Focused ultrasound transcranial nerve regulation and control platform and method based on photoacoustic imaging

Abstract

The invention discloses a focused ultrasound transcranial nerve regulation and control platform and method based on photoacoustic imaging. The system comprises a synchronous pulse generator, a pulse ultrasound transmitting system, a photoacoustic signal collecting system and a fixing device. According to the method, the limitation of other imaging monitoring modes is overcome, monitoring is carried out by utilizing the characteristics of non-invasiveness, high resolution and high contrast of photoacoustic imaging, the TUS progress can be monitored for providing real-time dynamic imaging, and functional information can be provided; photoacoustic imaging is applied to focused ultrasound transcranial nerve regulation for the first time. And meanwhile, by utilizing high sound resolution and high optical contrast of photoacoustic imaging, the strongest photoacoustic signal can be provided in a near-infrared region for hemoglobin of a seat endogenous contrast agent, so that the PAT becomes an ideal imaging tool for detecting cerebral hemodynamics. In addition, key pathophysiological parameters are evaluated through functional imaging provided by the PAT, and the method can be used for evaluating brain changes in the low-intensity focused ultrasound stimulation process.

Description

Technical Field

[0001] The present invention relates to the field of ultrasonic neuromodulation, and in particular to a focused ultrasound transcranial neuromodulation platform and method based on photoacoustic imaging. Background Art

[0002] As a non-invasive neuromodulation method, low-intensity focused ultrasound stimulation (TUS) has the advantages of precise spatial resolution and penetration depth, and has achieved remarkable breakthroughs in the field of neuromodulation. When transcranial ultrasound stimulates the brain tissue of animals, corresponding motor responses can be induced. Stimulating the corresponding brain regions of animals such as rabbits, rats, and mice with ultrasound can induce eye, forepaw, tail, and whisker movements. TUS also changes neural activity and synaptic transmission by activating voltage-gated ion channels, enhancing the neurovascular coupling of the cerebral cortex. Some studies measure the effect of TUS by simultaneously recording brain electrical activity using electroencephalogram (EEG) and local field potential (LFP), and using electromyogram (EMG) recording.

[0003] These methods provide a direct measurement means for TUS neural responses with high temporal resolution, but cannot obtain a broader perspective of brain activity at high spatial resolution and cannot monitor cerebral hemodynamic parameters. Functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) can observe the whole-brain information during the TUS process. Although fMRI and PET provide 3D information, they are also limited by high cost, large volume, low temporal resolution, and the complexity of implementation, especially for small animal models. Ultrasonic imaging has low contrast, while optical imaging has high sensitivity and contrast but shallow penetration depth, and invasive operations such as craniotomy are required for imaging the brains of small animals. The above detection methods all have very obvious disadvantages.

[0004] Therefore, a device capable of real-time dynamic imaging monitoring of cranial nerve modulation is needed. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a focused ultrasound transcranial neuromodulation platform based on photoacoustic imaging, which uses photoacoustic imaging technology to non-invasively monitor neuromodulation.

[0006] To achieve the above purpose, the present invention provides the following technical solutions: The focused ultrasound transcranial neuromodulation platform based on photoacoustic imaging provided by the present invention includes a synchronous pulse generator, a pulsed ultrasound emission system, a photoacoustic signal acquisition system, and a fixing device; The synchronous pulse generator is used to emit timing signals to realize the alternating working timing of the pulsed ultrasound emission system and the photoacoustic signal detection system; The pulsed ultrasound emission system is used to emit focused ultrasonic beams under the action of a synchronous timing signal; The photoacoustic signal acquisition system is used to acquire photoacoustic signals and generate photoacoustic images under the action of a synchronous timing signal; The fixing device is used to fix the ultrasonic emission unit and the photoacoustic imaging unit; so that the geometric focus of the ultrasonic emission unit, the center of the photoacoustic imaging unit after laser shaping, and the optimal imaging area of the receiving transducer coincide.

