Transcranial ultrasound methods and systems for penetrating the skull

Abstract

This invention provides a transcranial ultrasound method and system for penetrating the skull. The method includes applying a decalcifying agent to the skull region of a subject to make the skull region acoustically transparent, thereby enabling brain imaging and / or brain therapy; transmitting and receiving sound wave signals to the acoustically transparent head using an ultrasound transducer; acquiring ultrasound images of internal tissues of the head based on the received sound wave signals; and / or transmitting ultrasound waves to the acoustically transparent head using the ultrasound transducer to perform ultrasound therapy. This transcranial ultrasound method fundamentally eliminates the strong reflection, scattering, and energy attenuation of ultrasound waves caused by the skull as an acoustic barrier, significantly improving signal strength. Therefore, this invention not only achieves non-invasive, whole-brain-depth functional ultrasound imaging with resolution up to 20 micrometers, but also greatly improves the accuracy and safety of ultrasound therapy procedures such as targeted drug delivery and neuromodulation.

Description

Technical Field

[0001] This invention relates to the field of biomedical ultrasound, and more particularly to a transcranial ultrasound method and system for penetrating the skull. Background Technology

[0002] Ultrasound technology is one of the most widely used non-invasive imaging and treatment methods in the medical field. In recent years, functional ultrasound imaging (fUSI), as an emerging neuroimaging technology, can achieve high-resolution (better than 100 micrometers) and high-sensitivity whole-brain functional mapping by detecting changes in cerebral blood volume (CBV) caused by neurovascular coupling, showing great potential in neuroscience research and clinical auxiliary diagnosis. In addition, transcranial ultrasound also has important significance in the treatment of neural modulation, targeted drug delivery, and blood-brain barrier opening.

[0003] However, the application of transcranial ultrasound in the brain has long been severely hampered by the acoustic barrier of the skull. The skull is composed of highly mineralized bone matrix, whose acoustic impedance and sound velocity are significantly higher than those of the brain's soft tissue. According to acoustic principles, this drastic mismatch in acoustic properties leads to strong reflection, refraction, and scattering of ultrasound waves at the skull interface. Simultaneously, the heterogeneous microstructure of the skull causes severe signal attenuation and wavefront distortion (aberration), resulting in a significant decrease in imaging resolution, a reduced signal-to-noise ratio, and even making it impossible to image deep brain tissue structures.

[0004] To overcome the effects of the skull, physical invasive methods, such as surgical removal of part of the skull (craniotomy), are commonly used in clinical practice and research. While these methods can improve acoustic transmission, they cause irreversible tissue damage, increase the risk of infection, and are not suitable for long-term longitudinal observation or large-scale clinical application.

[0005] In non-invasive research, existing methods such as adaptive beamforming, full-wave phase correction, or ultrasonic positioning microscopy (ULM) can correct aberrations or improve the signal-to-noise ratio to some extent, but they cannot fundamentally recover the huge energy loss caused by skull reflection and absorption, and have limitations such as slow imaging speed and short microbubble cycle time.

[0006] Therefore, a new transcranial ultrasound technique is needed. Summary of the Invention

[0007] The purpose of this invention is to provide a transcranial ultrasound method and system for penetrating the skull that can maintain the integrity of the skull while significantly reducing acoustic obstruction.

[0008] To achieve the above objectives, the present invention provides a transcranial ultrasound method and system for penetrating the skull, comprising: A decalcifying agent was applied to the skull region of the subject to remove calcium from the skull and make the skull acoustically transparent. Based on the ultrasonic transducer to transmit and receive sound wave signals to the head in an acoustically transparent state; Based on the received acoustic signal, acquire an ultrasound image of the internal tissues of the head; and / or, The ultrasonic transducer emits ultrasonic waves to the head, which is in an acoustically transparent state, to perform ultrasonic therapy.

[0009] Preferably, the decalcifying agent comprises one or more compounds capable of binding, complexing, chelating, dissolving, or promoting the removal of mineralized components with calcium ions in bone tissue, wherein the compounds are selected from any one or more of aminopolycarboxylic acid chelating agents, organic acid decalcifying agents, phosphonic acid or phosphonate compounds, bisphosphonate compounds, citric acid and its salts, ethylenediaminetetraacetic acid and its salts, and ethylene glycol bis(β-aminoethyl ether)tetraacetic acid and its salts.

[0010] Preferably, when applying the decalcifying agent to the skull, a co-application agent containing hydrogen peroxide (H2O2) is also applied to the skull region.

[0011] Preferably, the decalcifying agent is applied in the form of a liquid solution or incorporated into a support medium containing agarose or hydrogel.

[0012] Preferably, after applying the decalcifying agent to the skull region, a low-frequency ultrasound signal is also applied to the skull region where the decalcifying agent has been applied to accelerate the penetration of the decalcifying agent.

[0013] Preferably, after receiving the acoustic signal, a recalcifying agent is also applied to the skull region to restore the acoustic properties of the skull.

[0014] Preferably, the recalcifying agent comprises calcium gluconate.

[0015] Preferably, a tissue protective layer comprising agarose or hydrogel is applied to the skull region before and / or after the application of the recalcifying agent.

[0016] Preferably, the ultrasound transducer is configured to perform any of the following operations: functional ultrasound imaging, B-mode imaging, neuromodulation, drug delivery, elastography, photoacoustic imaging, and therapeutic ultrasound.

