Non-invasive targeted deep brain neuromodulation system guided by photoacoustic imaging

Abstract

This invention discloses a non-invasive, targeted deep brain neuromodulation system guided by photoacoustic imaging, addressing the problem of insufficient precision in existing neuromodulation technologies. The invention comprises a photoacoustic imaging module, a positioning and navigation module, and a photothermal stimulation module. In the photoacoustic imaging module, a light source emits pulsed laser light to the target brain region, causing photothermal nanomaterials located in the target brain region to absorb the pulsed laser light and generate ultrasonic waves. These ultrasonic waves are received by an ultrasonic transducer array and sent to a signal processing unit. The signal processing unit reconstructs a three-dimensional distribution image of the photothermal nanomaterials in the target brain region and transmits it to the positioning and navigation module. Based on the three-dimensional distribution of the photothermal nanomaterials in the target brain region, the positioning and navigation module determines the target point of the laser beam and adjusts the position and angle of the laser beam irradiation via a laser control unit. This invention combines molecular targeting with photoacoustic imaging guidance, achieving non-invasive, precise, and controllable activation of specific neuronal populations in deep brain regions.

Description

Technical Field

[0001] This invention relates to neural modulation systems, specifically to a non-invasive, targeted deep brain neural modulation system guided by photoacoustic imaging. Background Technology

[0002] Neuromodulation refers to the technique of controlling the activity of specific targets in the nervous system through external physical or chemical means. As an important tool for brain science research and the analysis of neural circuit functions, the development of neuromodulation technology has greatly advanced researchers' understanding of the working mechanisms of the brain. According to the mode of action, existing neuromodulation technologies can be divided into two main categories: invasive implantable and non-invasive non-implantable.

[0003] Among invasive implantable neuromodulation techniques, deep brain stimulation (DBS) is the most representative. DBS involves surgically implanting stimulating electrodes into specific brain regions, where a pulse generator applies controllable electrical pulses to modulate local neuronal activity. Although DBS achieves millimeter-level spatial precision, the surgical implantation process still carries risks such as bleeding and infection. Long-term implantation can lead to electrode displacement and breakage, and the stimulation lacks cell type selectivity. In 2005, Boyden et al. pioneered optogenetics, which expresses light-sensitive ion channel proteins in specific neurons and uses implanted optical fibers to conduct visible light, achieving millisecond-level precision in light-controlled neuronal activation. While optogenetics offers high spatiotemporal resolution and cell type selectivity, the shallow penetration depth of visible light in biological tissues (typically less than 1 mm) necessitates implanted optical fibers, inevitably causing tissue damage and inflammatory responses. Furthermore, the wired connection severely restricts the free movement of experimental animals. Although redshifted light-sensitive proteins can extend the activation wavelength to the red light range, completely non-invasive deep brain neuromodulation remains difficult to achieve.

[0004] Non-invasive, non-implantable neuromodulation techniques mainly include two categories: repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). rTMS uses a time-varying magnetic field to induce currents within the skull to modulate the excitability of cortical neurons, while tDCS applies a weak direct current field through electrodes on the scalp surface to alter the neuronal membrane potential. The advantage of these two techniques is that they are completely non-invasive, but their spatial resolution is only at the centimeter level, and their effective depth is limited to the superficial regions of the cerebral cortex, unable to target neuronal populations in deep brain regions (such as the subthalamic nucleus and hippocampus). While low-intensity focused ultrasound (LIFU) technology, which has emerged in recent years, can achieve deep brain region modulation, the scattering and absorption attenuation of ultrasound waves as they pass through the skull are significant, and its spatial resolution is also limited.

[0005] Against this backdrop, photothermal genetics has emerged. This technology utilizes photothermal conversion nanomaterials as energy conversion media to convert the energy of near-infrared light into localized heat energy. This heat effect activates the TRPV1 thermosensitive ion channel expressed on the target neuron membrane, enabling wireless remote modulation of neuronal activity. Near-infrared light (especially within the NIR-II window, 1000–1700 nm) penetrates biological tissues significantly deeper than visible light, making non-invasive deep brain stimulation possible. Copper sulfide (CuS) nanoparticles, with their strong absorption and high photothermal conversion efficiency around 1064 nm, are ideal materials for NIR-II photothermal conversion. However, existing photothermal genetics technologies still have two key shortcomings: first, existing nanomaterials lack specific targeting capabilities for target neurons, making effective accumulation on target neurons difficult; second, current technologies lack real-time monitoring methods for the spatial distribution of nanomaterials in deep brain regions, thus compromising the precision of photothermal stimulation. Summary of the Invention

[0006] The purpose of this invention is to solve the technical problems in existing photothermal genetics techniques, such as the difficulty in effectively enriching nanomaterials on target neurons and the difficulty in ensuring the precision of photothermal stimulation, and to provide a non-invasive targeted deep brain neuromodulation system based on photoacoustic imaging guidance.

