20 to measure and analyze the sound field of the holographic ultrasound focusing module 10 and the modulated focused sound field and compare the numerical simulation results to optimize the modeling of the holographic lens 12
  • the structural design and processing of the ultrasonic transducer 11 are beneficial to further ensure the focusing resolution and accuracy of the holographic ultrasonic transcranial and neural loop control system.
  • the electronic cooperative control system 30 includes a plurality of electronic control systems, and the different ultrasonic transducers 11 are controlled by independent electronic control systems, and the vibration elements of the ultrasonic transducers 11 are controlled by the corresponding electronic control systems.
  • the above electronic control system is set to realize synchronous work, interval differential work or paired cooperative work.
  • the effectiveness recording and feedback system 40 includes an effectiveness recording unit 41, a real-time effectiveness monitoring module 42 connected to the effectiveness recording unit 41, and a feedback control unit connected to the real-time effectiveness monitoring module 42 43.
  • the effectiveness recording unit 41 is used to record in real time the stimulation site of the focused sound field formed by the modulation of the holographic lens 12 on the target area;
  • the real-time effectiveness monitoring module 42 is used to The consistency between the recorded stimulation site and the target point outputs real-time effectiveness monitoring information;
  • the feedback control unit 43 is used to feed back the real-time effectiveness monitoring information output by the real-time effectiveness monitoring module 42 to the electronic collaborative control system 30, to adjust the position of the holographic ultrasound focusing module 10 in real time via the electronic cooperative control system 30, so as to realize the real-time adjustment of the stimulation site.
  • the stimulation point is an effective stimulation point, and is recorded by the effectiveness recording unit 41, and the stimulation point
  • the real-time effectiveness monitoring module 42 cannot obtain the feedback of the effective stimulation site.
  • the effectiveness recording and feedback system 40 can Feedback to the electronic cooperative control system 30, through which the electronic cooperative control system 30 controls and adjusts the position of the holographic ultrasound focusing module 10, thereby adjusting the position of the stimulation site, so that the ultrasound of the holographic ultrasound focusing module 10 It can precisely act on the target point, that is, the position of the stimulation site can correspond to the position of the target point.
  • the present invention utilizes the effectiveness recording and feedback system 40 to verify the effectiveness of the stimulation site of the stimulation target, and provides a basis for the modeling of the holographic lens 12 and the design and processing of the ultrasonic transducer 11. Valid reverse authentication.
  • the electronic cooperative control system 30 adjusts the position of the stimulation site by fine-tuning the position of the holographic ultrasound focusing module 10 .
  • the holographic ultrasound transcranial and nerve loop control system also includes a signal excitation module 50, the signal excitation module 50 is connected to the holographic ultrasound focusing module 10 and the electronic cooperative control system 30, and includes parameter modulation unit 51 and a starting control unit 52, the parameter modulation unit 51 is used to set the ultrasonic parameters of the ultrasonic transducer 11; the starting control unit 52 is used to control the ultrasonic transducer 11 after setting the ultrasonic parameters to perform work, and is used to shut down the ultrasonic transducer 11 urgently when the ultrasonic parameter is set incorrectly.
  • the parameter modulation unit 51 is used to set the physical parameters of the ultrasonic transducer 11 in different ultrasonic operations.
  • the start-up control unit 52 is not only used to excite the ultrasonic transducer 11 after parameter setting to work, but also functions as a switch, impedance matching, etc., and is also used to shut down the ultrasonic transducer 11 urgently. That is to say, when the ultrasonic parameter setting is wrong and the output energy of the ultrasonic transducer 11 is too large, the start control unit 52 can emergency brake the ultrasonic transducer 11 to avoid using wrong parameters to excite the ultrasonic transducer 11. the ultrasonic transducer 11, thereby protecting the ultrasonic transducer 11.
  • the present invention also provides a design method of the holographic ultrasound transcranial and neural loop control system, including steps:
  • the phase of the incident sound wave is designed by the time inversion method, and the theoretical model of the holographic lens structure is established for different ultrasonic focused sound field requirements, and based on the theoretical model of the holographic lens structure design for different targets
  • the step S1 includes the steps of:
  • the step S4 includes the steps of:
  • the irregular geometric shape of the skull, non-uniform density, speed of sound, attenuation coefficient and other parameter distributions lead to phase distortion of the sound wave after passing through the skull, and it is impossible to synthesize the sound field shape designed in a homogeneous medium at a specified position, thereby achieving focus at a specific position.
  • the present invention is based on the reciprocity principle of sound wave emission-reception, and first designs the phase of the incident sound wave through the time inversion-method so that it can be focused at a specified position after passing through the skull, such as As shown in Figure 5(A) and Figure 5(B), the theoretical model of the holographic lens structure for different ultrasonic focused sound field requirements was established at the same time, and the holographic lens structure for different target stimulation requirements was designed based on the theoretical model of the holographic lens structure.
  • the main steps of designing the holographic lens structure for different target stimulation requirements are as follows: (1) Obtain the skull shape of the mouse through microCT (micro CT), and establish a small The three-dimensional geometric model of the mouse skull; (2) load the three-dimensional model of the skull, and establish the numerical calculation model of the sound wave penetrating the skull; (3) set a virtual point source at the target focus position, and calculate the emission plane to obtain the received signal; (4) The transmitted wave of the virtual sound source received by the plane is reversed in time sequence, and the phase of each reversed signal is obtained through Fourier transform, so as to calculate the phase of the incident sound wave after considering the phase compensation of the transcranial ; (5) According to the principle of adjusting the phase of the acoustic wave by the thickness of the lens, the holographic lens is designed so that the incident field generated on the surface of the single-vibrator probe reaches the designed phase after passing through the holographic lens;
  • step (6) the holographic lens is pasted on the probe surface of the single-element planar ultrasonic transducer through a coupling material, and the present invention does not limit the coupling method of the two.
  • Fig. 5 (A) is the numerical simulation diagram of the sound field modulation of the holographic lens structure
  • Fig. 5 (B) is the structural simulation diagram of the holographic lens structure penetrating the cranial precise focus
  • both simulation diagrams illustrate the first design of the present invention using the above-mentioned design method
  • the simulated focused sound field formed by the modulation of the first holographic lens 121 and the second holographic lens 122 can be seen from the two simulation diagrams, the holographic lenses with different structures are modulated to form different forms of sound field modulation points, and the design of the structural simulation is carried out through the time inversion method , which means that the modulation of each acoustic wavelength corresponding to each point is different, so that each output has a different phase, so as to achieve different depths, sizes, and shapes of focal points, so that the holographic ultrasound transcranial and nerve loop control system can Meet the stimulation needs of different targets.
  • Figure 6 and Figure 7 illustrate the structure of the holographic lens with different depth of focus, wherein Figure 6 illustrates the structure of the first holographic lens 121 formed by the 3D printing corresponding to step (6), and Figure 7 illustrates the 3D printing corresponding to step (6)
  • the structure of the formed second holographic lens 122 can be seen that according to the above design method, the holographic lens structure can be designed for different target stimulation requirements, which is conducive to improving the resolution and accuracy of ultrasonic deep brain focusing.
  • the present invention can use two or more different holographic lens structures to modulate the sound field to obtain a sound field with the same depth of focus, and realize two nuclei stimulations of uniform depth and size.
  • the present invention can also use two One or more different holographic lens structures are used to modulate the sound field to obtain sound fields with different focal depths, and to stimulate two or more nuclei with different depths and sizes, which is not limited in the present invention.
  • holographic lens structures designed by the present invention are not limited to the two examples shown in Fig. 6 and Fig. 7 , but also can be designed to obtain holographic lens structures corresponding to a variety of different target focusing requirements. No limit.
  • the size of the ultrasound transducer In view of the anatomical positions of different target nuclei in the functional neural circuit, in order to achieve multi-point and networked ultrasound stimulation, the size of the ultrasound transducer must be small (diameter less than 5mm, base frequency between 500kHz and 5MHz, expandable). 200kHz ⁇ 10MHz range). At the same time, the dimensional accuracy of the transducer structure layer, matching layer, piezoelectric layer and backing layer must meet the requirements to ensure the performance of the transducer.
  • the present invention comprehensively analyzes the structure, sound field and echo of the transducer, optimizes the size of the transducer on the basis of ensuring the bandwidth, signal strength, resolution and other performances of the transducer, and designs a multi-point stimulation size requirement
  • the ultrasonic transducer as shown in Figure 8.
  • the preparation of the ultrasonic transducer 11 mainly includes the steps of structural size material design, composite ceramic piezoelectric material preparation, material cutting and molding, laser polarization, lead packaging, testing and other steps.