[0007] Furthermore, the timing signal emitted by the synchronous pulse generator is used to control the photoacoustic signal acquisition system to synchronously re - emit a laser signal and acquire the photoacoustic image generated by the laser in the region of interest. At the same time, another timing signal emitted by the synchronous pulse generator enables the pulsed ultrasound emission system to emit focused ultrasonic signals at another interval time.

[0008] Furthermore, the pulsed ultrasound emission system includes an industrial control computer, a signal generator, a power amplifier, a focused ultrasound transducer, and a receiving transducer; The industrial control computer is used to control the signal generator to generate analog signals, and to receive photoacoustic signals and electromyographic signals; The signal generator is used to generate an analog signal to enable the power amplifier to generate an excitation signal; The power amplifier is used to excite the focused ultrasound transducer to generate focused ultrasonic beams; The focused ultrasound transducer is used to generate and emit focused ultrasonic beams; The receiving transducer is used to receive the photoacoustic signals generated in the region of interest; and receive the photoacoustic signals in the imaging area corresponding to the receiving transducer.

[0009] Furthermore, the photoacoustic signal acquisition system includes an OPO laser, an optical fiber, and an optical fiber coupling device; The OPO laser is used to generate pulsed laser; The optical fiber is used for laser coupling; The optical fiber coupling device is used to couple the laser emitted by the optical fiber to the region of interest of the focused ultrasound.

[0010] Furthermore, it also includes a small animal anesthesia machine, a brain stereotaxic apparatus, and an electromyograph; The small animal anesthesia machine is used to provide a mixture of oxygen and anesthetic for small animals; The brain stereotaxic apparatus is used to fix small animals; The electromyograph is used to record electromyographic signals; and transmit the electromyographic signals to the industrial control computer.

[0011] Further, the fixing device is used to fix the focused ultrasound transducer, the receiving transducer and the optical fiber, so that the geometric focus of the focused ultrasound transducer, the center after shaping of the optical fiber and the optimal imaging area of the receiving transducer coincide. The probe fixing device confirms the relative positional relationship among the focused ultrasound transducer, the ultrasonic array transducer and the optical fiber.

[0012] Further, the center frequency of the focused ultrasound transducer is 0.1 - 20 MHz.

[0013] Further, a timing interval is set between the control timing signal of the pulsed ultrasound emission system and the control timing signal of the pulsed laser synchronization signal, and the timing interval is generally set to 0.1 - 5 ms.

[0014] The method for focused ultrasound transcranial nerve regulation based on photoacoustic imaging using the above platform provided by the present invention includes the following steps: S1: Fix the target object on a brain stereotaxic apparatus and determine the region of interest; S2: Turn on the anesthetic machine to make the target object in an anesthetized state; S3: Place the electromyogram recording electrode on the corresponding muscle mass; S4: Adjust the system to make the ultrasound-photoacoustic focus located in the region of interest, perform nerve regulation using preset ultrasound parameters, simultaneously perform photoacoustic imaging, and collect electromyogram signals; S5: Analyze the changes in blood oxygen saturation and electrophysiological indexes.

[0015] Further, the blood oxygen saturation in step S5 is calculated according to the following formula: where represents the blood oxygen saturation; is the molar concentration of HbR; is the molar concentration of HbO.

[0016] The beneficial effects of the present invention are as follows: The focused ultrasound transcranial nerve regulation platform based on photoacoustic imaging provided by the present invention includes a synchronous pulse generator, a pulsed ultrasound emission system, a photoacoustic signal acquisition system, and a fixing device; this system overcomes the limitations of other imaging monitoring methods, utilizes the non-invasive, high-resolution, and high-contrast characteristics of photoacoustic imaging for monitoring, can provide real-time dynamic imaging to monitor the progress of TUS, and can provide functional information (changes in blood oxygen saturation); this is also the first time to apply photoacoustic imaging in focused ultrasound transcranial nerve regulation. At the same time, using the high acoustic resolution and high optical contrast of photoacoustic imaging (PAT), hemoglobin, which is an endogenous contrast agent in the body, can provide the strongest photoacoustic signal in the near-infrared region, making PAT an ideal imaging tool for detecting cerebral hemodynamics. In addition, through the functional imaging provided by PAT, key pathophysiological parameters such as oxygen saturation (sO2), hemoglobin concentration (HbT), and cerebral blood flow (CBF) are evaluated. These important parameters can be used to evaluate the changes in the brain during low-intensity focused ultrasound stimulation. Moreover, PAT can provide real-time dynamic imaging to monitor the progress of TUS, which will provide valuable insights into understanding the physiology and pathology of TUS nerve regulation.