[0007] To achieve the above objectives, the technical solution provided by this invention is as follows:

[0008] A non-invasive, targeted deep brain neural modulation system guided by photoacoustic imaging, characterized by the following features:

[0009] It includes a photoacoustic imaging module, a positioning and navigation module, and a photothermal stimulation module;

[0010] The photoacoustic imaging module includes a light source, an ultrasonic transducer array, and a signal processing unit. The light source is a multi-wavelength tunable laser source used to emit pulsed laser light to the target brain region, causing the photothermal nanomaterials in the target brain region to absorb the pulsed laser light and excite ultrasonic waves. The ultrasonic transducer array includes multiple ultrasonic transducers arranged in an array, and each ultrasonic transducer is connected to the signal processing unit. Each ultrasonic transducer is used to receive ultrasonic waves from different locations in the target brain region and send them to the signal processing unit. The signal processing unit is used to reconstruct a three-dimensional distribution image of the photothermal nanomaterials in the target brain region.

[0011] The photothermal stimulation module includes a laser and a laser control unit; the laser is used to emit a laser beam and irradiate the target brain region; the laser control unit is connected to the laser and is used to adjust the angle and power density of the laser beam.

[0012] The input end of the positioning and navigation module is connected to the signal processing unit, and the output end is connected to the laser control unit. The positioning and navigation module is used to determine the target point of the laser beam based on the three-dimensional distribution of photothermal nanomaterials in the target brain region, and adjust the position and angle of the laser beam irradiation through the laser control unit so that the laser beam activates the target neurons in the target brain region, thereby achieving non-invasive targeted deep brain nerve regulation.

[0013] Furthermore, the photothermal nanomaterial is a core-shell structured composite material, comprising a core, an intermediate layer, and an outer layer arranged sequentially from the inside out;

[0014] The core is copper sulfide nanoparticles; the intermediate layer is a polyethylene glycol modified layer, which is coordinated with the surface of the core through thiol groups or carboxyl groups; the outer layer is a TRPV1 antibody functionalized layer, which is covalently coupled to the outer end of the intermediate layer.

[0015] Furthermore, the copper sulfide nanoparticles have a particle size of 10~50nm, and the wavelength corresponding to their plasma resonance peak matches the emission wavelength of the laser.

[0016] In the polyethylene glycol modified layer, the molecular weight of polyethylene glycol is 1000~5000 Da.

[0017] Furthermore, the wavelength of the multi-wavelength tunable laser source covers two bands: 680~970nm and 1000~1700nm, with a pulse width of 5~10ns and a repetition frequency of 1~20Hz.

[0018] The center frequency of the ultrasonic transducer array is 1~15MHz, and the number of array elements is 64~256.

[0019] Furthermore, the laser control unit includes a power control device and a beam modulation device;

[0020] The power control device is connected to the laser and is used to adjust the power density of the laser beam; the input end of the beam control device is connected to the positioning and navigation module, and the output end is connected to the laser; the positioning and navigation module adjusts the position and angle of the laser beam illumination through the beam control device.

[0021] Furthermore, the laser is an Nd:YAG solid-state laser or a ytterbium-doped fiber laser, and the wavelength of its emitted laser beam is 1064 nm; the frequency adjustment range of the laser in pulse mode is 0.1~100 Hz, and the pulse width adjustment range is 1 ms~10 s.

[0022] The power control device employs an electrically controlled adjustable optical attenuator, with a power density adjustment range of 0.2~0.5W / cm². 2 The adjustment accuracy is better than 5%;

[0023] The beam control device uses an electrically controlled two-dimensional scanning galvanometer with an angle adjustment range of ±15° and a positioning accuracy of not less than 0.1°.