  • the holographic ultrasonic focusing module 10 includes the ultrasonic transducer 11 and the holographic lens 12 coupled to the ultrasonic transducer 11, and the ultrasonic transducer 11 is preferably a single vibration element
  • the ultrasonic transducer 11 is preferably a single vibration element
  • the single-element planar ultrasonic transducer includes a piezoelectric ceramic sheet 113, a bipolar lead 114 drawn from the piezoelectric ceramic sheet 113, and a Encapsulation housing 115 for bipolar leads 114 .
  • the present invention preferably adopts a single-element planar ultrasonic transducer is to realize the focusing of a single delivery focus, which is beneficial to use two different holographic lenses to modulate to form two focus points for dual-point pairing stimulation.
  • the present invention can also adopt multi-element planar ultrasonic transducers and multiple different holographic lens structures for modulation to form multiple focal points to realize simultaneous stimulation of multiple focal points, which is not limited in the present invention.
  • Figure 9 illustrates the acoustic characteristics of the single-element planar ultrasonic transducer measured by an acoustic impedance analyzer. It can be seen from the characterization diagram that the working performance of the single-element planar ultrasonic transducer is normal. Can meet the design requirements of the present invention.
  • the present invention uses a laser sound field scanner and an acoustic signal hydrophone to measure the sound fields of different ultrasonic transducers 11 based on holographic lenses, and quantifies the transverse and longitudinal directions of the transducers modulated by the corresponding holographic lenses 12. Resolution, focus position, sound pressure value and other parameters are analyzed and compared with numerical simulation results to optimize the modeling of the holographic lens and the structural design and processing of the ultrasonic transducer 11 , as shown in FIG. 10 .
  • the sound field measurement module 21 includes measurement equipment such as a laser sound field scanner and an acoustic signal hydrophone, which is not limited in the present invention.
  • Fig. 10 (A) illustrates the sound field characterization of a single vibration element planar ultrasonic transducer, that is, Fig. 10 (A) illustrates the sound field distribution of the ultrasonic transducer 11 without a holographic lens condition, and without a holographic lens condition,
  • the sound field of the ultrasonic transducer 11 is a beam-shaped or sheet-shaped uniform sound field with a relatively large range.
  • Fig. 10 (B) has schematically shown the acoustic field characterization of the single vibration element planar ultrasonic transducer coupled with the first holographic lens 121, that is, Fig. 10 (B) has illustrated that described ultrasonic transducer 11 is coupled with the first holographic lens 121 condition From the sound field distribution below, it can be seen that the modulation of the first holographic lens 121 can narrow the range of the sound field and form a point-shaped focused sound field.
  • Fig. 10 (C) has schematically shown the acoustic field characterization of the single vibration element planar ultrasonic transducer coupled with the second holographic lens 122, that is, Fig. 10 (C) has illustrated that described ultrasonic transducer 11 is coupled with the second holographic lens 122 condition From the sound field distribution below, it can be seen that the modulation of the second holographic lens 122 can narrow the range of the sound field and form a point-like focused sound field.
  • the present invention modulates the sound field of the ultrasonic transducer by using a holographic lens to form two focused sound fields with different depths and sizes, which can more accurately perform brain surgery.
  • the stimulation of a specific area within the sound field rather than the stimulation of the entire path of the sound field.
  • the present invention can modulate and form different forms of focused sound fields to meet the stimulation requirements of different targets.
  • the electronic cooperative control system 30 is mainly aimed at realizing the electronic control of the vibrating elements in the ultrasonic transducer, each vibrating element is lead separately, and different transducers are controlled by independent electronic systems.
  • various stimulation methods such as synchronous work, interval differential work, and paired cooperative work can be realized by setting the electronic control system among the vibrators.
  • the parameter modulation unit 51 and the start control unit 52 in the signal excitation module 50 can be used to control the different ultrasonic parameters including pulse amplitude, pulse repetition frequency, and pulse length respectively.
  • stimulation time course, etc. to set multi-target independent ultrasonic stimulation parameters, as shown in Figure 11.
  • Fig. 11 (A) has mainly set forth several routine indexes of the physical parameters that described ultrasonic transducer 11 is set, and Fig. 11 (B) is that two described ultrasonic transducers 11 pass through as shown in Fig. 11 (A)
  • different sequential excitation methods for neural circuit ultrasound intervention can be used one after the other, or different stimulation pairing methods, which are not limited by the present invention.
  • molecular biological methods are used to verify the stimulation sites of the deep nuclei of the mouse brain after the sound field modulation of the ultrasonic transducer based on the holographic lens, so as to achieve accurate and effective multi-point deep brain nuclei stimulation.
  • the design and fabrication of the model and the ultrasonic transducer 11 provide effective reverse authentication.
  • the method of locating the stimulation site is as follows: First, use ultrasound to regulate the characteristics of neuron activity, use neuron activation to cause high expression of c-Fos (immediate early gene), and calibrate the stimulation site by immunohistochemical staining. Precise positioning, as shown in Figure 12(A) and Figure 12(B); secondly, according to the real-time validity monitoring information (EEG, ECG, deep multi-channel electrophysiological real-time recording system, brain functional imaging, etc.), determine the ultrasound Can effectively stimulate neural targets.
  • EEG real-time validity monitoring information
  • the effectiveness recording and feedback system 40 does not obtain the effectiveness monitoring information, use the feedback control unit 43 to control the electronic cooperative control system 30 to adjust the position of the holographic ultrasound focusing module 10, and search for the precise stimulation site to achieve the target Real-time regulation of the stimulation site in the target area.
  • c-Fos (immediate early gene) is a fluorescent point in the figure, wherein the more fluorescent points, the more activation, as shown in Figure 12 (A) and Figure 12 (B), the present invention adds holographic lens After the structure, the number of activation of c-Fos (immediate early gene) is obviously more than that of the structure without holographic lens, which proves that the present invention can verify that the holographic ultrasonic transcranial and neural circuit regulation system can Realize accurate and effective multi-point deep brain nucleus stimulation.
  • the invention relates to a holographic ultrasonic precise cross-cranial and neural loop control system and a design method thereof. Based on the reciprocity principle of sound wave transmission-reception, it can effectively compensate the phase distortion of the sound wave passing through the skull caused by the irregular geometric shape of the skull, non-uniform density, sound velocity, attenuation coefficient, etc. Dispersion of the sound field caused by factors. Secondly, the phase of the incident sound wave is designed by the time-reversal-method, and a theoretical model of focusing for different anatomical positions is established. It can be applied to multinuclear clusters of different depths and sizes to achieve precise transcranial focusing, and the designed holographic lens structure can be prepared by 3D printing at low cost.
  • the ultrasonic transducer 11 has stable performance and can meet the needs of deep brain stimulation. Demand for wearable multi-point deep brain stimulation.
  • the holographic lens 12 used in the present invention has little influence on the performance of the ultrasonic transducer 11, and can significantly improve the resolution of the focal spot of the sound field of the ultrasonic transducer 11, which is more conducive to the ultrasonic wave in the deep Focusing within the nuclei.
  • the holographic ultrasound transcranial and nerve loop control system of the present invention integrates a holographic ultrasound focusing module 10, a sound field characterization and measurement system 20, an electronic collaborative control system 30, a signal excitation module 50, and an effectiveness recording and feedback system 40.
  • the sound field characterization and measurement system 20 uses the sound field characterization and measurement system 20 to measure and analyze the sound field of the holographic ultrasonic focusing module 10 and the focused sound field formed after modulation, and compare the numerical simulation results to optimize the holographic lens 12 and the ultrasonic transducer
  • the structural design and processing of the energy device 11 use the real-time effectiveness monitoring module 42 of the effectiveness recording and feedback system 40 to monitor the effectiveness of the stimulation site regulation of the target area by ultrasound under different focus stimulations, and according to the effectiveness
  • the feedback control unit 43 of the recording and feedback system 40 determines that the multi-target ultrasonic stimulation can accurately and effectively act on the target points; and according to the cooperative work of multiple modules, real-time accurate multi-target and multi-modal ultrasonic stimulation.
  • the holographic ultrasound transcranial and nerve loop control system of the present invention utilizes the electronic cooperative control system 30 to electronically control the vibrators in the ultrasonic transducer 11, and each vibrator is driven by an independent signal excitation module and electronic system control.
  • various stimulation methods such as synchronous work, interval differential work, and paired cooperative work are realized for each vibration element by the setting of the corresponding electronic control system.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Biomedical Technology (AREA)
  • Medical Informatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Primary Health Care (AREA)
  • Epidemiology (AREA)
  • Pathology (AREA)
  • Databases & Information Systems (AREA)
  • Data Mining & Analysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Radiology & Medical Imaging (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Business, Economics & Management (AREA)
  • General Business, Economics & Management (AREA)
  • Surgical Instruments (AREA)
  • Circuit For Audible Band Transducer (AREA)