[0017] The present invention also provides a transcranial ultrasound system for penetrating the skull, characterized in that the transcranial ultrasound system operates based on the transcranial ultrasound method according to any one of claims 1 to 9.

[0018] Compared with existing technologies, the transcranial ultrasound method provided by the above-mentioned technical solution effectively adjusts the volumetric modulus of the skull by applying a decalcifying agent to the skull region to remove skull calcium, thereby achieving a state of acoustic transparency by making its acoustic impedance highly matched with that of the brain soft tissue. This method, without requiring mechanical craniotomy and ensuring the integrity of the physical protection of the subject's head, fundamentally eliminates the strong reflection, scattering, and energy attenuation of ultrasound waves caused by the skull as an acoustic barrier, restoring the ultrasound transmission efficiency to over 90% of that in a free field and significantly improving signal strength. Therefore, this invention not only achieves non-invasive, whole-brain depth functional ultrasound imaging with a resolution up to 20 micrometers, but also significantly improves the accuracy and safety of ultrasound-based therapeutic operations such as targeted drug delivery and neuromodulation. Attached Figure Description

[0019] Figure 1 A system for performing a transcranial ultrasound method according to an embodiment of the present invention is shown.

[0020] Figure 2 An example flow for ultrasonic signal processing in an embodiment of the present invention is shown.

[0021] Figure 3 The transcranial ultrasound method in an embodiment of the present invention is shown, which modulates the acoustic properties of the skull by removing calcium.

[0022] Figure 4a A study based on an example implementation of the invention disclosed herein is shown, derived from fUSI images of an unprocessed skull.

[0023] Figure 4b A study based on an example implementation of the invention disclosed herein is shown, derived from fUSI images of the processed posterior skull.

[0024] Figure 4c An example implementation of the study according to the present invention is shown, in which the skull has been removed (fUSI image).

[0025] Figure 4d The study, based on an example implementation of the present invention, illustrates the analysis results of normalized signal intensity of processed and unprocessed skulls.

[0026] Figure 4e A study comparing the vascular density of treated and untreated skulls is shown, based on an example implementation of the invention disclosed herein.

[0027] Figure 4f The study, which is an example implementation of the present invention, illustrates the analysis of a processed skull image.

[0028] Figure 5a The illustration shows a study implemented according to an example disclosed in this invention, a procedure for detecting stimulus-induced brain activation.

[0029] Figure 5b The study, which is an example implementation of the present invention, illustrates the ultrasound imaging visualization of the stimulus-evoked response in the contralateral primary somatosensory cortex.

[0030] Figure 5c The study, which is an example implementation of the present invention, is shown to detect data status of stimulus-evoked responses in the contralateral primary somatosensory cortex.

[0031] Figure 5d The study, which is an example of an implementation of the present invention, is shown to detect the activation of the contralateral ventroposteromedial nucleus of the thalamus.

[0032] Figure 5e The illustration shows a study implemented according to an example disclosed in this invention, demonstrating pixel-wise Pearson correlation results between the fUSI signal and the stimulus time course.

[0033] Figure 5f The results of an S1BF response in a repeated stimulus test are shown in an example implementation of a study according to the present invention.

[0034] Figure 5 shows a correlation matrix diagram of an example implementation of the study disclosed in this invention.

[0035] Figure 6a An example implementation of a study according to the present invention is shown, involving ultrasound imaging in an online phantom.

[0036] Figure 6b The results of a study performed according to an example implementation of the present invention, using B-mode imaging, are shown.

[0037] Figure 6c An example spatial resolution result for B-mode imaging is shown, based on an example implementation of the study disclosed in this invention.

[0038] Figure 6d The study, which is an example implementation of the present invention, illustrates the sound pressure fields of an untreated skull, a treated skull, and a skull without a skull.

[0039] Figure 6e The study, which is an example implementation of the present invention, illustrates the relationship between sound pressure and voltage for treated skull, untreated skull, and skullless skull.

[0040] Figure 6f The study, which is an example implementation of the present invention, illustrates the relationship between amplitude and frequency in treated skull, untreated skull, and skullless skull.

[0041] Figure 6gA study demonstrating the effect of the skull on ultrasound propagation is shown, based on an example implementation of the invention disclosed herein.

[0042] Figure 6h The study, which is an example implementation of the present invention, is shown, with the sound velocity of the skull unprocessed.

[0043] Figure 6i An example implementation of the study according to the present invention is shown, addressing the effect on acoustic impedance.

[0044] Figure 7a A study implementing an example according to the present invention is shown, involving histological analysis of treated tissue.

[0045] Figure 7b A study implementing an example according to the present invention is shown, comparing treated and untreated skulls.

[0046] Figure 7c A longitudinal analysis of the treatment effect over time is shown, based on an example implementation of the present invention.

[0047] Figure 7d A study illustrating an example implementation of the present invention, showing signal strength before and after processing, is presented.

[0048] Figure 7e The study, which is an example implementation of the present invention, illustrates the resolution of vascular density.

[0049] Figure 7f The results of a study performed according to an example implementation of the present invention, after seven days of EDTA treatment, are shown.

[0050] Figure 7g A study on neurovascular responses over time is shown, based on an example implementation of the invention disclosed herein.

[0051] Figure 8a The study, carried out according to an example implementation of the present invention, is shown, with power Doppler imaging results of skull without, with unprocessed skull, and with processed skull.

