WO2025129148A1 - Wearable device for ultrasound-brain interfacing methods - Google Patents

Abstract

A wearable device to administer focused ultrasound (FUS) to the brain of a subject, and systems that include the wearable device.

Description

TITLE OF THE INVENTION

WEARABLE DEVICE FOR ULTRASOUND-BRAIN INTERFACING METHODS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application Serial No. 63/609,561 filed on December 13, 2023, which is incorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under EB030102 awarded by the National Institutes of Health. The government has certain rights in the invention.

MATERIAL INCORPORATED-BY-REFERENCE

[0003] Not applicable.

FIELD OF THE INVENTION

[0004] The present disclosure generally relates to wearable sonobiopsy devices, methods, and systems for targeted delivery of focused ultrasound to the BBB to facilitate liquid biopsy of brain biomarkers.

BACKGROUND OF THE INVENTION

[0005] Approximately 700,000 patients in the United States have a primary central nervous system tumor, and nearly 200,000 new cases of brain metastases are diagnosed annually. Brain tumors severely threaten human health due to their fast development and poor prognosis. For example, glioblastoma (GBM), the most common primary brain tumor in adults, has a median survival time of ~1 year. The current standard of care relies on MRI and CT to identify suspicious tumor lesions, followed by surgical resection or stereotactic biopsy for histological confirmation. However, invasive brain tumor biopsy carries a 5-7% risk of major morbidity and may not be feasible for medically inoperable patients or those with tumors in surgically inaccessible locations. Repeated tissue biopsies to assess treatment response and recurrence are not feasible due to the increased risk of complications and morbidity. These challenges limit the timely diagnosis and selection of treatment options, hinder a better understanding of the disease, and impair the development of effective treatment approaches.

[0006] Blood-based liquid biopsies provide noninvasive, rapid, and cost-effective methods for obtaining crucial information about tumors, showing promise for the diagnosis, molecular characterization, and monitoring of brain tumors by detecting circulating tumor-derived biomarkers (e.g., DNA, RNA, and proteins shed by tumor cells). Blood-based liquid biopsy-guided personalized therapy has entered clinical practice to treat several cancers; however, extending its application to brain cancer remains challenging. Three main challenges hinder the application of blood-based liquid biopsies for brain tumor diagnosis. First, some studies reported the ability to detect circulating brain tumor biomarkers, but these biomarkers generally had low abundance in a limited number of patients, which complicates routine clinical application. This is primarily due to the bloodbrain barrier (BBB), which restricts the release of brain tumor biomarkers into the peripheral circulation, resulting in extremely low concentrations of circulating tumor biomarkers. Current research focuses on developing more sensitive biomarker detection techniques, such as optimized next-generation sequencing and advanced spectroscopy, but no strategy can overcome the BBB and increase circulating tumor biomarker concentrations. Second, conventional blood-based liquid biopsy methods do not provide information on tumor location. Third, many tumor biomarkers have short half-lives in blood, e.g., circulating tumor DNA’s half-life is 16 min to 2.5 h.

[0007] Low-intensity focused ultrasound (FUS) combined with intravenously injected microbubbles can achieve noninvasive, spatially targeted, and reversible BBB opening, referred to as FUS-BBBO. FUS noninvasively penetrates the skull and focuses on a small focal region. Microbubbles, used in the clinic as ultrasound contrast agents, are administered by intravenous injection and are subsequently confined to the vasculature due to their relatively large sizes (1-10 pm). Microbubbles amplify and localize FUS-mediated mechanical effects on the vasculature through FUS-induced cavitation (i.e. , microbubble expansion, contraction, and collapse). Microbubble cavitation generates mechanical forces on the vasculature and increases the BBB permeability. The opened BBB usually closes within several hours. This technique has been established for the delivery of therapeutic agents from blood circulation to the brain, and its feasibility and safety have been established in patients with various brain diseases, including GBM, Alzheimer’s disease, and Parkinson’s disease.

SUMMARY OF THE INVENTION

[0008] Among the various aspects of the present disclosure is the provision of a wearable device to administer focused ultrasound (FUS) to the brain of a subject, and systems that include the wearable device.