Abstract

全息超声跨颅与神经环路调控系统及其设计方法，系统包括全息超声聚焦模块（10）、连接于全息超声聚焦模块（10）的声场表征与测量系统（20）、连接于全息超声聚焦模块（10）的电子协同控制系统（30）、以及连接于电子协同控制系统（30）的有效性记录与反馈系统（40）；设计方法针对颅骨不规则的几何外形、非均匀的密度、声速、衰减系数等参数分布所引起的相位失真进行补偿，对全息超声精准跨颅聚焦进行了系统、详细的理论模型的计算和数值仿真验证，建立面向不同超声聚焦声场需求的全息超声聚焦理论模型，能够实现对超声精准、多变的声场调制；同时设计了针对不同靶点刺激需求的全息透镜结构，有利于提高超声深部脑内聚焦的分辨率与精准性。

Description

全息超声跨颅与神经环路调控系统及其设计方法 技术领域
本发明涉及全息超声调控技术领域，特别是涉及一种全息超声跨颅与神经环路调控系统及其设计方法。
背景技术
研究表明，神经精神疾病的发生与脑深部神经核团功能异常密切相关，神经环路间的突触连接损伤促进了疾病病理进程。物理性刺激逆转疾病相关的神经核团及其在神经环路中的功能连接可减轻或治愈症状。另外，不同神经精神疾病发病机制的复杂性表明治疗的策略应侧重于选择"环路协同干预"，实现向颅内神经环路中不同靶点的刺激将有助于提高神经调控技术的临床疗效。
物理性的神经调控技术是一类利用植入性和非植入性技术应用于神经科学研究与神经疾病干预重要手段。利用电、磁、光等基本原理与神经科学相结合产生了深部电刺激、经颅磁刺激、光基因调控等神经刺激与调控技术。脑深部电刺激是将电极植入的脑内特定神经核团，通过可控的高频电流刺激抑制核团细胞的异常神经功能，达到有效干预和治疗疾病的目的。该技术为众多难治性的脑疾病如抑郁症、帕金森、难治性癫痫、肌张力失调、顽固性疼痛等提供了一种有效的新型干预方法。经颅磁刺激技术是一种无创的检测和治疗技术，用于评价神经电生理传导通路，以及抑郁症、癫痫、中风、精神分裂症、自闭症等疾病的神经康复治疗。光感基因神经调控是整合光学和基因工程学的知识来实现神经调控及潜在的疾病干预。医学超声波与人体组织相互作用，主要应 用了声波与物质相互作用的波动效应。除了基本的物理特性，超声还具有力学效应、热效应和空化效应三大基本声学效应。声场中的物体或生物组织由于吸收、散射、反射声波，将声波的能量转化为物理的动量，而受到力的作用，在声学中被定义为超声辐射力。在近年来，超声无创地对脑深部核团的刺激与调控作用为神经调控技术打开了新的视野，多层次，多物种的研究证实了经颅超声调控脑神经的有效性及干预不同神经精神类疾病的应用前景。
神经精神类疾病的发生往往不局限于单一核团内神经元功能异常，常常与脑功能网络中多核团异常有着直接联系。例如，多功能环路功能异常在癫痫的发病过程中扮演着至关重要的角色，这其中主要包含了海马杏仁核环路，皮层-皮层下环路，基底神经节环路等等。深部脑电刺激技术利用手术定向将多根刺激电极植入到脑内不同核团，通过给予安全可控的电流实现核团及迷走神经的刺激，为临床众多的难治性癫痫提供了一种安全有效的治疗手段。经颅磁刺激是一种利用脉冲磁场作用于中枢神经系统，改变神经元的膜电位，使之产生感应电流，影响脑内代谢和神经元电活动，从而引起一系列生理生化反应的神经调控技术。该技术主要应用于难治性脑功能疾病的治疗，作为一种非药物的无创物理治疗手段，同样通过两个刺激靶点进行经颅磁刺激,通过脑功能网络聚焦达到调控难治性癫痫的应用。光遗传技术是近些年快速发展起来的新型神经调控技术，该技术首先采用基因操作技术将光感基因(ChR2,Arch等)表达在神经系统中特定类型的神经元中，利用光感通道在不同波长的光刺激下分别对离子的通过产生选择性，达到对神经元选择性调控的目的，利用不同区域的病毒表达结合光刺激从而实现对癫痫动物模型异常放电的抑制。如上越来越多证据表明，神经精神疾病发病机制的复杂性需要治疗的策略更侧重于选择"多靶点协同干预"，实现向颅内多个不同靶点的刺激将有助于神经调控技术的临 床疗效。
不同的物理性神经调控技术具有不同的优缺点：深部脑刺激技术的应用需通过开颅手术将电极植入脑深部组织，刺激靶点无法更换，整个电源供给装备要手术植入到身体中。经颅磁刺激技术存在刺激的深度不够、无法聚焦、刺激分辨率低和刺激区域难以确定等瓶颈。光感基因调控技术由于需要转染病毒蛋白，所以无法用于临床脑疾病治疗。尽管上述技术已有多靶点应用于脑功能网络刺激，但多电极的脑内植入或磁线圈硬件的空间限制大大降低了患者的收受性。新型超声神经调控技术具有无创，深部脑刺激，焦点动态可调等独特优势。然而，针对疾病病理性进程中的神经环路的干预，特别是环路突触功能的超声干预手段目前尚无相关技术与报道。
超声神经调控技术作为一种新型物理性神经刺激技术有着其独特的非侵入性,强穿透性及高时空分辨率等优势，具有重要的临床疾病干预价值和广阔的应用前景。然而，针对疾病病理性进程中的神经环路干预，特别是环路突触功能的超声干预手段目前尚无相关技术与报道。而且，超声神经调控技术的临床前研究及部分人的临床研究主要应用单一焦点刺激。
发明内容
本发明的一目的是，提供一种全息超声跨颅与神经环路调控系统及其设计方法，该系统能够实现全息超声精准跨颅聚焦刺激和实现神经环路功能的实时调控，并采用不同结构的全息透镜结构来调制形成不同形式的聚焦声场，满足双点或多点刺激位点需求。
本发明在一方面提供了全息超声跨颅与神经环路调控系统，包括：
全息超声聚焦模块，所述全息超声聚焦模块包括至少两个超声换能器和分别耦合于对应的所述超声换能器上的全息透镜，所述全息透镜用于将对应的所述超声换能器的声场调制形成聚焦声场；
声场表征与测量系统，所述声场表征与测量系统用于对所述全息超声聚焦模块的声场和调制后形成的聚焦声场进行测量，和分析对比数值仿真结果，以优化所述全息透镜和所述超声换能器的结构设计与加工；
电子协同控制系统，所述电子协同控制系统连接于所述全息超声聚焦模块，用于实时调控所述全息超声聚焦模块的超声刺激参数和所述全息超声聚焦模块的位置；以及
有效性记录与反馈系统，所述有效性记录与反馈系统连接于所述电子协同控制系统，并用于实时监测、记录与反馈所述全息透镜调制后的聚焦声场对目标靶区的刺激位点的有效信息，并将该有效信息传输给所述电子协同控制系统，以经由所述电子协同控制系统实时调控所述全息超声聚焦模块的超声刺激参数和位置，从而实现对目标靶区的刺激位点的实时调控。
在本发明的一实施例中，所述全息超声聚焦模块包括第一超声换能器、耦合于所述第一超声换能器的第一全息透镜、第二超声换能器、以及耦合于所述第二超声换能器的第二全息透镜，其中所述第一全息透镜与所述第二全息透镜采用不同结构，以能够使得所述全息超声聚焦模块形成双点配对刺激的聚焦声场。
在本发明的一实施例中，所述全息透镜被设置由以下设计方法得到：基于声波发射-接收的互易性原理，通过时间反演方法设计所述超声换能器的入射声波的相位，建立面向不同超声聚焦声场需求的全息透镜结构理论模型，设计针对不同靶点刺激需求的全息透镜结构。
在本发明的一实施例中，所述声场表征与测量系统包括声场测量模块和连接于所述声场测量模块的声场表征模块，所述声场测量模块用于对耦合有不同的全息透镜的超声换能器的声场进行测量，所述声场表征模块用于定量经对应的所述全息透镜调制后的超声换能器的横向和纵向分辨率、焦点位置、声压值参数，分析对比数值仿真结果。
在本发明的一实施例中，所述电子协同控制系统包括多个电子控制系统，不同的所述超声换能器由独立的所述电子控制系统控制，所述超声换能器的振元由对应的所述电子控制系统设置实现同步工作、间隔差分工作或配对协同工作。
在本发明的一实施例中，所述有效性记录与反馈系统包括有效性记录单元、连接于所述有效性记录单元的实时有效性监测模块以及连接于所述实时有效性监测模块的反馈控制单元，所述有效性记录单元用于实时记录所述全息透镜调制形成的聚焦声场对目标靶区的刺激位点；所述实时有效性监测模块用于基于所述有效性记录单元记录的刺激位点与目标靶点的一致性输出实时有效性监控信息；所述反馈控制单元用于将所述实时有效性监测模块输出的实时有效性监控信息反馈至所述电子协同控制系统，以经由所述电子协同控制系统实时调控所述全息超声聚焦模块的位置，从而实现对刺激位点的实时调整。
在本发明的一实施例中，所述全息超声跨颅与神经环路调控系统还包括信号激励模块，所述信号激励模块连接于所述全息超声聚焦模块和所述电子协同控制系统，并包括参数调制单元和启动控制单元，所述参数调制单元用于设置所述超声换能器的超声参数；所述启动控制单元用于控制设置超声参数后的所述超声换能器进行工作，并用于在超声参数设置有误时紧急关闭所述超声换能器。
在本发明的一实施例中，所述超声换能器为单振元平面超声换能器，所述单振元平面超声换能器包括压电陶瓷片、自所述压电陶瓷片引出的双极引线、以及用于封装所述压电基底和所述双极引线的封装外壳。
本发明在另一方面还提供了所述全息超声跨颅与神经环路调控系统的设计方法，包括步骤：