[0052] Figure 8b The study, carried out according to an example implementation of the present invention, is shown, with B-mode imaging results of no skull, with untreated skull, and with treated skull.

[0053] Figure 8c The study, which is an example implementation of the present invention, illustrates the acoustic propagation parameters of isolated human skull samples before and after processing. Detailed Implementation

[0054] To illustrate the technical content, structural features, objectives, and effects of the present invention in detail, the following description is provided in conjunction with the embodiments and accompanying drawings.

[0055] The following describes the transcranial ultrasound technique in further detail with reference to several embodiments. Unless otherwise stated, the acoustic transparency state referred to herein means that, after processing, the acoustic impedance, sound velocity, and frequency response of the skull are more closely matched to the propagation conditions of soft tissue or free field, thereby significantly reducing ultrasound transmission loss, reflection loss, phase distortion, and scattering effects, sufficient to support imaging and / or therapeutic operations on the internal tissues of the skull. The subject can be a mammal, preferably a human, or an experimental animal such as a mouse.

[0056] This embodiment discloses a transcranial ultrasound method for penetrating the skull, such as... Figure 1 This method can be implemented by the applicator 100, the ultrasonic transducer 110 and the controller 120 working together.

[0057] The applicator 100 is used to apply a decalcifying agent to the skull region of the subject, so that the skull in the target region is gradually decalcified and enters an acoustically transparent state.

[0058] The ultrasonic transducer 110 is used to transmit and receive sound wave signals to intracranial tissues through the skull after the skull has reached an acoustically transparent state.

[0059] The controller 120 is electrically connected to the ultrasonic transducer 110 and is used to control the transmission power, frequency, operating mode, receiving gain and data acquisition rhythm of the ultrasonic transducer 110, and to reconstruct and output the received acoustic signal.

[0060] The controller 120 can be further connected to the display 121 to display ultrasound images, and can also be connected to the user interface 122 so that the operator can adjust the power, frequency and imaging or treatment parameters of the transducer.

[0061] If necessary, the controller 120 may also include a computing module, a storage module, and a communication module to complete signal acquisition, beamforming, image reconstruction, treatment parameter control, and result output.

[0062] The specific execution flow of this method is as follows: S1. Apply a decalcifying agent to the target area of ​​the subject's skull until the skull beneath that area becomes acoustically transparent. It should be noted that the methods of applying the decalcifying agent include, but are not limited to, percutaneous application, injection, local delivery, or administration via other delivery systems, or a combination of multiple methods.

[0063] The skull poses a significant obstacle to transcranial ultrasound because the calcification in bone tissue causes its acoustic impedance, sound velocity, and frequency-dependent attenuation characteristics to differ markedly from those of soft tissue. When ultrasound waves pass through the skull, they undergo reflection, scattering, phase distortion, and energy loss, thus reducing the effective acoustic energy entering the cranium and deteriorating echo quality. By removing some calcium from the skull, the acoustic impedance and sound velocity of the skull can be made closer to those of the surrounding soft tissue, significantly reducing interface reflections caused by impedance mismatch and alleviating phase disturbances in the sound beam propagation path. This change does not rely on mechanical bone removal, thinning, or fenestration, but rather improves propagation conditions by adjusting the acoustic properties of the skull material itself. Therefore, while maintaining the integrity of the skull, an ultrasound path suitable for imaging or treatment can still be established.

[0064] S2. After the skull reaches an acoustically transparent state, use an ultrasonic transducer 110 to emit sound waves into the area and receive echo signals.

[0065] The sound waves can pass through the treated skull to reach the brain tissue, where they are scattered or reflected by blood vessels, nerve tissue, interface structures, or treatment target areas. The echoes then return to the ultrasound transducer 110 via the skull.

[0066] After receiving these echo signals, the controller 120 reconstructs an ultrasound image of the internal tissues of the head according to a preset algorithm; or in treatment mode, the controller 120 drives the ultrasound transducer 110 to emit therapeutic ultrasound waves to the acoustically transparent head with set parameters to perform neuromodulation, drug delivery, elastography, photoacoustic imaging-assisted detection, or therapeutic ultrasound operation.

[0067] Since the main sources of attenuation and distortion in the propagation path are suppressed, both the transmitted and received sound fields are closer to free field conditions, thereby improving the image resolution and treatment focusing accuracy.

[0068] In image acquisition mode, the controller 120 can proceed as follows: Figure 2 The process shown is for processing received signals, that is: First, multiple unfocused plane wave pulses with different emission angles are acquired, with the emission angles ranging from approximately -9° to +9°. As one possible implementation, 19 plane wave images can be acquired, and the number of angles can be increased or decreased according to the array aperture, target depth, and desired frame rate.

[0069] Subsequently, beamforming is performed on the echoes of each channel, and apodization is applied as needed, such as zero-mean apodization and second or third apodization, to suppress sidelobes and improve main lobe quality.

[0070] Then, the continuously acquired frames are combined into a spatiotemporal matrix. The number of frames acquired can be selected between approximately 100 and 3000 frames, depending on the observation target, signal-to-noise ratio, and time resolution requirements, for example, 1000 frames.

[0071] Finally, singular value decomposition (SVD) filtering is performed to separate tissue clutter from blood flow-related signals, thereby generating pixel-by-pixel power Doppler images to display intracranial blood flow and vascular distribution. The combination of multi-angle plane wave composite and SVD filtering allows for clearer vascular images even when penetrating the skull, and improves the detection capability of fine structures and functional activities.