[0009] In one aspect, a wearable mounting device for facilitating a focused ultrasound procedure in a patient is disclosed that includes a cap custom-fitted to a shape and size of at least a portion of a head of the patient. The cap includes an outer surface and a contact surface opposite the outer surface, wherein the contact surface comprises a contact contour conforming with a corresponding outer contour of the at least a portion of the head of the patient; at least one circular opening defined through the cap, each opening configured to receive and retain at least one ultrasound probe at a predetermined position and orientation relative to the head of the patient; at least one attachment fitting, each attachment fitting comprising a rim outwardly protruding from the outer surface of the cap and attached at a perimeter of each opening, each attachment fitting further comprising a locking element to retain the at least one ultrasound probe in the at a predetermined position and orientation; at least one locking plate, each locking plate comprising a disc sized to fit within each opening, wherein each disc further comprises an insertion element formed on at least a portion of a perimeter of the disc, wherein each locking plate is configured to insert over the ultrasound probe positioned within each opening and lock in place by interaction of the attachment element with the locking element of the attachment fitting. In some aspects, the device further includes a fastener attached to the outer surface of the rim in at least two positions, wherein the fastener is configured to hold the cap securely in place on the head of the patient. . In some aspects, the fastener comprises a chin strap. . In some aspects, the device further includes at least one additional opening formed through the cap, wherein each additional opening is configured to provide an inlet to facilitate the introduction of an acoustic coupling medium between the inner surface of the cap and an underlying portion of the head of the patient; a fiduciary marker to confirm that the cap is positioned correctly; and any combination thereof. In some aspects, the device further includes at least two alignment fittings formed within an inner surface of the collar and extending to an exposed surface of the collar, wherein each alignment fitting is configured to receive a locking plate alignment tab projecting radially outward from a perimeter of the locking plate and a probe alignment tab projecting radially outward from the ultrasound probe, wherein the at least two alignment fittings are configured to align the locking plate and the ultrasound probe in the predetermined position and orientation when positioned within the attachment fitting. In some aspects, the locking element comprises at least one radial set screw advanced though a threaded bore defined through the rim of the attachment fitting toward the center of the opening and the locking element comprises an indentation within at least a portion of the perimeter of the locking plate, wherein the indentation is configured to receive a tip of the set screw advanced into the opening through the threaded bore; the locking element comprises a threaded fitting formed within an inner surface of the collar and the circumference of the locking plate comprises circumferential threads configured to thread into the threaded; or the locking element comprises at least two spiral channels formed within the inner surface of the collar, each spiral channel extending circumferentially from one alignment fitting and ending, wherein the at least two spiral channels are configured to receive at least alignment tabs of the locking plate or ultrasound probe when twisted into the collar of the attachment fitting. In some aspects, the inner surface of the cap is contoured to match the corresponding outer contour of the head of the patient as measured using at imaging method selected from MR imaging methods, CT imaging methods, 3D scanning methods, and 3D optical scanning methods. In some aspects, the medical imaging method is MR imaging method, wherein the use of MR imaging method ensures that an ultrasound coordinate system of the at least one ultrasound probe is registered to an MR coordinate system. In some aspects, the focused ultrasound procedure is selected from focused ultrasound-aided opening of the brain-blood barrier for sonobiopsy or delivery of therapeutic agents to a brain of the patient, passive cavitation imaging, ultrasound imaging, and any combination thereof.