[0024] Furthermore, the signal processing unit reconstructs the three-dimensional distribution image of the photothermal nanomaterials in the target brain region using the following method: the signal processing unit sequentially amplifies, filters, and performs analog-to-digital conversion on the received ultrasound waves, and then uses a delay superposition or back projection algorithm to reconstruct the three-dimensional distribution image of the photothermal nanomaterials in the target brain region.

[0025] Furthermore, the positioning and navigation module determines the target point of the laser beam by the following method: the positioning and navigation module analyzes the three-dimensional distribution image of photothermal nanomaterials in the target brain region, then performs threshold segmentation on the three-dimensional distribution image, extracts the region in the three-dimensional distribution image where the photoacoustic signal intensity is higher than a preset threshold, and uses this region as the enriched region of photothermal nanomaterials. Then, it calculates the centroid coordinates of the region or takes the peak point coordinates of the photoacoustic signal intensity in the region as the spatial coordinates of the target point.

[0026] Furthermore, the threshold segmentation employs a segmentation algorithm based on maximum intensity projection or region growing.

[0027] The beneficial effects of this invention are as follows:

[0028] 1. The non-invasive targeted deep brain neuromodulation system based on photoacoustic imaging guidance provided by this invention adopts a technical architecture of "targeted nanomaterials - photoacoustic imaging - photothermal stimulation - feedback control". It eliminates the need for implanted optical fibers, fundamentally avoiding tissue damage and the constraints of wired connections; it also eliminates the need for implanted electrodes, thus avoiding surgical trauma and the risk of hardware failure. This invention combines molecular targeting with photoacoustic imaging guidance, as well as the cooperation between various modules, to achieve non-invasive, precise, and controllable activation of specific neuronal populations in deep brain regions.

[0029] 2. The photothermal nanomaterial of the present invention is a core-shell structure composite material, comprising copper sulfide nanoparticles as the core, a polyethylene glycol modified layer as the middle layer, and an outer TRPV1 antibody functionalized layer. This structure integrates three functions: molecular targeting recognition of neuronal TRPV1 receptor, near-infrared II photoacoustic imaging contrast enhancement, and photothermal conversion, thereby achieving precise regulation of target neurons.

[0030] 3. In the photothermal nanomaterial of the present invention, the particle size of the core copper sulfide nanoparticles is 10~50nm, which has good dispersion stability, uniform distribution in the brain, and good biological safety; at the same time, the wavelength corresponding to the plasma resonance peak of the copper sulfide nanoparticles matches the emission wavelength of the laser, which has high photothermal conversion efficiency and strong photoacoustic signal, and can simultaneously meet the dual needs of imaging and stimulation.

[0031] 4. In the photoacoustic imaging module of the present invention, the wavelength of the light source covers two bands: 680~970nm and 1000~1700nm. These two bands cover the optical windows of biological tissues in the near-infrared region I (NIR-I) and the near-infrared region II (NIR-II), respectively. Within these optical windows, the absorption of hemoglobin and water is weak, the tissue scattering is low, and the light penetration depth is the greatest, thus taking into account both imaging depth and contrast.

[0032] 5. Compared with rTMS and tDCS, the spatial resolution of this invention is improved from the centimeter level to the sub-millimeter level (200~500μm), and the effective penetration depth reaches 6~7mm of brain region, thereby achieving precise localization and selective activation of target neurons. Attached Figure Description

[0033] Figure 1 This is a schematic diagram of the structure of an embodiment of the present invention.

[0034] Figure 2 This is a schematic diagram of the preparation process of photothermal nanomaterials in an embodiment of the present invention.

[0035] Figure 3 This is a schematic diagram illustrating the working principle of the photothermal nanomaterial in an embodiment of the present invention.

[0036] Figure 4 This is a schematic diagram of the workflow of an embodiment of the present invention.

[0037] Figure 5 This is a temperature change curve of photothermal nanomaterials with different concentrations under 1064nm laser irradiation in an embodiment of the present invention.

[0038] Figure 6 This is a diagram showing the temperature rise curves of photothermal nanomaterials under different laser power densities in embodiments of the present invention.

[0039] Figure 7 This is a comparison chart of the stability test results of photothermal nanomaterials after three heating-cooling cycles in an embodiment of the present invention.

[0040] The attached figures are labeled as follows:

[0041] 1-Photoacoustic imaging module, 2-Laser control unit. Detailed Implementation

[0042] To make the objectives, advantages, and features of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. Those skilled in the art should understand that these embodiments are merely used to explain the technical principles of the present invention and are not intended to limit the scope of protection of the present invention.