[0072] like Figure 3 As shown, after removing calcium from the skull, measurable changes occur in the acoustic properties of the skull, manifested as increased transmission, reduced reflection, and lessened propagation distortion. These changes directly lead to objective technical benefits: the use of chelation or decalcification techniques on the skull reduces the acoustic mismatch between the skull and soft tissue, thereby decreasing frequency-dependent attenuation and scattering during ultrasound propagation, and improving the effective sound pressure and echo detectability after penetrating the skull. Since mechanical removal of the skull is not required, the procedure can be performed under skull conditions, providing a structural basis for repeat imaging, longitudinal observation, and post-treatment recovery.

[0073] In some alternative implementations, the ultrasonic transducer 110 can be a linear array transducer, a planar array transducer, or an array transducer capable of performing plane wave emission. The controller 120 can be implemented using dedicated hardware, a general-purpose processor executing software algorithms, or a combination of hardware and software, as long as it can perform signal acquisition, reconstruction, and control functions.

[0074] In another embodiment, based on the above-described embodiments, to make the acoustic transparency adjustment of the skull more widely applicable, the decalcifying agent applied to the target skull region includes one or more compounds capable of binding, complexing, chelating, dissolving, or promoting the removal of mineralized components with calcium ions in bone tissue. The compounds are selected from any one or more of aminopolycarboxylic acid chelating agents, organic acid decalcifying agents, phosphonic acid or phosphonate compounds, bisphosphonate compounds, citric acid and its salts, ethylenediaminetetraacetic acid and its salts, and ethylene glycol bis(β-aminoethyl ether)tetraacetic acid and its salts.

[0075] like Figure 1The applicator 100 can continuously supply the aforementioned agents to the target area, causing them to chelate or decalcify calcium ions in the skull. Both ethylenediaminetetraacetic acid (EDTA) and ethylene glycol bis(β-aminoethyl) ether can form stable complexes with calcium ions, thereby reducing the effective content of mineralized components in bone tissue. Citrates can participate in the decalcification process by complexing and modulating the local ionic environment. Bisphosphonates can also act as another type of feasible decalcification or bone mineral modulator to participate in the modulation of skull acoustic properties.

[0076] The above-mentioned agents can be used alone or in combination as needed to balance the rate of decalcification, the depth of action, and the subsequent recovery requirements.

[0077] In practical applications, the type of agent can be selected based on the target tissue depth, skull thickness, desired imaging frequency, and allowable processing time.

[0078] For applications primarily involving functional ultrasound imaging, chelating agents capable of forming relatively stable acoustically transparent windows should be prioritized. For applications primarily involving enhanced acoustic field transmission, the type and intensity of the agent can be adjusted according to the treatment frequency range.

[0079] Different drugs act on bone mineralization components through different pathways, but their ultimate goal is to shift the acoustic impedance and velocity of the skull towards the soft tissue side, thereby reducing interface reflection and propagation phase distortion. This allows the same ultrasound transducer to obtain higher intracranial echo signals at lower transmission power, or to achieve a larger effective therapeutic sound field coverage at the same transmission power.

[0080] In another embodiment, a co-application agent containing hydrogen peroxide may be applied to the target skull region simultaneously with the application of the decalcifying agent.

[0081] The co-administered agent can act synergistically with the decalcifying agent during step S1 above. Hydrogen peroxide can improve the local chemical environment, promote the decalcification process, and enable the agent to induce acoustic property changes more quickly in the target skull region.

[0082] For scenarios requiring a shorter acoustic transparency formation time, co-administration can bring the skull to a state suitable for imaging or treatment earlier, thereby reducing the waiting period between drug administration and ultrasound operation.

[0083] In some alternative implementations, the co-administered agent can be used in combination with ethylenediaminetetraacetic acid, ethylene glycol bis(β-aminoethyl) ether, citrate, or bisphosphonate, and the ratio can be adjusted according to the subject type, the area to be treated, and the desired transparency. The hydrogen peroxide is not limited to a single liquid component; it can also be co-dispersed with a chelating agent in the same drug delivery system. This allows for optimization of skull acoustic modulation efficiency solely through adjustments to the drug delivery system without altering the main structure of the ultrasound device.

[0084] In another embodiment, the decalcifying agent can be applied in liquid solution form or incorporated into a supporting medium. The supporting medium may include agarose or hydrogel.

[0085] like Figure 1 As shown, the applicator 100 can be configured as a reservoir-type applicator head, an adhesive medicated pad, a medicated gel carrier layer, or other structures capable of holding the medicated agent in the target skull region.

[0086] In step S1, the applicator 100 stably holds the agent in the area to be treated, ensuring continuous contact between the agent and the target area and creating a localized treatment environment. When a liquid solution is used, the agent can quickly cover the target skull area and establish mass transfer pathways, making it suitable for scenarios requiring rapid treatment.

[0087] When agarose or hydrogel is used as a support medium, the support medium can act as a drug carrier, enabling the drug to form a relatively stable reservoir in the target area, reducing drug loss and improving local coverage uniformity, while also making subsequent ultrasound coupling more stable.

[0088] Both agarose and hydrogels have high water content, which can play a role in drug storage, interfacial adhesion, and acoustic coupling. Since the supporting medium can reduce the interfacial air gap and maintain the continuity of the application area, it is beneficial to maintain more stable incident acoustic beam conditions during subsequent imaging or treatment.