S1、基于声波发射-接收的互易性原理，通过时间反演方法设计入射声波的相位，建立面向不同超声聚焦声场需求的全息透镜结构理论模型，并基于全息透镜结构理论模型设计针对不同靶点刺激需求的全息透镜结构；
S2、对超声换能器的结构、声场和回波进行综合分析，在确保换能器带宽、信号强度、分辨率性能的基础上优化所述超声换能器的尺寸，设计出符合多点刺激尺寸要求的超声换能器；
S3、利用声场表征与测量系统对基于不同全息透镜结构的超声换能器的声场进行测量，并定量经对应的全息透镜结构调制后的超声换能器的横向和纵向分辨率、焦点位置、声压值参数，分析对比数值仿真结果，从而优化全息透镜结构建模和超声换能器的结构设计与加工；以及
S4、利用有效性记录与反馈系统记录与反馈经由对应的全息透镜调制后的聚焦声场对目标靶区的刺激位点的有效信息，为全息透镜和超声换能器的设计和加工提供反向认证。
在本发明的一实施例中，所述步骤S1包括步骤：
S11、获得刺激目标的颅骨外形，建立颅骨三维模型；
S12、加载颅骨三维模型，建立声波穿颅的数值计算模型；
S13、在刺激目标的聚焦位置设置虚拟点源，计算发射平面得到接收到的信号；
S14、对发射平面接收到的虚拟声源的发射波在时序上进行反转，并通过傅里叶变换，获得每个反转信号的相位，从而计算得到对穿颅进行相位补偿后的入射声波的相位；
S15、根据透镜厚度调控声波相位的原理设计全息透镜结构，使得所述超声换能器产生的入射声场在经过对应的全息透镜结构后，达到设计的相位；以及
S16、基于设计的全息透镜结构，加工形成全息透镜，并将全息透镜耦合于对应的超声换能器表面。
在本发明的一实施例中，所述步骤S4包括步骤：
S41、利用超声调控神经元活动的特性，利用神经元激活导致即刻早期基因的高表达，通过免疫组织化学染色的方法标定从而实现刺激位点的精准定位；
S42、根据所述有效性记录与反馈系统实时记录与反馈的有效性监控信息，确定超声能够有效刺激到神经靶点；以及
S43、在所述有效性记录与反馈系统未获得有效性监控信息时，利用反馈控制单元控制电子协同控制系统调整全息超声聚焦模块的位置，以实现对目标靶区的刺激位点的实时调控。
本发明针对颅骨不规则的几何外形、非均匀的密度、声速、衰减系数等参数分布所引起的相位失真进行补偿，建立了全息超声精准跨颅聚焦进行了系统、详细的理论模型的计算和数值仿真验证，建立面向不同超声聚焦声场需求的全息超声聚焦理论模型，目的在于实现对超声精准，多变的声场调制；同时设计了针对不同靶点刺激需求的全息透镜结构，提高超声深部脑内聚焦的分辨率与精准性。
本发明以在体多焦点超声刺激为应用背景，根据不同刺激脑区空间与解剖位置，设计制备了低成本、小尺寸的超声换能器，所述超声换能器性能稳定，能够满足深部脑刺激的需求，同时可以满足在体可穿戴式多点脑深部刺激的需求。而且本发明采用的所述全息透镜对所述超声换能器的性能影响较小，并能够显著提高所述超声换能器的声场焦斑的分辨率，更有利于超声声波在深部核团内的聚焦。
本发明的所述全息超声跨颅与神经环路调控系统集合了全息超声聚焦模块、声场表征与测量系统、电子协同控制系统、信号激励模块以及有效性记录与反馈系统等系统协调工作，利用声场表征与测量系统对所述全息超声聚焦模块的声场和调制后形成的聚焦声场进行测量和分析对比数值仿真结果，来优化所述全息透镜和所述超声换能器的结构设计与加工；利用所述有效性记录与反馈系统的实时有效性监测模块监测不同焦点刺激下超声对目标靶区的刺激位点调控的有效性，根据所述有效性记录与反馈系统的反馈控制单元确定多靶点超声刺激能精准有效地作用到目标靶点；并根据多模块的协同工作，实时精确多靶点、多模态的超声刺激。
本发明的所述全息超声跨颅与神经环路调控系统利用所述电子协同控制系统对所述超声换能器中振元的实现电子控制，各振元由独立的信号激励模块及电子系统控制。同时，各振元由对应的所述电子控制系统的设置实现同步工作，间隔差分工作，配对协同工作等多种刺激方式。
通过对随后的描述和附图的理解，本发明进一步的目的和优势将得以充分体现。
附图说明
图1为本发明的一优选实施例的所述全息超声跨颅与神经环路调控系统的结构框图。
图2、图3和图4为本发明的上述优选实施例的所述全息超声跨颅与神经环路调控系统的设计方法流程框图。
图5为本发明的上述优选实施例的所述全息超声跨颅与神经环路调控系统的全息透镜的结构及其调制形成的聚焦声场的仿真图。
图6为本发明设计的第一全息透镜对应的3D打印结构示意图。
图7为本发明设计的第二全息透镜对应的3D打印结构示意图。
图8为本发明的上述优选实施例的所述全息超声跨颅与神经环路调控系统的全息超声聚焦模块的结构示意图。
图9为本发明的上述优选实施例的所述全息超声跨颅与神经环路调控系统的超声换能器的声学特性表征图。
图10为本发明的上述优选实施例的所述全息超声跨颅与神经环路调控系统在无全息透镜、采用第一全息透镜、采用第二全息透镜条件下的声场表征图。
图11为本发明的上述优选实施例的所述全息超声跨颅与神经环路调控系统的超声参数设置与电子协同控制系统配对刺激的示意图。
图12为本发明的上述优选实施例的所述全息超声跨颅与神经环路调控系统采用免疫组织化学染色的方法标定c-Fos(即刻早期基因)，从而实现刺激位点定位的示意图。
附图标号说明：全息超声聚焦模块10；超声换能器11；压电陶瓷片113；双极引线114；封装外壳115；第一超声换能器111；第二超声换能器112；全息透镜12；第一全息透镜121；第二全息透镜122；声场表征与测量系统20；声场测量模块21；声场表征模块22；电子协同控制系统30；有效性记录与反 馈系统40；有效性记录单元41；实时有效性监测模块42；反馈控制单元43；信号激励模块50；参数调制单元51；启动控制单元52。
具体实施方式
以下描述用于揭露本发明以使本领域技术人员能够实现本发明。以下描述中的优选实施例只作为举例，本领域技术人员可以想到其他显而易见的变型。在以下描述中界定的本发明的基本原理可以应用于其他实施方案、形变方案、改进方案、等同方案以及没有背离本发明的精神和范围的其他技术方案。
本领域技术人员应理解的是，在本发明的揭露中，术语“竖向”、“横向”、“上”、“下”、“前”、“后”、“左”、“右”、“竖直”、“水平”、“顶”、“底”“内”、“外”等指示的方位或位置关系是基于附图所示的方位或位置关系，其仅是为了便于描述本发明和简化描述，而不是指示或暗示所指的装置或元件必须具有特定的方位、以特定的方位构造和操作，因此上述术语不能理解为对本发明的限制。
可以理解的是，术语“一”应理解为“至少一”或“一个或多个”，即在一个实施例中，一个元件的数量可以为一个，而在另外的实施例中，该元件的数量可以为多个，术语“一”不能理解为对数量的限制。
在本发明的描述中，需要说明的是，除非另有明确的规定和限定，术语“安装”、“相连”、“连接”应做广义理解，例如，可以是固定连接，也可以是可拆卸连接，或一体地连接；可以是机械连接，也可以是电连接或可以相互通讯；可以是直接相连，也可以通过中间媒介间接相连，可以是两个元件内部的连通或两个元件的相互作用关系。对于本领域的普通技术人员而言，可以根据具体情况理解上述术语在本发明中的具体含义。
本发明涉及一种全息超声跨颅与神经环路调控系统及其设计方法，本发明首先通过对全息透镜结构的仿真设计与加工，补偿颅骨非均匀的密度，界面效 应、声速、衰减系数等参数所导致的声波穿过颅骨相位失真，实现深脑的精准跨颅聚焦与刺激。根据不同刺激脑区空间与解剖位置，结合前述全息透镜结构层设计和低成本、小尺寸的适配型超声换能器的设计与加工，并利用两种或多种不同的全息透镜结构实现神经环路上的双点或多点配对刺激，旨在实现神经环路水平的突触功能调控与干预。同时，结合电子协同控制系统、信号激励模块、声场测量与表征系统以及有效性记录与反馈系统建立了基于全息超声精准跨颅的神经环路调控系统。该系统不仅包含了基于全息精准跨颅的新理论、新技术，同时包含了基于STDP(Spike Timing Dependent Plasticity，峰值时间依赖塑性)学习法则实现对神经环路的超声调控与干预。
如图1至图12所示，本发明的全息超声跨颅与神经环路调控系统及其设计方法被具体阐明。
如图1所示，所述全息超声跨颅与神经环路调控系统包括全息超声聚焦模块10、声场表征与测量系统20、连接于所述全息超声聚焦模块10的电子协同控制系统30、以及连接于所述电子协同控制系统30的有效性记录与反馈系统40；其中所述全息超声聚焦模块10包括至少两个超声换能器11和分别耦合于对应的所述超声换能器11上的全息透镜12，所述全息透镜12用于将对应的所述超声换能器11的声场调制形成聚焦声场；其中所述声场表征与测量系统20用于对所述全息超声聚焦模块10的声场和调制后形成的聚焦声场进行测量，和分析对比数值仿真结果，以优化所述全息透镜12和所述超声换能器11的结构设计与加工；其中所述电子协同控制系统30用于实时调控所述全息超声聚焦模块10的超声刺激参数和所述全息超声聚焦模块10的位置；其中所述有效性记录与反馈系统40用于实时监测、记录与反馈所述全息透镜12调制后的聚焦声场对目标靶区的刺激位点的有效信息，并将该有效信息传输给所述电子协同控制系统30，以经由所述电子协同控制系统30实时调控所述全息超声聚焦模块10的超声刺激参数和位置，从而实现对目标靶区的刺激位点的实时调控。