[0017] Other advantages, objectives, and features of the present invention will be described to some extent in the subsequent specification, and to some extent, will be obvious to those skilled in the art based on the study of the following text, or can be taught from the practice of the present invention. The objectives and other advantages of the present invention can be achieved and obtained through the following specification. Brief Description of the Drawings

[0018] In order to make the objectives, technical solutions, and beneficial effects of the present invention clearer, the present invention provides the following drawings for illustration.

[0019] Figure 1 It is a schematic diagram of the focused ultrasound transcranial nerve regulation platform based on photoacoustic imaging.

[0020] Figure 2 It is a timing diagram of pulsed laser and focused ultrasound control.

[0021] Figure 3 It is a flowchart of the method for focused ultrasound transcranial nerve regulation based on photoacoustic imaging.

[0022] Figure 4 It is an effect diagram of photoacoustic imaging of the coronal section of a mouse skull.

[0023] Figure 5 It is a schematic diagram of the electromyogram measurement instrument for real-time recording of electromyogram signals.

[0024] In the figure, there are a synchronization pulse generator 1, an OPO laser 2, a small animal anesthesia machine 3, a stereotaxic apparatus for brain 4, a single optical fiber 5; a receiving transducer 6; a focused ultrasound transducer 7, a photoacoustic signal acquisition system 8, a power amplifier 9, an industrial control computer 10, a signal generator 11, an electromyograph 12; and a breathing mask 13. Detailed implementation mode

[0025] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, so that those skilled in the art can better understand the present invention and be able to implement it, but the embodiments cited do not limit the present invention.

[0026] Embodiment 1 As Figure 1 shown, Figure 1 is a schematic diagram of a focused ultrasound transcranial nerve regulation platform based on photoacoustic imaging. The focused ultrasound transcranial nerve regulation platform based on photoacoustic imaging provided in this embodiment includes a synchronization pulse generator, a pulsed ultrasound emission system, a photoacoustic signal acquisition system, and a fixing device; The synchronization pulse generator is used to emit a timing signal to realize the alternating working timing of the pulsed ultrasound emission system and the photoacoustic signal detection system; The pulsed ultrasound emission system is used to emit a focused ultrasonic beam; The photoacoustic signal acquisition system is used to acquire photoacoustic signals; the photoacoustic signals are generated by the thermal expansion of tissues caused by pulsed lasers; The fixing device is used to fix the synchronization pulse generator, the ultrasonic emission unit, and the photoacoustic imaging unit; so that the geometric focus and the optimal imaging area of the ultrasonic emission unit, and the center after shaping of the photoacoustic imaging unit coincide; In this embodiment, the timing signal emitted by the synchronization pulse generator is used to control the photoacoustic signal acquisition system to re-emit laser signals and synchronously acquire the photoacoustic images generated by the laser in the region of interest. At the same time, another timing signal emitted by the synchronization pulse generator enables the control of the pulsed ultrasound emission system to emit focused ultrasound signals at another interval time, ensuring that the signals received by the photoacoustic signal acquisition system are only the photoacoustic images formed by the photoacoustic signals generated by the photoacoustic effect; avoiding signal interference caused by other factors, thereby improving the accuracy and reliability of photoacoustic image acquisition.

[0027] The pulsed ultrasound emission system in this embodiment includes an industrial control computer, a signal generator, a power amplifier, a focused ultrasound transducer, and a receiving transducer; The industrial control computer is used to control the signal generator to generate analog signals and receive photoacoustic signals; The signal generator is used to generate analog signals to make the power amplifier generate excitation signals; The power amplifier is used to excite the focused ultrasound transducer to generate a focused ultrasonic beam; The focused ultrasound transducer is used to generate and emit a focused ultrasonic beam; to excite the receiving transducer for the corresponding imaging region (region of interest, ROI), and to cause the tissue in this region to generate photoacoustic signals. In this embodiment, the center frequency of the focused ultrasound transducer is 0.1 - 20 MHz, and 0.5 MHz is selected in this embodiment.