[0089] In another embodiment, to further improve the efficiency of the decalcifying agent in targeting the skull region, a low-frequency ultrasound signal can be applied to the region after the agent is applied.

[0090] Additionally, the system may further include an application aid capable of emitting low-frequency ultrasound. This low-frequency ultrasound application process can be performed during or before / after step S1. Low-frequency ultrasound can improve the delivery efficiency of the drug in the application area through mechanical vibration, local microflow, and interface disturbance, allowing the drug to act more fully on the target skull region, thereby accelerating the establishment of acoustic transparency.

[0091] The application aid can be separate from the ultrasound transducer 110 used for imaging or treatment, or the same transducer structure can be used in different operating modes. For the former, the application aid can be used to promote penetration during the drug application phase, before switching to the ultrasound transducer 110 for imaging or treatment. For the latter, the controller 120 can switch the same transducer between the penetration-promoting mode and the imaging / treatment mode by changing the drive parameters. Since the penetration-promoting phase focuses primarily on drug efficacy, while the imaging or treatment phase focuses primarily on beam quality and energy control, the controller 120 can set different frequencies, duty cycles, and output power for the two phases respectively. This allows the skull to reach a state suitable for transcranial ultrasound propagation more quickly without increasing invasive steps and shortens the overall procedure.

[0092] In another embodiment, after image acquisition and / or ultrasound treatment, a recalcifying agent can be applied to the treated area to gradually restore the skull to its original acoustic properties.

[0093] The recalcification process can be performed after step S2 above. The aforementioned chelation or decalcification steps are used to temporarily alter the acoustic properties of the skull, while the recalcification step is used to restore the skull's mineralization state after imaging or treatment, thereby bringing the skull's acoustic impedance, sound velocity, and overall mechanical properties back to their pre-treatment state. This process makes the acoustic transparency reversible, suitable for longitudinal imaging, staged treatment, or repeated observation scenarios.

[0094] The realization of recalcification does not require a chemical pathway that is completely symmetrical with the aforementioned decalcification process, as long as the calcium source can be reintroduced into the treated area and local tissue recovery can be promoted.

[0095] In some alternative implementations, the recalcifying agent can be applied immediately after a single ultrasound procedure or applied uniformly after multiple imaging or treatment cycles. For scenarios requiring repeated imaging within a short period, recalcification can be performed after longitudinal observation has ceased; for scenarios where tissue recovery is more important, it can be performed as soon as possible after each ultrasound procedure to reduce the duration of acoustic transparency in the treated area.

[0096] Furthermore, calcium gluconate may be used as the recalcifying agent, and a tissue protective layer containing agarose or hydrogel may be applied before and / or after recalcification.

[0097] like Figure 7a and Figure 7b As shown, histological analysis of the treated tissue and comparison with treated and untreated skulls allows observation of structural changes in the treated area. Figure 7cAs shown, longitudinal analysis of the treatment effect over time can evaluate the acoustic transparency state and its recovery process. Calcium gluconate can provide a usable calcium source for the treated area, and combined with local environmental regulation, it can gradually restore the decalcified area. The tissue protective layer formed by agarose or hydrogel can cover the target skull area, which can isolate and buffer the surrounding tissues. It can limit the diffusion of the agent to non-target areas during decalcification and provide a stable and moist environment during recalcification, thus promoting local recovery.

[0098] like Figure 7d and Figure 7e As shown, a graph comparing the signal intensity and resolved blood vessel density before and after processing reveals that the ultrasound signal is enhanced and the number of resolvable blood vessels increases after processing.

[0099] like Figure 7f As shown, in the results after seven days of treatment with ethylenediaminetetraacetic acid, the treated area still maintained effective ultrasound observation conditions.

[0100] like Figure 7g As shown, the neurovascular response over time indicates that signal intensity and vascular density can recover to baseline levels by day 14, demonstrating that the resulting acoustic transparency is reversible. The combined approach of calcium gluconate recalcification and a tissue protective layer allows the skull to gradually recover after transcranial ultrasound imaging or treatment, preserving the temporary function of the ultrasound window while avoiding the persistent effects of long-term alterations to the skull's acoustic properties. This makes it more suitable for longitudinal studies and repeated procedures.

[0101] Furthermore, based on the above-described embodiments, functional ultrasound imaging of the processed skull can be used. For example... Figures 4a to 4c As shown, functional ultrasound images of the unprocessed skull, processed skull, and skull-free conditions are presented respectively. In the unprocessed skull condition, due to the strong attenuation and scattering effect of the skull on the sound beam, the intracranial blood flow-related signal is weak, and the number of resolvable small blood vessels in the image is limited. In the processed skull condition, the sound beam penetration is enhanced, the intracranial blood flow signal is significantly enhanced, and the image contrast and spatial details are improved. The skull-free condition serves as an approximate free-field reference and can be used to evaluate the degree of approximation between the processed skull and ideal propagation conditions.

[0102] like Figure 4d and Figure 4e As shown, analysis of the normalized signal intensity and vascular density of processed and unprocessed skulls reveals that the processed skull significantly improves the detection of ultrasound signals and vascular resolution.