值得一提的是，在本发明的这一具体实施例中，所述目标靶区为大脑深部核团，刺激位点即为超声跨颅聚焦的作用点，刺激目标可以为小动物，也可以为非人灵长类大动物及人等刺激对象，本发明对所述全息超声跨颅与神经环路调控系统的具体应用对象不作限制。
进一步地，在本发明的这一实施例中，所述全息超声跨颅与神经环路调控系统利用两种不同的全息透镜结构实现神经环路上的双点配对刺激，旨在实现神经环路水平的突触功能调控与干预。
具体地，所述全息超声聚焦模块10包括第一超声换能器111、耦合于所述第一超声换能器111的第一全息透镜121、第二超声换能器112、以及耦合于所述第二超声换能器112的第二全息透镜122，其中所述第一全息透镜121与所述第二全息透镜122采用不同结构，以能够使得所述全息超声聚焦模块10形成双点配对刺激的聚焦声场。
应该理解的是，在本发明的一些实施例中，所述全息超声跨颅与神经环路调控系统也可以采用多种不同的全息透镜结构实现多点聚焦刺激，本发明对此不作限制。
特别地，本发明基于声波发射-接收的互易性原理，通过时间反演方法设计所述超声换能器11的入射声波的相位，建立面向不同超声聚焦声场需求的全息透镜结构理论模型，设计针对不同靶点刺激需求的全息透镜结构，以使得所述全息超声跨颅与神经环路调控系统能够满足不同靶点刺激需求。
进一步地，所述声场表征与测量系统20包括声场测量模块21和连接于所述声场测量模块21的声场表征模块22，所述声场测量模块21用于对耦合有不同的全息透镜的超声换能器的声场进行测量，所述声场表征模块22用于定量经对应的所述全息透镜12调制后的超声换能器的横向和纵向分辨率、焦点位置、声压值参数，分析对比数值仿真结果。
可以理解的是，本发明利用声场表征与测量系统20对所述全息超声聚焦模块10的声场和调制后形成的聚焦声场进行测量和分析对比数值仿真结果， 来优化所述全息透镜12的建模和所述超声换能器11的结构设计与加工，有利于进一步确保所述全息超声跨颅与神经环路调控系统的聚焦分辨率与精准性。
进一步地，所述电子协同控制系统30包括多个电子控制系统，不同的所述超声换能器11由独立的所述电子控制系统控制，所述超声换能器11的振元由对应的所述电子控制系统设置实现同步工作、间隔差分工作或配对协同工作。
进一步地，所述有效性记录与反馈系统40包括有效性记录单元41、连接于所述有效性记录单元41的实时有效性监测模块42以及连接于所述实时有效性监测模块42的反馈控制单元43，所述有效性记录单元41用于实时记录所述全息透镜12调制形成的聚焦声场对目标靶区的刺激位点；所述实时有效性监测模块42用于基于所述有效性记录单元41记录的刺激位点与目标靶点的一致性输出实时有效性监控信息；所述反馈控制单元43用于将所述实时有效性监测模块42输出的实时有效性监控信息反馈至所述电子协同控制系统30，以经由所述电子协同控制系统30实时调控所述全息超声聚焦模块10的位置，从而实现对刺激位点的实时调整。
可以理解的是，在所述刺激位点与所述目标靶点的位置对应一致时，该刺激位点为有效的刺激位点，则被所述有效性记录单元41记录，在所述刺激位点与所述目标靶点之间出现偏差时，所述实时有效性监测模块42不能获得有效刺激位点的反馈，在此时，所述有效性记录与反馈系统40经由所述反馈控制单元43反馈至所述电子协同控制系统30，经由所述电子协同控制系统30控制调整所述全息超声聚焦模块10的位置，从而调整所述刺激位点的位置，使得所述全息超声聚焦模块10的超声能够精准地作用于所述目标靶点，即使得所述刺激位点的位置能够与所述目标靶点的位置对应一致。
也就是说，本发明利用所述有效性记录与反馈系统40对刺激目标的刺激位点进行有效性验证，为所述全息透镜12的建模和所述超声换能器11的设计与加工提供有效的反向认证。
优选地，所述电子协同控制系统30通过微调所述全息超声聚焦模块10的位置的方式来调整所述刺激位点的位置。
特别地，所述全息超声跨颅与神经环路调控系统还包括信号激励模块50，所述信号激励模块50连接于所述全息超声聚焦模块10和所述电子协同控制系统30，并包括参数调制单元51和启动控制单元52，所述参数调制单元51用于设置所述超声换能器11的超声参数；所述启动控制单元52用于控制设置超声参数后的所述超声换能器11进行工作，并用于在超声参数设置有误时紧急关闭所述超声换能器11。
可以理解的是，所述参数调制单元51用于设置所述超声换能器11在不同超声工作时的物理参数。所述启动控制单元52除了用于激励参数设置后的所述超声换能器11工作，起到开关，阻抗匹配等作用外，还用于起到紧急关闭所述超声换能器11的作用，也就是说，当超声参数设置错误而导致所述超声换能器11输出能量过大时，所述启动控制单元52可以紧急制动所述超声换能器11，以避免采用错误参数去激励所述超声换能器11，从而保护所述超声换能器11。
如图2至图4所示，本发明在另一方面还提供了所述全息超声跨颅与神经环路调控系统的设计方法，包括步骤：
S1、基于声波发射-接收的互易性原理，通过时间反演方法设计入射声波的相位，建立面向不同超声聚焦声场需求的全息透镜结构理论模型，并基于全息透镜结构理论模型设计针对不同靶点刺激需求的全息透镜结构；
S2、对超声换能器的结构、声场和回波进行综合分析，在确保换能器带宽、信号强度、分辨率性能的基础上优化所述超声换能器的尺寸，设计出符合多点刺激尺寸要求的超声换能器；
S3、利用声场表征与测量系统20对基于不同全息透镜结构的超声换能器的声场进行测量，并定量经对应的全息透镜结构调制后的超声换能器的横向和纵向分辨率、焦点位置、声压值参数，分析对比数值仿真结果，从而优化全息 透镜结构建模和超声换能器的结构设计与加工；以及
S4、利用有效性记录与反馈系统40记录与反馈经由对应的全息透镜调制后的聚焦声场对目标靶区的刺激位点的有效信息，为全息透镜和超声换能器的设计和加工提供反向认证。
具体地，如图3所示，所述步骤S1包括步骤：
S11、获得刺激目标的颅骨外形，建立颅骨三维模型；
S12、加载颅骨三维模型，建立声波穿颅的数值计算模型；
S13、在刺激目标的聚焦位置设置虚拟点源，计算发射平面得到接收到的信号；
S14、对发射平面接收到的虚拟声源的发射波在时序上进行反转，并通过傅里叶变换，获得每个反转信号的相位，从而计算得到对穿颅进行相位补偿后的入射声波的相位；
S15、根据透镜厚度调控声波相位的原理设计全息透镜结构，使得所述超声换能器产生的入射声场在经过对应的全息透镜结构后，达到设计的相位；以及
S16、基于设计的全息透镜结构，加工形成全息透镜，并将全息透镜耦合于对应的超声换能器表面。
具体地，如图4所示，所述步骤S4包括步骤：
S41、利用超声调控神经元活动的特性，利用神经元激活导致即刻早期基因的高表达，通过免疫组织化学染色的方法标定从而实现刺激位点的精准定位；
S42、根据所述有效性记录与反馈系统40实时记录与反馈的有效性监控信息，确定超声能够有效刺激到神经靶点；以及
S43、在所述有效性记录与反馈系统40未获得有效性监控信息时，利用反馈控制单元43控制电子协同控制系统30调整所述全息超声聚焦模块10的位置，以实现对目标靶区的刺激位点的实时调控。
以下将对本发明的所述全息超声跨颅与神经环路调控系统的结构和设计方法进行具体说明。
1.全息超声精准穿颅聚焦的理论设计与硬件加工：
颅骨不规则的几何外形、非均匀的密度、声速、衰减系数等参数分布，导致声波穿过颅骨后发生相位失真，无法在指定位置合成均匀介质中设计的声场形态，从而实现特定位置的聚焦。因此，为了补偿颅骨引起的相位失真，本发明基于声波发射-接收的互易性原理，首先通过时间反演-方法来设计入射声波的相位，使其经过颅骨后，可在指定位置聚焦，如图5(A)和图5(B)所示，同时建立面向不同超声聚焦声场需求的全息透镜结构理论模型，并基于全息透镜结构理论模型设计针对不同靶点刺激需求的全息透镜结构。
以小鼠作为刺激目标为例，基于全息透镜结构理论模型，设计针对不同靶点刺激需求的全息透镜结构主要步骤如下：(1)通过microCT(显微CT)获得小鼠的颅骨外形，建立小鼠颅骨的三维几何模型；(2)加载颅骨三维模型，建立声波穿颅的数值计算模型；(3)在目标聚焦位置设置虚拟点源，计算发射平面得到接收到的信号；(4)对发射平面接收到的虚拟声源的发射波在时序上进行反转，并通过傅里叶变换，获得每个反转信号的相位，从而计算得到考虑了对穿颅做相位补偿后的入射声波的相位；(5)根据透镜厚度调控声波相位的原理，设计全息透镜，使得单振元探头表面产生的入射场，经过全息透镜后，达到设计的相位；(6)3D打印全息透镜，并贴合在单振元平面超声换能器的探头表面。
值得一提的是，在步骤(6)中，所述全息透镜通过耦合材料粘贴于所述单振元平面超声换能器的探头表面，本发明对两者的耦合方式不作限制。