[0028] The receiving transducer is used to receive the photoacoustic signals generated in the region of interest; to receive the photoacoustic signals of the corresponding imaging region (region of interest, ROI) of the receiving transducer. In this embodiment, a linear array ultrasound transducer with a center frequency of 7.5 MHz and 128 array elements is used; The photoacoustic signal acquisition system in this embodiment includes an OPO laser, a single optical fiber, and an optical fiber coupling device; The OPO laser is used to generate pulsed laser light; The single optical fiber is used for laser coupling; The optical fiber coupling device is used to couple the laser light emitted by the optical fiber to the region of interest of the focused ultrasound; The optical fiber coupling device provided in this embodiment is an optical lens shaping module. The optical lens shaping module is used to convert the laser light emitted by the optical fiber into a narrow rectangular beam, and the narrow rectangular beam is used to irradiate the region of interest; the optical lens shaping module includes a plano - concave lens and three plano - convex lenses. The plano - concave lens is used to diverge the light beam. The plano - concave lens is placed near the optical fiber output end to diverge the laser light emitted by the optical fiber, preparing for the subsequent shaping by the plano - convex lenses. The multiple plano - convex lenses are placed after the plano - concave lens and converge according to the diverged light beam. By adjusting the shape and convergence degree of the light beam, the light beam is shaped into a narrow rectangle.

[0029] It also includes a small animal anesthesia machine, a brain stereotaxic apparatus, and an electromyograph; The small animal anesthesia machine is used to provide a mixture of oxygen and anesthetic for small animals; The brain stereotaxic apparatus is used to fix small animals; The electromyograph is used to record muscle electrical signals; and transmit the muscle electrical signals to an industrial control computer; The fixing device in this embodiment is used to fix the focused ultrasound transducer, the receiving transducer, and the optical fiber, so that the geometric focus of the focused ultrasound transducer, the center after optical fiber shaping, and the best imaging region (region of interest, ROI) of the receiving transducer coincide. The probe fixing device confirms the relative positional relationship among the focused ultrasound transducer, the ultrasonic array transducer, and the optical fiber; As Figure 2 shown, Figure 2It is a timing diagram for controlling pulsed laser and focused ultrasound. In the diagram, Laser pulse represents the pulsed laser signal; Data acquisition represents data acquisition; Ultrasound represents focused ultrasound. In this embodiment, the synchronization signal of the pulsed laser is synchronized with the synchronization signal of the photoacoustic signal acquisition system, so that the moment of emitting the pulsed laser is synchronized with the acquisition of the photoacoustic signal; In this embodiment, there is a timing interval between the control timing signal of the pulsed ultrasound emission system and the control timing signal of the pulsed laser synchronization signal. The timing interval is generally set to 0.1 - 5 ms, and the timing interval selected in this embodiment is 0.2 ms; The pulsed laser synchronization signal emits a pulsed laser signal every 10 ms; the laser irradiates the tissue to generate a photoacoustic signal and performs photoacoustic imaging to obtain the blood oxygen saturation value as a reference, and then the emitted ultrasound signal is used for neuromodulation. At this time, only ultrasonic waves are emitted to stimulate the tissue; the fundamental frequency FF of the focused ultrasound is 500 kHz, the pulse repetition frequency PRF is 1 kHz, and the entire ultrasound stimulation time is 7 ms.

[0030] Embodiment 2 As Figure 3 shown, the working process of the focused ultrasound transcranial neuromodulation method based on photoacoustic imaging in this embodiment includes the following steps: S1: Remove the hair on the head of the small animal and fix it on the stereotaxic apparatus for the brain, and apply a coupling agent on the skin surface; S2: Turn on the anesthesia machine, put a breathing mask on the target object, and make the target object fall into an anesthetized state; S3: Place the electromyogram recording electrodes on the corresponding muscle masses; S4: Adjust the system to make the ultrasound - photoacoustic focus located in the region of interest, perform neuromodulation using specific ultrasound parameters, while perform photoacoustic imaging, and collect electromyogram signals; S5: Analyze the changes in blood oxygen saturation and electrophysiological indexes.