[0103] like Figure 4fAs shown, under the processed skull conditions, vascular density increased by approximately 11-fold, and vessels as small as approximately 19 micrometers could be resolved, achieving spatial resolution comparable to the skull-free conditions. This result demonstrates that by making the skull acoustically transparent, near-skull-free functional ultrasound imaging can be achieved without removing the skull. Further combining this with the overall results disclosed in the disclosure document, ultrasound transmission can be restored to approximately 92% to 94% of the free field, with signal intensity obtained through the skull increased by approximately 13-fold compared to unprocessed conditions, achieving an imaging resolution on the order of approximately 20 micrometers. Since ultrasound signals related to blood flow, blood volume, and neural activity can penetrate the skull with higher fidelity, this method can be used for continuous observation of functional activities in the deep brain and across a wide field of view.

[0104] Furthermore, to verify that the processed skull not only improves static structural imaging but also supports the detection of stimulus-induced brain functional activity, a stimulus-response experiment can be performed in functional ultrasound mode.

[0105] like Figure 5a As shown, a detection process for stimulation-induced brain activation can be constructed. After a subject (such as a mouse) receives external stimulation, hemodynamic changes in the brain region are obtained by ultrasound acquisition of the processed skull.

[0106] like Figure 5b and Figure 5c As shown, a stimulus-evoked response can be detected in the contralateral primary somatosensory cortex, indicating that the treated acoustic transparent skull can support the localization of functional activities in specific cortical areas.

[0107] like Figure 5d As shown, corresponding activation can also be observed in the contralateral ventroposteromedial nucleus of the thalamus, indicating that this method is not only suitable for detection at the cortical level, but can also achieve functional imaging of deeper brain regions.

[0108] like Figure 5e As shown, pixel-by-pixel Pearson correlation analysis between the fUSI signal and the stimulation time process can yield a correlation map reflecting the degree of brain region response. This analysis method can link the stimulation time series with pixel-level blood flow changes, thereby improving the reliability of functional area determination from a temporal perspective.

[0109] like Figure 5f As shown, the S1BF response is reproducible in the repeated stimulus test.

[0110] like Figure 5g As shown, the correlation matrix can further reflect the consistency of responses between different trials and different regions.

[0111] This demonstrates that the functional ultrasound system processing the skull using the above method can not only obtain high spatial resolution images but also achieve temporally correlated brain function mapping. For scenarios requiring research on neurovascular coupling, sensory pathway activation, or brain region network activity, this method provides a feasible approach for high spatiotemporal resolution functional imaging under skull-crossing conditions.

[0112] On the other hand, the processed skull can also be used for B-mode imaging and acoustic performance calibration.

[0113] like Figure 6a As shown, ultrasound imaging can be performed in an online phantom to evaluate the imaging effect under different skull processing conditions.

[0114] like Figure 6b As shown, the B-mode imaging results can be obtained.

[0115] like Figure 6c As shown, the spatial resolution of B-mode imaging can be further evaluated. Under phantom conditions, the imaging target can have known size and reflectivity, which facilitates quantitative comparison of image axial resolution, lateral resolution, and contrast.

[0116] By conducting parallel tests on untreated skulls, treated skulls, and skull-free conditions, the extent to which acoustic transparency of the skull improves conventional structural imaging can be clearly determined.

[0117] like Figure 6d As shown, the sound pressure field distribution can be compared under conditions of untreated skull, treated skull, and skullless conditions.

[0118] like Figure 6e As shown, the relationship between sound pressure and driving voltage can be analyzed.

[0119] like Figure 6f As shown, the relationship between amplitude and frequency can be analyzed.

[0120] like Figure 6g As shown, this can comprehensively characterize the influence of the skull on ultrasound propagation.

[0121] The above tests demonstrate that the attenuation, phase distortion, and energy coupling relationships along the propagation path underwent systematic changes before and after skull treatment. In particular, under the condition of treated skull, the sound pressure field is closer to the reference condition without skull, indicating that the treated skull no longer forms a significant barrier to sound waves as the untreated skull.

[0122] To further characterize acoustic changes at the material level, sound velocity and acoustic impedance can be tested on skull samples.

[0123] like Figure 6hAs shown, the sound velocity of the untreated skull can be measured and compared with the processed result. The sound velocity can be calculated based on the time-of-flight delay ΔTOF introduced by the skull sample relative to the water-only control, combined with the sound velocity in water, which is usually taken as 1480 m / s. The transmitted signal is then normalized to the skull-free condition after performing a fast Fourier transform to obtain the frequency response curve.

[0124] like Figure 6i As shown, the influence on acoustic impedance can be analyzed and processed. In the pulse echo test, the linear array imaging probe can be configured as a single-element mode, with each element sequentially emitting ultrasonic pulses and receiving corresponding reflected echoes. The reflection signals of the untreated skull, the acoustically transparent skull, and the flat quartz reference plate are collected respectively, and the reflection pressure amplitude Vr of the skull sample and the reflection pressure amplitude Vi of the reference reflector are recorded. The acoustic impedance of the skull is further calculated using the reflection coefficient R=Vr / Vi, and the calculation relationship is Z_skull=Z_water×(1+R) / (1-R).

[0125] Because the acoustic velocity and acoustic impedance of the processed skull change towards the soft tissue side, the reflection of ultrasound waves at the interface is reduced and the penetration efficiency is improved. This is the material basis for the effective implementation of subsequent imaging and treatment.