图5(A)为全息透镜结构声场调制的数值仿真图，图5(B)为全息透镜结构穿颅精准聚焦的结构仿真图，两个仿真图均示意了本发明采用上述设计方法设计的第一全息透镜121和第二全息透镜122调制形成的仿真聚焦声场，可以从两个仿真图看出，不同结构的全息透镜调制形成不同形式的声场调制点， 通过时间反演方式进行结构仿真的设计，相当于每个点对应的每个声波波长调制不同，从而对每个输出不同相位，从而实现不同深度，大小，形状的聚焦焦点，以使得所述全息超声跨颅与神经环路调控系统能够满足不同靶点刺激需求。
图6和图7示意了不同聚焦深度的全息透镜结构，其中图6示意了对应步骤(6)的3D打印形成的第一全息透镜121的结构，图7示意了对应步骤(6)的3D打印形成的第二全息透镜122的结构，可以看出，根据上述设计方法，能够设计针对不同靶点刺激需求的全息透镜结构，有利于提高超声深部脑内聚焦的分辨率与精准性。
应该理解的是，本发明可以采用两种或多种不同的全息透镜结构来对声场进行调制，获得聚焦深度相同的声场，实现两个统一深度和大小的核团刺激，本发明也可以采用两种或多种不同的全息透镜结构来对声场进行调制获得聚焦深度不同的声场，实现对两个或多个不同深度和大小的核团的刺激，本发明对此不作限制。
还应该理解的是，本发明设计得到的全息透镜结构不限于图6和图7举例的两种，同时也可以设计得到对应于多种不同靶点聚焦需求的全息透镜结构，本发明对此也不作限制。
2.小尺寸适配性超声换能器的设计与加工：
鉴于功能性神经环路中不同目标核团的解剖位置，为了实现多点、网络化超声刺激，超声换能器的尺寸必须较小(直径小于5mm，基础频率在500kHz～5MHz之间，可拓展为200kHz～10MHz范围)。同时需要换能器结构层、匹配层、压电层和背衬层的尺寸精度达到要求才能保证换能器的性能。本发明通过对换能器的结构、声场和回波进行综合分析，在保证换能器带宽、信号强度、分辨率等性能的基础上优化换能器的尺寸，设计出符合多点刺激尺寸要求的超声换能器，如图8所示。所述超声换能器11的制备主要包含结构尺寸材料设计，复合陶瓷压电材料制备，材料切割与成型，激光分极，引线封装，测试等步骤。
如图8所示，所述全息超声聚焦模块10包括所述超声换能器11和耦合于所述超声换能器11的所述全息透镜12，所述超声换能器11优选为单振元平面超声换能器，所述单振元平面超声换能器包括压电陶瓷片113、自所述压电陶瓷片113引出的双极引线114、以及用于封装所述压电基底和所述双极引线114的封装外壳115。
本发明之所以优选采用单振元平面超声换能器，是为了实现单个交割焦点的聚焦，有利于利用两种不同的全息透镜调制形成两个焦点进行双点配对刺激。本发明也可以采用多振元平面超声换能器和多种不同的全息透镜结构调制形成多个焦点，实现多个焦点同时刺激，本发明对此不作限制。
图9示意了通过声学阻抗分析仪测量得到的所述单振元平面超声换能器的声学特性，可以从该表征图中看出，所述单振元平面超声换能器的工作性能正常，能够满足本发明的设计要求。
3.声场表征与测量系统20：
本发明利用激光声场扫描仪及声信号水听器分别对不同基于全息透镜的所述超声换能器11的声场进行测量，定量经对应的所述全息透镜12调制后换能器的横向和纵向分辨率，焦点位置，声压值等参数，分析对比数值仿真结果从而优化全息透镜建模及所述超声换能器11的结构设计与加工，如图10所示。
可以理解的是，所述声场测量模块21包括激光声场扫描仪和声信号水听器等测量设备，本发明对此不作限制。
图10(A)示意了单振元平面超声换能器的声场表征，即图10(A)示意了所述超声换能器11无全息透镜条件下的声场分布，在无全息透镜条件下，所述超声换能器11的声场为束状或者片状的较大范围的均匀声场。
图10(B)示意了耦合有第一全息透镜121的单振元平面超声换能器的声场表征，即图10(B)示意了所述超声换能器11耦合有第一全息透镜121条件下的声场分布，可以看出，通过第一全息透镜121的调制，能够缩小声场的范围，形成点状的聚焦声场。
图10(C)示意了耦合有第二全息透镜122的单振元平面超声换能器的声场表征，即图10(C)示意了所述超声换能器11耦合有第二全息透镜122条件下的声场分布，可以看出，通过第二全息透镜122的调制，能够缩小声场的范围，形成点状的聚焦声场。
根据图10(B)和图10(C)可以看出，本发明通过采用全息透镜对超声换能器的声场进行调制形成两个不同深度和大小的聚焦声场的方式，能够更精准地进行脑内特定区域的刺激，而不是一片、整个声场路径上的刺激。另外，本发明通过设计和采用不同结构的全息透镜，能够调制形成不同形式的聚焦声场，满足不同靶点刺激需求。
4.电子协同控制系统30与信号激励模块50：
电子协同控制系统30主要针对超声换能器中振元的实现电子控制，各振元单独引线，不同换能器由独立的电子系统控制。同时，各振元之间可由电子控制系统的设置实现同步工作，间隔差分工作，配对协同工作等多种刺激方式。另外可根据疾病类型，病情严重性、刺激靶点选择和刺激效果，可以利用信号激励模块50中的参数调制单元51和启动控制单元52分别对不同超声参数包括脉冲幅度、脉冲重复频率、脉冲长度，刺激时程等进行多靶点独立超声刺激参数的设置，如图11所示。
图11(A)主要阐述了所述超声换能器11设置的物理参数的几个常规的指标，图11(B)是两个所述超声换能器11经过如图11(A)所示的参数设置后，对神经环路超声干预的不同时序性的激励方式，可以采用一个先一个后，或者不同的刺激配对方式，本发明对此不作限制。
5.有效性记录与反馈系统40：
首先利用分子生物学手段验证基于全息透镜的超声换能器声场调制后对小鼠大脑深部核团的刺激位点验证，实现精准有效的多点深部脑核团刺激，同时也为全息透镜结构理论模型及所述超声换能器11的设计和加工提供有效的反向认证。
刺激位点的定位方法如下：首先，利用超声调控神经元活动的特性，利用神经元激活导致c-Fos(即刻早期基因)的高表达，通过免疫组织化学染色的方法标定从而实现刺激位点的精准定位，如图12(A)和图12(B)所示；其次，根据实时有效性监控信息(脑电、心电、深部多通道电生理实时记录系统，脑功能成像等)，确定超声能有效刺激到神经靶点。最后，如所述有效性记录与反馈系统40未获得有效性监控信息时，利用反馈控制单元43控制电子协同控制系统30调整全息超声聚焦模块10的位置，搜索精确刺激位点，以实现对目标靶区的刺激位点的实时调控。
c-Fos(即刻早期基因)在图中为一个个荧光点，其中荧光点越多，则表示激活越多，如图12(A)和图12(B)所示，本发明在加入全息透镜结构后，c-Fos(即刻早期基因)激活的数量明显比无全息透镜结构的数量要多，证明本发通过利用分子生物学手段，能够验证所述全息超声跨颅与神经环路调控系统能够实现精准有效的多点深部脑核团刺激。
本发明涉及全息超声精准跨颅与神经环路调控系统及其设计方法。通过基于声波发射-接收的互易性原理首先能有效对颅骨不规则的几何外形、非均匀的密度、声速、衰减系数等参数所导致的声波穿过颅骨相位失真进行补偿，规避因颅骨这一因素所引起的声场弥散。其次，通过时间反演-方法来设计入射声波的相位，建立了针对不同解剖位置实现聚焦的理论模型。可以适用于不同深度，大小等多核团实现精准跨颅聚焦，而且设计的全息透镜结构可以通过3D打印制备，成本低。同时，根据不同刺激脑区空间与解剖位置，设计制备了低成本、小尺寸的超声换能器，所述超声换能器11性能稳定，能够满足深部脑刺激的需求，同时可以满足在体可穿戴式多点脑深部刺激的需求。而且本发明采用的所述全息透镜12对所述超声换能器11的性能影响较小，并能够显著提高所述超声换能器11的声场焦斑的分辨率，更有利于超声声波在深部核团内的聚焦。
另外，本发明的所述全息超声跨颅与神经环路调控系统集合了全息超声聚 焦模块10、声场表征与测量系统20、电子协同控制系统30、信号激励模块50以及有效性记录与反馈系统40等系统协调工作，利用声场表征与测量系统20对所述全息超声聚焦模块10的声场和调制后形成的聚焦声场进行测量和分析对比数值仿真结果，来优化所述全息透镜12和所述超声换能器11的结构设计与加工；利用所述有效性记录与反馈系统40的实时有效性监测模块42监测不同焦点刺激下超声对目标靶区的刺激位点调控的有效性，根据所述有效性记录与反馈系统40的反馈控制单元43确定多靶点超声刺激能精准有效地作用到目标靶点；并根据多模块的协同工作，实时精确多靶点、多模态的超声刺激。
最后，本发明的所述全息超声跨颅与神经环路调控系统利用所述电子协同控制系统30对所述超声换能器11中振元的实现电子控制，各振元由独立的信号激励模块及电子系统控制。同时，各振元由对应的所述电子控制系统的设置实现同步工作，间隔差分工作，配对协同工作等多种刺激方式。
以上实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上实施例仅表达了本发明的优选的实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (11)