[0031] In this embodiment, the target object is a small animal, such as a mouse. To fix it, the hair on the head of the small animal needs to be removed.

[0032] The system provided in this embodiment uses photoacoustic tomography to provide a non - invasive and highly sensitive imaging effect, and uses the DAS algorithm for image reconstruction. As Figure 4 shown, Figure 4 is the photoacoustic imaging effect diagram of the coronal section of the mouse skull. The least - squares spectral fitting method is used to unmix the results, obtain the concentrations of HbO and HbR, calculate the blood oxygen saturation, systematically evaluate the effect of low - intensity transcranial ultrasound stimulation on blood oxygen saturation in cerebral hemodynamics, and use an electromyogram measuring instrument to record electromyogram signals in real time to monitor motor responses, providing a high - time - resolution view of these changes. AsFigure 5 As shown Figure 5 is a schematic diagram of the electromyogram measurement instrument for real-time recording of electromyogram signals.

[0033] The specific process of the regulation method provided in this embodiment is as follows: First, the fixing device sets the relevant positions of the focused ultrasound transducer, the receiving transducer, and the optical fiber fixing module as Figure 1 shown. Secondly, the synchronous pulse transmitter outputs a tigger signal, and at the same time controls the opo laser and the acquisition system. The opo laser alternately outputs 780nm and 830nm lasers. At the same time, the industrial control computer controls the signal transmitter to emit an excitation analog signal. When the excitation analog signal amplified by the power amplifier reaches the focused ultrasound transducer, the industrial control computer controls the acquisition system to start collecting photoacoustic signals; Finally, the industrial control computer brings the original data into the photoacoustic image obtained by the band-pass filter and the delay superposition algorithm, and then uses the least squares spectral fitting to decompose the result to obtain the concentrations of HbO and HbR. The least squares method can be described as follows: where is the PAT image reconstructed at a specific wavelength ; is the local light flux; and are the molar extinction coefficients of HbR and HbO, respectively; and are the molar concentrations of HbR and HbO, respectively; By solving the linear equations of multiple wavelengths, CHbR(x, y) and CHbO(x, y) can be used to calculate the change in blood oxygen saturation; the calculation formula for the blood oxygen saturation ( ) is: where represents the blood oxygen saturation.

[0034] The above embodiments are only preferred embodiments given to fully illustrate the present invention, and the protection scope of the present invention is not limited thereto. Equivalent substitutions or transformations made by those skilled in the art on the basis of the present invention are all within the protection scope of the present invention. The protection scope of the present invention shall be subject to the claims.

Claims

1. A focused ultrasound transcranial nerve regulation platform based on photoacoustic imaging, characterized by: It comprises a synchronous pulse generator, a pulsed ultrasonic emission system, a photoacoustic signal collection system and a fixing device; the synchronous pulse generator is used to emit a timing signal to realize the alternating working timing of the pulsed ultrasonic emission system and the photoacoustic signal collection system; the pulsed ultrasonic emission system is used to emit a focused ultrasonic beam under the action of the synchronous timing signal; the photoacoustic signal collection system is used to collect photoacoustic signals and generate photoacoustic images under the action of the synchronous timing signal; the fixing device is used to fix the ultrasonic emission unit and the photoacoustic imaging unit so that the geometric focus of the ultrasonic emission unit, the center of the photoacoustic imaging unit after laser shaping and the optimal imaging area of ​​the receiving transducer coincide with each other.

2. The focused ultrasound transcranial nerve regulation platform based on photoacoustic imaging according to claim 1, characterized in that: The timing signal emitted by the synchronization pulse generator is used to control the photoacoustic signal acquisition system to emit pulsed laser and collect the photoacoustic signal generated by the laser in the area of ​​interest synchronously. At the same time, another timing signal emitted by the synchronization pulse generator controls the pulsed ultrasound emission system to emit a focused ultrasound signal within another interval time.