[0043] Photoacoustic imaging (PAI) is an emerging imaging modality that combines the high contrast of optical imaging with the deep penetration of ultrasound. Both PAI and photothermal genetics rely on the same near-infrared absorbing materials, theoretically allowing for simultaneous imaging and modulation functions based on the same nanomaterial. Therefore, this embodiment utilizes a multifunctional photothermal nanomaterial integrating target recognition, photoacoustic imaging, and photothermal conversion to construct a non-invasive deep brain neural modulation system guided by photoacoustic imaging.

[0044] like Figure 1 As shown, this embodiment provides a non-invasive targeted deep brain neural modulation system based on photoacoustic imaging guidance. It adopts a technical architecture of "targeted nanomaterials-photoacoustic imaging-photothermal stimulation-feedback control" and includes a photoacoustic imaging module 1, a positioning and navigation module, and a photothermal stimulation module.

[0045] The photoacoustic imaging module 1 is used to acquire three-dimensional spatial distribution images of photothermal nanomaterials in the target brain region. The module includes a light source, an ultrasonic transducer array, and a signal processing unit. The light source is a multi-wavelength tunable laser source used to emit pulsed laser light to the target brain region, causing the photothermal nanomaterials in the target brain region to absorb the pulsed laser light and excite ultrasonic waves. In this embodiment, the wavelength of the light source covers two bands: 680–970 nm and 1000–1700 nm. These two bands cover the near-infrared I (NIR-I) and near-infrared II (NIR-II) optical windows of biological tissues, respectively. Within these windows, the absorption of hemoglobin and water is weak, tissue scattering is low, and the light penetration depth is maximum. The 680–970 nm band can be used for imaging shallower brain regions and functional imaging such as blood oxygenation; the 1000–1700 nm band penetrates deeper into tissues and has an absorption peak near 1064 nm for the plasma covering copper sulfide nanoparticles, making it suitable for photoacoustic imaging of deep brain regions. Meanwhile, the dual-band design avoids the strong absorption band of water around 970~1000nm, allowing for the selection of appropriate wavelengths based on the depth of the target brain region and imaging requirements, thus balancing imaging depth and contrast.

[0046] The pulse width of the light source is 5~10ns, which can efficiently generate photoacoustic signals. This requires meeting the thermal and stress constraints, namely, the laser pulse width must be shorter than the thermal and acoustic relaxation times of the tissue. Simultaneously, the nanosecond-level pulse width not only allows light energy to be deposited instantaneously on nanomaterials, efficiently exciting ultrasound and improving photoacoustic conversion efficiency and signal strength, but also avoids heat diffusion to surrounding tissues, preventing thermal damage.

[0047] The repetition frequency of the light source is 1~20Hz, which matches the output capability of commonly used pulsed lasers (Nd:YAG and its pumped OPO tunable lasers). While ensuring a large single pulse energy (ensuring the imaging signal-to-noise ratio), the average power is controlled within a safe range to avoid thermal accumulation damage to brain tissue. In addition, its acquisition rate can meet the time requirements of three-dimensional scanning imaging.

[0048] The ultrasound transducer array comprises multiple ultrasound transducers arranged in an array, with each transducer connected to a signal processing unit. Each transducer receives ultrasound waves from different locations within the target brain region and sends them to the signal processing unit. In this embodiment, the ultrasound transducer array is preferably an arc-shaped (concave) array, with multiple transducers uniformly arranged along an arc or a partial spherical surface. The receiving direction of each element (i.e., the ultrasound transducer) is focused towards the target brain region. The arc-shaped arrangement is chosen because it conforms to the contour of the head (skull), shortening the acoustic path between each element and the deep brain region. Furthermore, each element forms a confocal reception of the target region, significantly improving the receiving sensitivity and imaging signal-to-noise ratio of weak photoacoustic signals from the deep brain region. Alternatively, other forms such as a ring array or a planar rectangular array can be used. In this embodiment, the ultrasound transducer is a conventional piezoelectric ultrasound transducer, such as a PZT piezoelectric ceramic transducer or a PVDF piezoelectric thin film transducer.

[0049] In this embodiment, the center frequency of the ultrasonic transducer array is 1~15MHz. Higher ultrasonic frequencies result in higher imaging resolution but also greater tissue attenuation and shallower penetration; lower ultrasonic frequencies result in deeper penetration but decreased resolution. Therefore, this embodiment selects a range of 1~15MHz to balance the required penetration depth and imaging resolution for penetrating the skull / deep brain tissue.