[0010] In another aspect, a system for facilitating a focused ultrasound procedure in a patient is disclosed that includes a cap custom-fitted to a shape and size of at least a portion of a head of the patient and at least one ultrasound probe mounted to the cap. The cap includes an outer surface and a contact surface opposite the outer surface, wherein the contact surface comprises a contact contour conforming with a corresponding outer contour of the at least a portion of the head of the patient; at least one circular opening defined through the cap, each opening configured to receive and retain at least one ultrasound probe at a predetermined position and orientation relative to the head of the patient; at least one attachment fitting, each attachment fitting comprising a rim outwardly protruding from the outer surface of the cap and attached at a perimeter of each opening, each attachment fitting further comprising a locking element to retain the at least one ultrasound probe in the at a predetermined position and orientation; at least one locking plate, each locking plate comprising a disc sized to fit within each opening, wherein each disc further comprises an insertion element formed on at least a portion of a perimeter of the disc, wherein each locking plate is configured to insert over the ultrasound probe positioned within each opening and lock in place by interaction of the attachment element with the locking element of the attachment fitting, a transducer housing unit configured to contain the ultrasound transducer. Each ultrasound probe is configured to deliver ultrasound energy to a predetermined region of interest within a brain of the subject, wherein each ultrasound probe comprises an ultrasound transducer selected from a focused ultrasound transducer, an unfocused ultrasound transducer, and an unfocused ultrasound transducer acoustically coupled in series with an acoustic lens configured to focus the ultrasound energy to the predetermined region of interest. The ultrasound probe is positioned within the opening of the attachment fitting over an underlying portion of the head and locked into place at the predetermined position and orientation by the locking plate inserted and locked into the opening of the attachment fitting over the ultrasound probe. In some aspects, the device further includes a fastener attached to the outer surface of the rim in at least two positions, wherein the fastener is configured to hold the cap securely in place on the head of the patient. In some aspects, the fastener comprises a chin strap. In some aspects, the device further includes at least one additional opening formed through the cap, wherein each additional opening is configured to provide an inlet to facilitate the introduction of an acoustic coupling medium between the inner surface of the cap and an underlying portion of the head of the patient; a fiduciary marker to confirm that the cap is positioned correctly; and any combination thereof. In some aspects, the device further includes at least two alignment fittings formed within an inner surface of the collar and extending to an exposed surface of the collar, wherein each alignment fitting is configured to receive a locking plate alignment tab projecting radially outward from a perimeter of the locking plate and a probe alignment tab projecting radially outward from the ultrasound probe, wherein the at least two alignment fittings are configured to align the locking plate and the ultrasound probe in the predetermined position and orientation when positioned within the attachment fitting. In some aspects, the locking element comprises at least one radial set screw advanced though a threaded bore defined through the rim of the attachment fitting toward the center of the opening and the locking element comprises an indentation within at least a portion of the perimeter of the locking plate, wherein the indentation is configured to receive a tip of the set screw advanced into the opening through the threaded bore; the locking element comprises a threaded fitting formed within an inner surface of the collar and the circumference of the locking plate comprises circumferential threads configured to thread into the threaded; or the locking element comprises at least two spiral channels formed within the inner surface of the collar, each spiral channel extending circumferentially from one alignment fitting and ending, wherein the at least two spiral channels are configured to receive at least alignment tabs of the locking plate or ultrasound probe when twisted into the collar of the attachment fitting. In some aspects, the inner surface of the cap is contoured to match the corresponding outer contour of the head of the patient as measured using at imaging method selected from MR imaging methods, CT imaging methods, 3D scanning methods, and 3D optical scanning methods. In some aspects, the medical imaging method is MR imaging method, wherein the use of MR imaging method ensures that an ultrasound coordinate system of the at least one ultrasound probe is registered to an MR coordinate system. In some aspects, the focused ultrasound procedure is selected from focused ultrasound-aided opening of the brain-blood barrier for sonobiopsy or delivery of therapeutic agents to a brain of the patient, passive cavitation imaging, ultrasound imaging, and any combination thereof. In some aspects, the device further includes an amount of an acoustic coupling medium between the ultrasound probe and the head of the subject, wherein the acoustic coupling medium comprises mineral oil. In some aspects, the ultrasound probe comprises a flat transducer coupled to the acoustic lens, the acoustic lens comprising an acoustically transmissive material configured to spatially modulate the ultrasound energy produced by the flat transducer to produce a uniform ultrasound beam through the predetermined region of interest. In some aspects, the acoustic lens is selected from an Airy lens and a Fresnel lens. In some aspects, the acoustic lens comprises a first surface contacting the flat transducer and a second surface contacting the underlying portion of the head of the patient, wherein the first surface defines a plurality of phase modulation features configured to focus the acoustic beam produced by the flat transducer into a uniform ultrasound beam through the predetermined region of interest of the patient. In some aspects, the second surface of the acoustic lens defines a plurality of additional phase modulation features configured to compensate for non-homogeneous tissue types present in the underlying portion of the head of the patient between the head surface and the predetermined region of interest, wherein the non-homogeneous tissue types are selected from skin tissue, bone tissues, circulatory vessels, grey matter, white matter, cerebrospinal fluid, and any combination thereof. In some aspects, the ultrasound probe further comprises a passive cavitation detector (PCD). In some aspects, the ultrasound probe further includes at least one port configured to electrically connect the ultrasound transducer to at least one additional system selected from a data acquisition (DAQ) system, a detector system, and an ultrasound transducer driving system. In some aspects, the device further includes at least one of the additional systems operatively coupled to the at least one ports of the ultrasound probe.