  1. 全息超声跨颅与神经环路调控系统，其特征在于，包括：
    全息超声聚焦模块，所述全息超声聚焦模块包括至少两个超声换能器和分别耦合于对应的所述超声换能器上的全息透镜，所述全息透镜用于将对应的所述超声换能器的声场调制形成聚焦声场；
    声场表征与测量系统，所述声场表征与测量系统用于对所述全息超声聚焦模块的声场和调制后形成的聚焦声场进行测量，和分析对比数值仿真结果，以优化所述全息透镜和所述超声换能器的结构设计与加工；
    电子协同控制系统，所述电子协同控制系统连接于所述全息超声聚焦模块，用于实时调控所述全息超声聚焦模块的超声刺激参数和所述全息超声聚焦模块的位置；以及
    有效性记录与反馈系统，所述有效性记录与反馈系统连接于所述电子协同控制系统，并用于实时监测、记录与反馈所述全息透镜调制后的聚焦声场对目标靶区的刺激位点的有效信息，并将该有效信息传输给所述电子协同控制系统，以经由所述电子协同控制系统实时调控所述全息超声聚焦模块的超声刺激参数和位置，从而实现对目标靶区的刺激位点的实时调控。
  2. 根据权利要求1所述的全息超声跨颅与神经环路调控系统，其特征在于，所述全息超声聚焦模块包括第一超声换能器、耦合于所述第一超声换能器的第一全息透镜、第二超声换能器、以及耦合于所述第二超声换能器的第二全息透镜，其中所述第一全息透镜与所述第二全息透镜采用不同结构，以能够使得所述全息超声聚焦模块形成双点配对刺激的聚焦声场。
  3. 根据权利要求1所述的全息超声跨颅与神经环路调控系统，其特征在 于，所述全息透镜被设置由以下设计方法得到：基于声波发射-接收的互易性原理，通过时间反演方法设计所述超声换能器的入射声波的相位，建立面向不同超声聚焦声场需求的全息透镜结构理论模型，设计针对不同靶点刺激需求的全息透镜结构。
  4. 根据权利要求1所述的全息超声跨颅与神经环路调控系统，其特征在于，所述声场表征与测量系统包括声场测量模块和连接于所述声场测量模块的声场表征模块，所述声场测量模块用于对耦合有不同的全息透镜的超声换能器的声场进行测量，所述声场表征模块用于定量经对应的所述全息透镜调制后的超声换能器的横向和纵向分辨率、焦点位置、声压值参数，分析对比数值仿真结果。
  5. 根据权利要求1所述的全息超声跨颅与神经环路调控系统，其特征在于，所述电子协同控制系统包括多个电子控制系统，不同的所述超声换能器由独立的所述电子控制系统控制，所述超声换能器的振元由对应的所述电子控制系统设置实现同步工作、间隔差分工作或配对协同工作。
  6. 根据权利要求1所述的全息超声跨颅与神经环路调控系统，其特征在于，所述有效性记录与反馈系统包括有效性记录单元、连接于所述有效性记录单元的实时有效性监测模块以及连接于所述实时有效性监测模块的反馈控制单元，所述有效性记录单元用于实时记录所述全息透镜调制形成的聚焦声场对目标靶区的刺激位点；所述实时有效性监测模块用于基于所述有效性记录单元记录的刺激位点与目标靶点的一致性输出实时有效性监控信息；所述反馈控制单元用于将所述实时有效性监测模块输出的实时有效性监控信息反馈至所述电子协同控制系统，以经由所述电子协同控制系统实时调控所述全息超声聚焦模块的位置，从而实现对刺激位点的实时调整。
  7. 根据权利要求1至6中任一项所述的全息超声跨颅与神经环路调控系统，其特征在于，所述全息超声跨颅与神经环路调控系统还包括信号激励模块，所述信号激励模块连接于所述全息超声聚焦模块和所述电子协同控制系统，并包括参数调制单元和启动控制单元，所述参数调制单元用于设置所述超声换能器的超声参数；所述启动控制单元用于控制设置超声参数后的所述超声换能器进行工作，并用于在超声参数设置有误时紧急关闭所述超声换能器。
  8. 根据权利要求1至6中任一项所述的全息超声跨颅与神经环路调控系统，其特征在于，所述超声换能器为单振元平面超声换能器，所述单振元平面超声换能器包括压电陶瓷片、自所述压电陶瓷片引出的双极引线、以及用于封装所述压电基底和所述双极引线的封装外壳。
  9. 根据权利要求1至8中任一项所述的全息超声跨颅与神经环路调控系统的设计方法，其特征在于，包括步骤：
    S1、基于声波发射-接收的互易性原理，通过时间反演方法设计入射声波的相位，建立面向不同超声聚焦声场需求的全息透镜结构理论模型，并基于全息透镜结构理论模型设计针对不同靶点刺激需求的全息透镜结构；
    S2、对超声换能器的结构、声场和回波进行综合分析，在确保换能器带宽、信号强度、分辨率性能的基础上优化所述超声换能器的尺寸，设计出符合多点刺激尺寸要求的超声换能器；
    S3、利用声场表征与测量系统对基于不同全息透镜结构的超声换能器的声场进行测量，并定量经对应的全息透镜结构调制后的超声换能器的横向和纵向分辨率、焦点位置、声压值参数，分析对比数值仿真结果，从而优化全息透镜结构建模和超声换能器的结构设计与加工；以及
    S4、利用有效性记录与反馈系统记录与反馈经由对应的全息透镜调制后的 聚焦声场对目标靶区的刺激位点的有效信息，为全息透镜和超声换能器的设计和加工提供反向认证。
  10. 根据权利要求9所述的全息超声跨颅与神经环路调控系统的设计方法，其特征在于，所述步骤S1包括步骤：
    S11、获得刺激目标的颅骨外形，建立颅骨三维模型；
    S12、加载颅骨三维模型，建立声波穿颅的数值计算模型；
    S13、在刺激目标的聚焦位置设置虚拟点源，计算发射平面得到接收到的信号；
    S14、对发射平面接收到的虚拟声源的发射波在时序上进行反转，并通过傅里叶变换，获得每个反转信号的相位，从而计算得到对穿颅进行相位补偿后的入射声波的相位；
    S15、根据透镜厚度调控声波相位的原理设计全息透镜结构，使得所述超声换能器产生的入射声场在经过对应的全息透镜结构后，达到设计的相位；以及
    S16、基于设计的全息透镜结构，加工形成全息透镜，并将全息透镜耦合于对应的超声换能器表面。
  11. 根据权利要求9所述的全息超声跨颅与神经环路调控系统的设计方法，所述步骤S4包括步骤：
    S41、利用超声调控神经元活动的特性，利用神经元激活导致即刻早期基因的高表达，通过免疫组织化学染色的方法标定从而实现刺激位点的精准定位；
    S42、根据所述有效性记录与反馈系统实时记录与反馈的有效性监控信息，确定超声能够有效刺激到神经靶点；以及
    S43、在所述有效性记录与反馈系统未获得有效性监控信息时，利用反馈控制单元控制电子协同控制系统调整全息超声聚焦模块的位置，以实现对目标靶 区的刺激位点的实时调控。
PCT/CN2022/076195 2021-12-18 2022-02-14 全息超声跨颅与神经环路调控系统及其设计方法 WO2023108876A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111557236.1 2021-12-18
CN202111557236.1A CN116266484A (zh) 2021-12-18 2021-12-18 全息超声跨颅与神经环路调控系统及其设计方法