[0050] Meanwhile, the number of elements in an ultrasonic transducer array ranges from 64 to 256, as the number of elements determines the imaging field of view, spatial sampling density, and image quality. 64 elements can meet basic three-dimensional imaging requirements, while 256 elements can achieve a higher signal-to-noise ratio and image resolution. This range strikes a balance between imaging quality and system cost and complexity.

[0051] The signal processing unit uses a delay superposition or back projection algorithm to reconstruct a three-dimensional distribution image of photothermal nanomaterials in the target brain region, with a spatial resolution of no less than 200 μm.

[0052] The photothermal nanomaterial of this embodiment is a core-shell composite material, which is injected into the target brain region via stereotactic injection. The photothermal nanomaterial comprises a core, an intermediate layer, and an outer layer arranged sequentially from the inside out, with the chemical formula CuS-PEG-TRPV1. The core consists of copper sulfide (CuS) nanoparticles with a particle size of 10-50 nm (preferably 20-30 nm), exhibiting significant near-infrared II absorption characteristics. The wavelength corresponding to the plasmon resonance peak of the copper sulfide nanoparticles (approximately 1064 nm) matches the emission wavelength of the laser (Nd:YAG). In this embodiment, the particle size of the copper sulfide nanoparticles is selected as 10-50 nm because: nanoparticles with a particle size smaller than 10 nm have too large a specific surface area, are prone to aggregation, and are quickly cleared from the body, resulting in lower photothermal conversion efficiency; particles larger than 50 nm are difficult to diffuse in the interstitial spaces of brain tissue and are not conducive to effective binding with receptors on the neuronal membrane surface. Nanoparticles with a particle size in the 10-50 nm range exhibit good dispersion stability, uniform distribution within the brain, and good biocompatibility. In addition, copper sulfide nanoparticles of 10~50nm have strong local surface plasmon resonance absorption near 1064nm, resulting in high photothermal conversion efficiency and strong photoacoustic signal, which can simultaneously meet the dual needs of imaging and stimulation.

[0053] The intermediate layer is a polyethylene glycol (PEG) modified layer, which coordinates with the surface of copper sulfide nanoparticles through thiol or carboxyl groups, endowing the nanomaterials with good water solubility and biocompatibility. In this embodiment, the molecular weight of PEG is 1000~5000 Da. If the molecular weight is below 1000 Da, the PEG chain is too short, the steric hindrance effect is insufficient, and it is difficult to effectively shield the non-specific adsorption of biomolecules (proteins), and the nanoparticles are prone to aggregation and have a short residence time in vivo. If the molecular weight is above 5000 Da, the PEG chain is too long, which will significantly increase the overall hydrated particle size of the nanomaterial, weaken its diffusion ability in the interstitial spaces of brain tissue, and the excessively long PEG chain may block the antigen binding site of the outer TRPV1 antibody, reducing the targeting efficiency. The molecular weight of PEG in the range of 1000~5000 Da can achieve a better balance between water solubility / biocompatibility / antifouling ability and targeting recognition efficiency.

[0054] The outer layer is a TRPV1 antibody-functionalized layer, which is covalently coupled to the end of polyethylene glycol, enabling the nanomaterial to target TRPV1 receptors on the surface of neurons.

[0055] Combination Figure 2 As shown, the photothermal nanomaterial of this embodiment is prepared by the following method:

[0056] First, CuS nanoparticles were synthesized via a hydrothermal method. Specifically, 34.1 mg CuCl2 and 40 mg sodium citrate (C6H5Na3O7) were dissolved in 180 mL of deionized water and stirred magnetically to form a clear solution. Then, 20 mL of Na2S solution was added dropwise to the above solution to form a mixture, which gradually turned dark brown. After complete addition, stirring was continued for 5 minutes, and the mixture was then transferred to a constant-temperature water bath and heated to 90°C, where it was stirred continuously for 15 minutes. Finally, the mixture was rapidly cooled in an ice-water bath to obtain CuS.

[0057] Next, functional PEG was added, and the mixture was reacted at room temperature for more than 12 hours to obtain PEG-modified nanomaterial CuS-PEG.