3. The focused ultrasound transcranial nerve regulation platform based on photoacoustic imaging according to claim 1, characterized in that: The pulsed ultrasonic transmitting system comprises an industrial computer, a signal generator, a power amplifier, a focused ultrasonic transducer and a receiving transducer; The industrial computer is used to control the signal generator to generate analog signals and receive photoacoustic signals and muscle electrical signals; the signal generator is used to generate analog signals to enable the power amplifier to generate excitation signals; the power amplifier is used to excite the focused ultrasonic transducer to generate a focused ultrasonic beam; the focused ultrasonic transducer is used to generate and transmit a focused ultrasonic beam; the receiving transducer is used to excite the corresponding imaging area and cause the tissue in the area to generate photoacoustic signals, and the receiving transducer is used to receive the photoacoustic signals generated in the area of ​​interest; and the photoacoustic signals of the corresponding imaging area of ​​the receiving transducer are received.

4. The focused ultrasound transcranial nerve regulation platform based on photoacoustic imaging according to claim 1, characterized in that: The photoacoustic signal acquisition system comprises an OPO laser, an optical fiber and an optical fiber coupling device; the OPO laser is used to generate pulsed laser; The optical fiber is used for laser coupling; the optical fiber coupling device is used for coupling the laser emitted by the optical fiber to the focused ultrasound region of interest.

5. The focused ultrasound transcranial nerve regulation platform based on photoacoustic imaging according to claim 1, characterized in that: It also includes a small animal anesthesia machine, a brain stereotaxic instrument and an electromyography instrument; the small animal anesthesia machine is used to provide oxygen and an anesthetic mixture for the small animal; the brain stereotaxic instrument is used to fix the small animal; the electromyography instrument is used to record muscle electrical signals; And the electromyographic signal is transmitted to the industrial computer.

6. The focused ultrasound transcranial nerve regulation platform based on photoacoustic imaging according to claim 1, characterized in that: The fixing device is used to fix the focused ultrasonic transducer, the receiving transducer and the optical fiber so that the geometric focus of the focused ultrasonic transducer, the center of the optical fiber after shaping and the optimal imaging area of ​​the receiving transducer coincide with each other. The probe fixing device confirms the relative position relationship between the focused ultrasonic transducer, the ultrasonic array transducer and the optical fiber.

7. The focused ultrasound transcranial nerve regulation platform based on photoacoustic imaging according to claim 1, characterized in that: The center frequency of the focused ultrasonic transducer is 0.1-20 MHz, the center frequency of the receiving transducer is 0.1-20 MHz, and linear array, semi-ring, and spherical transducers are used.

8. The focused ultrasound transcranial nerve regulation platform based on photoacoustic imaging according to claim 1, characterized in that: A timing interval is set between the control timing signal of the pulsed ultrasonic emission system and the control timing signal of the pulsed laser synchronization signal, and the timing interval is set to 0.1-5ms.

9. A method for transcranial nerve regulation based on photoacoustic imaging using the focused ultrasound transcranial nerve regulation platform based on photoacoustic imaging according to any one of claims 1 to 8, characterized in that: The following steps are involved: S1: Fix the target object on the stereotaxic apparatus and determine the region of interest; S2: Turn on the anesthesia machine to put the target subject in an anesthesia state; S3: Place the electromyographic recording electrodes on the corresponding muscle mass; S4: Adjust the system so that the ultrasound-photoacoustic focus is located in the region of interest, use preset ultrasound parameters to perform neural regulation, perform photoacoustic imaging, and collect electromyographic signals at the same time; S5: Analyze changes in blood oxygen saturation and electrophysiological indicators.

10. The method for transcranial nerve regulation based on focused ultrasound using photoacoustic imaging according to claim 9, characterized in that: The blood oxygen saturation in step S5 is calculated according to the following formula: in, Indicates blood oxygen saturation; is the molar concentration of HbR; is the molar concentration of HbO.

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