Publications (1)

Publication Number Publication Date
WO2023108876A1 true WO2023108876A1 (zh) 2023-06-22

Family

ID=86743972

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/076195 WO2023108876A1 (zh) 2021-12-18 2022-02-14 全息超声跨颅与神经环路调控系统及其设计方法

Country Status (2)

Country Link
CN (1) CN116266484A (zh)
WO (1) WO2023108876A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117065239B (zh) * 2023-10-14 2023-12-12 北京小超科技有限公司 一种超声聚焦补偿的方法和系统

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104548390A (zh) * 2014-12-26 2015-04-29 中国科学院深圳先进技术研究院 一种超声深部脑刺激方法及系统
US20180192990A1 (en) * 2015-07-01 2018-07-12 Centre National De La Recherche Scientifique - Cnrs Insonification Method for Obtaining a Predetermined Field of Ultrasonic Waves and Production Method for Making an Ultrasonic Lens for These Purposes
CN108463778A (zh) * 2015-12-11 2018-08-28 马克斯-普朗克科学促进学会 用于在物体中产生全息超声场的设备和方法
US20200300814A1 (en) * 2019-03-18 2020-09-24 X Development Llc Dynamically reconfigurable acoustic diffractive device
US20210016113A1 (en) * 2019-07-17 2021-01-21 X Development Llc Closed loop neurostimulation of large-scale brain networks
US20210187330A1 (en) * 2018-08-16 2021-06-24 University Of Washington Apparatus and method for ultrasound beam shaping
CN113195052A (zh) * 2018-10-22 2021-07-30 瓦伦西亚理工大学 一种生产透镜的方法和包含透镜的超声波装置

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104548390A (zh) * 2014-12-26 2015-04-29 中国科学院深圳先进技术研究院 一种超声深部脑刺激方法及系统
US20180192990A1 (en) * 2015-07-01 2018-07-12 Centre National De La Recherche Scientifique - Cnrs Insonification Method for Obtaining a Predetermined Field of Ultrasonic Waves and Production Method for Making an Ultrasonic Lens for These Purposes
CN108463778A (zh) * 2015-12-11 2018-08-28 马克斯-普朗克科学促进学会 用于在物体中产生全息超声场的设备和方法
US20210187330A1 (en) * 2018-08-16 2021-06-24 University Of Washington Apparatus and method for ultrasound beam shaping
CN113195052A (zh) * 2018-10-22 2021-07-30 瓦伦西亚理工大学 一种生产透镜的方法和包含透镜的超声波装置
US20200300814A1 (en) * 2019-03-18 2020-09-24 X Development Llc Dynamically reconfigurable acoustic diffractive device
US20210016113A1 (en) * 2019-07-17 2021-01-21 X Development Llc Closed loop neurostimulation of large-scale brain networks

Also Published As

Publication number Publication date
CN116266484A (zh) 2023-06-20

Similar Documents

Publication Publication Date Title
Fomenko et al. Low-intensity ultrasound neuromodulation: an overview of mechanisms and emerging human applications
WO2016101487A1 (zh) 一种超声深部脑刺激方法及系统
Naor et al. Ultrasonic neuromodulation
Pashaei et al. Flexible body-conformal ultrasound patches for image-guided neuromodulation
EP2571574B1 (en) System of operating a multi focused acoustic wave source
CN105536156A (zh) 一种基于大规模面阵元的超声脑刺激或调控方法及装置
CN107693962A (zh) 一种头戴式超声传导装置
Cadoni et al. Ectopic expression of a mechanosensitive channel confers spatiotemporal resolution to ultrasound stimulations of neurons for visual restoration
WO2023108876A1 (zh) 全息超声跨颅与神经环路调控系统及其设计方法
CN105251141A (zh) 一种闭环式经颅磁声刺激装置
Liu et al. A noninvasive deep brain stimulation method via temporal-spatial interference magneto-acoustic effect: simulation and experimental validation
JP2023516533A (ja) マルチビーム神経調節技術
US20230226380A1 (en) Noninvasive tissue displacement control and monitoring for neuromodulation
WO2022126420A1 (zh) 多焦点超声波的生成装置及生成方法
CN112774048A (zh) 一种闭环超声神经调控系统及方法
US20210205636A1 (en) Neuromodulation techniques
WO2023108879A1 (zh) 可穿戴式超声刺激兼容电生理记录系统
Ma et al. Study on the role of physical fields in TMAS to modulate synaptic plasticity in mice
WO2017035767A1 (zh) 声敏感离子通道遗传操作方法及系统
Slopsema et al. Deep brain stimulation
Machado et al. Low Intensity Focused Ultrasound Modulation of Neural Circuits Activity
WO2024109759A1 (zh) 一种变频超声调控装置
US20230061046A1 (en) Systems and methods for responsive ultrasound stimulation for immuno-modulation treatment
Zhu et al. A novel noninvasive multi-target electrical stimulation method: simulation and experimental validation
Huan et al. A Wearable Dual-Mode Probe for Image-Guided Closed-Loop Ultrasound Neuromodulation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22905648

Country of ref document: EP

Kind code of ref document: A1