[0058] Subsequently, 1 mL of the above solution was taken, and 3.36 μmol of EDC (crosslinking agent) and 3.36 μmol of NHS were added. The mixture was allowed to stand at room temperature for 30 minutes to activate the carboxyl groups on the CuS surface. Then, 2 μg of TRPV1 antibody was added, and the reaction was continued with gentle stirring for 12 hours to prepare CuS-PEG-TRPV1. Finally, the mixture was centrifuged and washed several times to disperse it in PBS (phosphate buffer) for further use.

[0059] The photothermal nanomaterials of this embodiment have three functions: (1) Targeting function - using antibody-antigen specific recognition, the photothermal nanomaterials selectively anchor to the surface of target neurons expressing TRPV1; (2) Photoacoustic imaging function - the CuS nucleus strongly absorbs light energy in the near-infrared band, generates thermoelastic expansion and excites ultrasonic signals, which can be used as an exogenous contrast agent for photoacoustic imaging; (3) Photothermal conversion function - the CuS nucleus absorbs 1064nm near-infrared light energy and converts the light energy into heat energy through non-radiative relaxation, thereby increasing the local temperature to activate the TRPV1 channel.

[0060] The photothermal stimulation module includes a laser and a laser control unit 2. The laser emits a laser beam to irradiate the target brain region. The laser is a 1064nm laser, selected from either an Nd:YAG solid-state laser or a ytterbium-doped fiber laser. It supports both continuous and pulsed operating modes. The continuous mode is suitable for stimulation scenarios requiring stable and sustained temperature rise, such as experiments where the local temperature needs to be maintained above the TRPV1 activation threshold (approximately 43°C) to achieve sustained neural activation over a longer period. The pulsed mode is suitable for scenarios requiring precise control of the stimulation timing and dosage, such as intermittent stimulation synchronized with neurophysiological recordings, or repetitive stimulation experiments where heat accumulation to avoid tissue damage is necessary. The wavelength of the emitted laser beam is 1064nm, and the frequency adjustment range of the laser in pulsed mode is 0.1~100Hz, and the pulse width adjustment range is 1ms~10s.

[0061] The laser control unit 2 is connected to the laser and is used to adjust the angle and power density of the laser beam.

[0062] The input end of the positioning and navigation module is connected to the signal processing unit, and the output end is connected to the laser control unit 2. The positioning and navigation module is used to determine the target point of the laser beam based on the three-dimensional distribution of photothermal nanomaterials in the target brain region, and adjust the position and angle of the laser beam irradiation through the laser control unit 2 so that the laser beam activates the target neurons in the target brain region, thereby achieving non-invasive targeted deep brain nerve regulation.

[0063] The laser control unit 2 in this embodiment includes a power control device and a beam modulation device. The power control device employs an electrically controlled adjustable optical attenuator (such as an electrically adjustable neutral density attenuator, an acousto-optic modulator (AOM), or an electro-optic modulator (EOM), which is connected to the laser and used to adjust the power density of the laser beam. The operating range of the power control device is 0.2~0.5 W / cm². 2 Alternatively, closed-loop adjustment of power density can be achieved by adjusting the laser's drive current / pump power, and with real-time feedback from a power meter, an adjustment accuracy better than 5% can be achieved.

[0064] The beam control device uses an electrically controlled two-dimensional scanning galvanometer (such as a Galvo galvanometer) or an electric reflector adjustment mechanism driven by a piezoelectric / stepper motor. The input end of the beam control device is connected to the positioning and navigation module, and the output end is connected to the laser. The positioning and navigation module adjusts the position and angle of the laser beam through the beam control device, and can achieve an angle adjustment accuracy of not less than 0.1° within a range of ±15°.

[0065] In summary, this embodiment employs a dual precision localization strategy: the first layer is molecular targeting, utilizing the specific binding of the TRPV1 antibody-functionalized layer on the outer layer of the photothermal nanomaterial to the TRPV1 receptor of the neuron, enabling the photothermal nanomaterial to selectively accumulate on the surface of the target neuron; the second layer is image-guided localization, where the localization and navigation module uses the photoacoustic imaging module 1 to acquire real-time images of the spatial distribution of the photothermal nanomaterial in the target brain region, and determines the laser irradiation target point based on the photoacoustic signal intensity distribution, and finally adjusts the position and angle of the laser beam irradiation through the beam control device.