[0126] Based on the above embodiments, the processed skull can also be used for transmission evaluation and imaging feasibility verification under the condition of an isolated human skull sample. In this embodiment, the object being processed is an isolated human skull sample, which is placed between the ultrasound transducer and the object under test to simulate the transcranial transmission path under the condition of a thicker skull. The object under test can be a phantom, or biological tissue located below the isolated human skull sample, or an in vivo preparation, thereby distinguishing and characterizing "modulation of the skull barrier" from "imaging verification of the target below," thus avoiding confusion between the skull sample itself and the object being imaged.

[0127] In one validation method, an isolated human skull sample is placed between a transducer and a phantom to evaluate penetration capability and imaging clarity under conventional B-mode imaging conditions. By extending the chelation treatment time and combining it with ultrasound-assisted penetration, the isolated human skull sample can be gradually made acoustically transparent. Before treatment, the isolated human skull strongly reflects, refracts, and scatters incident sound waves, resulting in insufficient effective acoustic energy reaching the phantom, making the phantom outline and internal structure difficult to discern. After treatment, due to the reduction in calcium in the skull, the bulk modulus decreases, causing the acoustic impedance and sound velocity to shift towards the soft tissue side. The acoustic mismatch at the water-skull-tissue interface is reduced, allowing more incident sound energy to penetrate the skull and form effective focusing and echo reception at the target location. Based on this change in propagation conditions, the phantom, which was previously obscured by the skull, can be visualized at a greater depth, thus verifying that this method also has an anti-permeability effect on thicker bony barriers.

[0128] In another validation approach, an ex vivo human skull sample can be placed between an ultrasound probe and biological tissue to assess the power Doppler imaging and B-mode imaging capabilities across the ex vivo human skull.

[0129] like Figure 8a As shown, power Doppler imaging can be compared under three conditions: no skull, presence of unprocessed excised human skull, and presence of processed excised human skull. Under the unprocessed excised human skull condition, due to significant propagation loss, the effective ultrasound energy penetrating to underlying tissues is significantly insufficient, resulting in severe echo signal attenuation and difficulty in stably extracting blood flow-related information. After processing, the penetration ability is enhanced, the echo signal is restored, and power Doppler images significantly superior to those under the unprocessed condition can be obtained. These results indicate that the acoustic transparency processing not only alters the acoustic properties of the excised human skull sample itself but also improves blood flow imaging conditions across the skull sample.

[0130] Furthermore, such as Figure 8b As shown, when comparing B-mode imaging under the same three conditions, the transmission through the isolated human skull was enhanced by approximately 32.8 times after processing, and deep structures that were previously shielded by the skull, such as the hippocampus, could be visualized. This result indicates that the processed isolated human skull sample significantly reduces the occlusion effect on structural imaging, allowing the incident sound beam to retain sufficient energy and low wavefront distortion after passing through the bony barrier, thus forming identifiable structural echoes in the underlying tissues. Since this validation was performed in the presence of an isolated human skull sample, it reflects the method's adaptability to the scale and structural complexity of the human skull, rather than simply extrapolating from small animal skull conditions.

[0131] like Figure 8c As shown, a comparison of the propagation parameters of isolated human skull samples before and after treatment reveals that the sound velocity decreased from 2793±29 m / s to 1540±32 m / s after treatment, and the acoustic impedance decreased from 5.18±0.11 MRayl to 2.10±0.07 MRayl. Human skulls typically have greater thickness, more pronounced inner and outer plates and diploic structures, and stronger spatial heterogeneity, making them more prone to enhanced reflection, decreased transmission, and beam distortion in the untreated state. After chelation treatment, the skull material parameters approach the range of parameters of the surrounding soft tissue and coupling medium, reducing the interface reflection coefficient, decreasing the propagation delay, and increasing the effective energy entering the intracranial direction. This allows the receiver to obtain a stronger echo signal or form a more usable sound field distribution in therapeutic applications.

[0132] Therefore, validation under in vitro human skull sample conditions demonstrates that the mechanism of action of the method is not limited to thin skulls or single animal models, but rather improves transosseous ultrasound propagation conditions by adjusting the material parameters of the bony barrier itself. This mechanism can provide an experimental basis for subsequent structural imaging, blood flow observation, functional ultrasound detection, and therapeutic energy delivery under human skull conditions, and provide a basis for parameter optimization, processing time setting, and safety evaluation in preclinical translation.

[0133] In another preferred embodiment, the processed skull can be used for ultrasound procedures other than functional ultrasound and mode B imaging.

[0134] like Figure 1 As shown, the ultrasound transducer 110 can operate in neuromodulation mode, drug delivery mode, elastography mode, photoacoustic imaging-assisted mode, and therapeutic ultrasound mode under the control of the controller 120.

[0135] For the neural modulation mode, modulated sound beams can be output to selected brain regions through the processed skull, so that local neural tissues are subjected to controllable mechanical stimulation.

[0136] For drug delivery modalities, microbubble-assisted methods can be used to selectively open the blood-brain barrier at the target location using ultrasound, thereby delivering drugs to brain tissue.

[0137] For elastography, the mechanical characteristics of brain tissue can be assessed while improving beam penetration and echo reception quality.

[0138] For photoacoustic imaging-assisted mode, optical excitation can be combined with ultrasonic reception to improve the detection capability of deep structures.

[0139] In therapeutic ultrasound mode, therapeutic energy can be delivered to the target area through the processed skull.