[0066] Combination Figures 1 to 4 As shown, the working process of the non-invasive targeted deep brain neural modulation system guided by photoacoustic imaging in this embodiment includes the following steps:

[0067] Step 1 involves expressing the TRPV1 thermosensitive ion channel on target neurons in the target brain region using a viral vector, which is equivalent to installing a thermally responsive switch.

[0068] Step 2: The photothermal nanomaterial is injected into the target brain region through stereotactic brain localization (i.e., by using a stereotactic brain localization instrument and brain atlas, a three-dimensional coordinate system can be established based on anatomical landmarks on the skull (such as the anterior fontanelle, posterior fontanelle, ear canal, orbit, or sagittal suture, etc.) to determine the precise location of specific structures in the brain). The outer layer of the photothermal nanomaterial specifically binds to the TRPV1 thermosensitive ion channel on the target neuron and selectively anchors to the surface of the target neuron.

[0069] Step 3: A pulsed laser is emitted to the target brain region through a light source. The photothermal nanomaterial absorbs the pulsed laser and excites ultrasound waves, which are then received by an ultrasound transducer array and transmitted to the signal processing unit.

[0070] Step 4: The signal processing unit amplifies, filters, and performs analog-to-digital conversion on the received ultrasound waves in sequence. Then, it uses a delay superposition or back projection algorithm to reconstruct the three-dimensional distribution image of the photothermal nanomaterials in the target brain region and transmits it to the positioning and navigation module.

[0071] Step 5: Analyze the three-dimensional distribution image of photothermal nanomaterials in the target brain region through the positioning and navigation module, and then use the maximum intensity projection or region growing segmentation algorithm to perform threshold segmentation on the three-dimensional distribution image to extract the region in the three-dimensional distribution image where the photoacoustic signal intensity is higher than the preset threshold. Use this region as the enriched region of photothermal nanomaterials, and then calculate the centroid coordinates of the region or take the peak point coordinates of the photoacoustic signal intensity in the region as the spatial coordinates of the irradiation target.

[0072] Step 6: Based on the spatial coordinates of the target point, the positioning and navigation module drives the beam control device to adjust the position and angle of the laser beam, aligning it with the target point. The photothermal nanomaterial then absorbs the light energy of the laser beam and converts it into heat energy, causing the local temperature to rise to the TRPV1 activation threshold (approximately 43°C). This opens the channel and causes Ca... 2+ Influx and membrane depolarization induce action potentials, which activate the target neurons to which they are anchored, thus achieving non-invasive, targeted regulation of deep brain neurons.

[0073] Figure 5 The figure shows the temperature change curves of photothermal nanomaterials with different concentrations under 1064nm laser irradiation. It can be seen from the figure that the photothermal nanomaterials have a good photothermal heating effect, and the higher the concentration of nanomaterials, the better the heating effect. This indicates that the heating effect can be controlled by preparing photothermal nanomaterial solutions with different concentrations.

[0074] Figure 6 The graph shows the heating curves of photothermal nanomaterials under different laser power densities. It can be seen from the graph that the higher the laser power density, the more obvious the heating effect of the photothermal nanomaterials, indicating that the heating temperature in the neuromodulation process can be controlled by adjusting the laser power density.

[0075] Figure 7 The figure shows a comparison of the stability test results of three heating-cooling cycles. It can be seen from the figure that the temperature curves of the three cycles are basically the same, indicating that the photothermal nanomaterial used in this embodiment has good photothermal stability and can be repeatedly used in the neuromodulation process.

[0076] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein, and such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the present invention.

Claims

1. A non-invasive, targeted deep brain neural modulation system guided by photoacoustic imaging, characterized in that: It includes a photoacoustic imaging module (1), a positioning and navigation module, and a photothermal stimulation module; The photoacoustic imaging module (1) includes a light source, an ultrasonic transducer array, and a signal processing unit. The light source is a multi-wavelength tunable laser source used to emit pulsed laser light to the target brain region, so that the photothermal nanomaterials in the target brain region absorb the pulsed laser light and excite ultrasonic waves. The ultrasonic transducer array includes multiple ultrasonic transducers arranged in an array, and each ultrasonic transducer is connected to the signal processing unit. Each ultrasonic transducer is used to receive ultrasonic waves from different locations in the target brain region and send them to the signal processing unit. The signal processing unit is used to reconstruct a three-dimensional distribution image of the photothermal nanomaterials in the target brain region. The photothermal stimulation module includes a laser and a laser control unit (2); the laser is used to emit a laser beam and irradiate the target brain region; the laser control unit (2) is connected to the laser and is used to adjust the angle and power density of the laser beam. The input end of the positioning and navigation module is connected to the signal processing unit, and the output end is connected to the laser control unit (2). The positioning and navigation module is used to determine the target point of the laser beam based on the three-dimensional distribution of photothermal nanomaterials in the target brain region, and adjust the position and angle of the laser beam irradiation through the laser control unit (2) so that the laser beam activates the target neurons in the target brain region and achieves non-invasive targeted deep brain nerve regulation.

2. The non-invasive targeted deep brain neural modulation system based on photoacoustic imaging guided according to claim 1, characterized in that: The photothermal nanomaterial is a core-shell structured composite material, comprising a core, an intermediate layer, and an outer layer arranged sequentially from the inside out. The core is copper sulfide nanoparticles; the intermediate layer is a polyethylene glycol modified layer, which is coordinated with the surface of the core through thiol groups or carboxyl groups; the outer layer is a TRPV1 antibody functionalized layer, which is covalently coupled to the outer end of the intermediate layer.

3. The non-invasive targeted deep brain neural modulation system based on photoacoustic imaging guided according to claim 2, characterized in that: The copper sulfide nanoparticles have a particle size of 10~50nm, and the wavelength corresponding to their plasma resonance peak matches the emission wavelength of the laser. In the polyethylene glycol modified layer, the molecular weight of polyethylene glycol is 1000~5000 Da.

4. The non-invasive targeted deep brain neural modulation system based on photoacoustic imaging guided according to claim 1, characterized in that: The multi-wavelength tunable laser source has wavelengths covering two bands: 680~970nm and 1000~1700nm, with a pulse width of 5~10ns and a repetition frequency of 1~20Hz. The center frequency of the ultrasonic transducer array is 1~15MHz, and the number of array elements is 64~256.

5. The non-invasive targeted deep brain neural modulation system based on photoacoustic imaging guided according to any one of claims 1 to 4, characterized in that: The laser control unit (2) includes a power control device and a beam modulation device; The power control device is connected to the laser and is used to adjust the power density of the laser beam; the input end of the beam control device is connected to the positioning and navigation module, and the output end is connected to the laser; the positioning and navigation module adjusts the irradiation position and angle of the laser beam through the beam control device.

6. The non-invasive targeted deep brain neural modulation system based on photoacoustic imaging guided according to claim 5, characterized in that: The laser is an Nd:YAG solid-state laser or a ytterbium-doped fiber laser, and its emitted laser beam wavelength is 1064nm; the frequency adjustment range of the laser in pulse mode is 0.1~100Hz, and the pulse width adjustment range is 1ms~10s. The power control device employs an electrically controlled adjustable optical attenuator, with a power density adjustment range of 0.2~0.5W / cm². 2 The adjustment accuracy is better than 5%; The beam control device uses an electrically controlled two-dimensional scanning galvanometer with an angle adjustment range of ±15° and a positioning accuracy of not less than 0.1°.

7. The non-invasive targeted deep brain neural modulation system based on photoacoustic imaging guided according to claim 6, characterized in that: The signal processing unit reconstructs a three-dimensional distribution image of the photothermal nanomaterials in the target brain region using the following method: The signal processing unit amplifies, filters, and performs analog-to-digital conversion on the received ultrasound waves in sequence, and then uses a delay superposition or back projection algorithm to reconstruct a three-dimensional distribution image of the photothermal nanomaterials in the target brain region.

8. The non-invasive targeted deep brain neural modulation system based on photoacoustic imaging guided according to claim 7, characterized in that: The positioning and navigation module determines the target point of the laser beam using the following method: The positioning and navigation module analyzes the three-dimensional distribution image of photothermal nanomaterials in the target brain region, then performs threshold segmentation on the three-dimensional distribution image to extract the region in the three-dimensional distribution image where the photoacoustic signal intensity is higher than a preset threshold, and uses this region as the enrichment region of photothermal nanomaterials. Then, it calculates the centroid coordinates of the region or takes the peak point coordinates of the photoacoustic signal intensity in the region as the spatial coordinates of the irradiation target.

9. The non-invasive targeted deep brain neural modulation system based on photoacoustic imaging guided according to claim 8, characterized in that: The threshold segmentation employs segmentation algorithms based on maximum intensity projection or region growing.

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