[0140] The common premise of the above-mentioned different working modes is that the skull, after chelation or decalcification, no longer constitutes a significant acoustic barrier, or its barrier effect is significantly weakened, thereby improving the spatial distribution, energy density, and fidelity of the emitted sound beam and the echo or response signal. The controller 120 can set the emitted pulse length, repetition frequency, operating frequency, receiving gain, and post-processing algorithm according to different modes, and switch modes through the user interface 124. For scenarios that require simultaneous observation and intervention, imaging can be performed first to determine the target area, and then the treatment or modulation mode can be switched to complete the intervention, thus forming a complete closed loop of "acoustic transparency of the skull - transcranial imaging localization - transcranial treatment or modulation - recalcification recovery".

[0141] In summary, this invention discloses a transcranial ultrasound method for penetrating the skull, and its complete transcranial ultrasound implementation process is as follows: First, a decalcifying agent is applied to the target area of ​​the subject's skull using applicator 100. The agent can be ethylenediaminetetraacetic acid (EDTA), ethylene glycol bis(β-aminoethyl) ether, citrate, or bisphosphonate, and hydrogen peroxide can be added as a co-application agent if necessary. The agent can be in liquid solution form or incorporated into agarose or hydrogel to form a supporting medium. If necessary, a low-frequency ultrasound applicator can be used to further improve the efficiency of the agent's action, making the skull beneath the target area acoustically transparent.

[0142] Subsequently, the ultrasound transducer 110 transmits and receives sound wave signals to intracranial tissues via the skull, and the controller 120 performs processing steps such as plane wave acquisition, beamforming, spatiotemporal matrix construction, and SVD filtering to acquire power Doppler images, B-mode images, or other types of ultrasound images; or in treatment mode, it outputs therapeutic ultrasound waves to the target brain region to perform neuromodulation, drug delivery, elastography, photoacoustic imaging-assisted detection, or therapeutic ultrasound operations.

[0143] After imaging or treatment, recalcifying agents such as calcium gluconate can be applied to the treated area, and agarose or hydrogel tissue protective layers can be applied before and after recalcification to gradually restore the original acoustic properties of the skull.

[0144] Through the above process, the acoustic impedance and velocity of the skull can be temporarily adjusted to a state more conducive to ultrasound propagation, thus freeing transcranial ultrasound from the significant limitations imposed by the traditional bony barrier. This results in a transcranial ultrasound technique that combines imaging, treatment, reversible recovery, and longitudinal observation while penetrating the skull.

[0145] In another preferred embodiment of the present invention, a transcranial ultrasound system for penetrating the skull is also disclosed, which operates based on the transcranial ultrasound method described in the above embodiments.

[0146] The above-disclosed embodiments are merely preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. Therefore, any equivalent variations made in accordance with the claims of the present invention are still within the scope of the present invention.

Claims

1. A transcranial ultrasound method for penetrating the skull, characterized in that, include: A decalcifying agent was applied to the skull region of the subject to remove calcium from the skull and make the skull acoustically transparent. Based on the ultrasonic transducer to transmit and receive sound wave signals to the head in an acoustically transparent state; Based on the received acoustic signal, acquire an ultrasound image of the internal tissues of the head; and / or, The ultrasonic transducer emits ultrasonic waves to the head, which is in an acoustically transparent state, to perform ultrasonic therapy.

2. The transcranial ultrasound method according to claim 1, characterized in that, The decalcifying agent includes one or more compounds capable of binding, complexing, chelating, dissolving, or promoting the removal of mineralized components with calcium ions in bone tissue. The compounds are selected from any one or more of aminopolycarboxylic acid chelating agents, organic acid decalcifying agents, phosphonic acid or phosphonate compounds, bisphosphonate compounds, citric acid and its salts, ethylenediaminetetraacetic acid and its salts, and ethylene glycol bis(β-aminoethyl ether)tetraacetic acid and its salts.

3. The transcranial ultrasound method according to claim 1, characterized in that, When the decalcifying agent is applied to the skull, a co-application agent containing hydrogen peroxide (H2O2) is also applied to the skull region.

4. The transcranial ultrasound method according to claim 1, characterized in that, The decalcifying agent is applied in the form of a liquid solution or incorporated into a supporting medium containing agarose or hydrogel.

5. The transcranial ultrasound method according to claim 1, characterized in that, After applying the decalcifying agent to the skull region, a low-frequency ultrasound signal is applied to the skull region where the decalcifying agent has been applied to accelerate the penetration of the decalcifying agent.

6. The transcranial ultrasound method according to claim 1, characterized in that, After receiving the acoustic signal, a recalcifying agent is also applied to the skull region to restore the acoustic properties of the skull.

7. The transcranial ultrasound method according to claim 6, characterized in that, The recalcifying agent includes calcium gluconate.

8. The transcranial ultrasound method according to claim 6, characterized in that, Before and / or after the application of the recalcifying agent, a tissue protective layer comprising agarose or hydrogel is applied to the skull region.

9. The transcranial ultrasound method according to claim 1, characterized in that, The ultrasound transducer is configured to perform any of the following operations: functional ultrasound imaging, B-mode imaging, neuromodulation, drug delivery, elastography, photoacoustic imaging, and therapeutic ultrasound.

10. A transcranial ultrasound system for penetrating the skull, characterized in that, The transcranial ultrasound system operates based on the transcranial ultrasound method according to any one of claims 1 to 9.

Images