[0011] In another aspect, a method to perform a sonobiopsy on a subject is disclosed. The method includes providing the focused ultrasound (FUS) system described above, placing the head device of the focused ultrasound (FUS) system onto the head of the subject; continuously infusing microbubbles into the subject using a syringe pump, performing closed-loop feedback control FUS sonication using the FUS transducer; and collecting a first blood sample from the subject before sonication and at least one additional blood sample at least once during or after sonication. In some aspects, the method further includes performing an assay on the first blood sample and the at least one additional blood sample to quantify at least one disease biomarker. In some aspects, the microbubbles are Definity microbubbles. In some aspects, the method further includes applying an acoustic coupling medium to the head of the subject. In some aspects, the acoustic coupling medium is hydrophobic mineral oil.

[0012] In another aspect, a method to enhance drug delivery to the brain of a subject is disclosed that includes providing a focused ultrasound (FUS) system as described above, placing the head device of the focused ultrasound (FUS) system onto the subject, continuously infusing microbubbles into the subject using a syringe pump, performing closed-loop feedback control FUS sonication using the FUS transducer, and administering the drug to the subject before, during, or after sonication. In some aspects, the drug is administered by infusion. In some aspects, the microbubbles are Definity microbubbles. In some aspects, the method further includes applying an acoustic coupling medium to the head of the subject. In some aspects, the acoustic coupling medium is hydrophobic mineral oil.

[0013] Other objects and features will be in part apparent and in part pointed out hereinafter.

DESCRIPTION OF THE DRAWINGS

[0014] Those of skill in the art will understand that the drawings, described below, are for illustrative purposes only. The drawings are not intended to limit the scope of the present teachings in any way.

[0015] FIG. 1 is a block diagram schematically illustrating a system in accordance with one aspect of the disclosure.

[0016] FIG. 2 is a block diagram schematically illustrating a computing device in accordance with one aspect of the disclosure.

[0017] FIG. 3 is a block diagram schematically illustrating a remote or user computing device in accordance with one aspect of the disclosure.

[0018] FIG. 4 is a block diagram schematically illustrating a server system in accordance with one aspect of the disclosure.

[0019] FIG. 5A is an image of a glioblastoma (GMB) patient undergoing a sonobiopsy procedure. The current sonobiopsy procedure includes a singleelement focused ultrasound (FUS) transducer is coupled to a neuronavigation probe with an adaptor. The FUS transducer is positioned using robotic or mechanical arms.

[0020] FIG. 5B is a graph of stable cavitation (orange) and inertial cavitation (blue) levels measured during FUS sonication for monitoring the sonication procedure (FIG. 5A).

[0021] FIG. 5C is a set of graphs of plasma biomarkers from GMB patients who underwent a sonobiopsy. The left graph shows the concentration of cell-free DNA (cfDNA) before and after the sonobiopsy. The right graph shows the patient-specific tumor variants detected using a personalized tumor-informed circulating tumor DNA assay which were significantly increased when comparing post-FUS time points with pre-FUS.

[0022] FIG. 6A is an image of a prototype sonocap which use a CT scan for 3-D reconstruction of the sonocap.

[0023] FIG. 6B is an image of a sonocap on a human subject which used an MRI scan for 3D reconstruction of the sonocap.

[0024] FIG. 6C is a set of images of the 3D reconstruction of the sonocap for testing the couplant seal (left) and acoustic passive cavitation detector (PCD; right).

[0025] FIG. 7A is a set of MRI images of a human skull at multiple plans, used to generate a patient specific 3D-printed cap.

[0026] FIG. 7B is an image of a patient specific mask in Meshmixer software.

[0027] FIG. 7C is an image of a patient specific cap with the PCD. [0028] FIG. 8A is an illustration of the sonocap which is a patient-specific 3D- printed cap 102 to guide the position of the FUS transducer 110. The cap can be tailored to an individual patient’s head shape and size based on MRI an CT images for precise registration of patient’s head in the physical space with the virtual imaging space. The cap has an opening 116 at the accurate location required to guide FUS transducer 110 positioning without requiring complex and bulky robotic/mechanical arms. The cap can be secured by a faster like a chin strap 103.

[0029] FIG. 8B is a schematic of the sonocap with consists of four main components. An acoustic coupling medium 114, an ultrasound transducer lens 110 (such as an Airy beam lens), a transducer housing unit 108, and a locking plate 106 which locks into the raised rim 118 locking element 119 of the opening 116 to secure the transducer 110 and other components within the transducer housing unit 108. The transducer housing unit 108 has ports 125 to connect the ultrasound transducer 110 to systems. The opening 116 is positioned on the cap 102 such that the transducer 110 is perpendicular to the acoustic axis 112, which is the closes position to a selected target.

[0030] FIG. 8C is a line drawing of the sonocap 102 which consists of the opening 116, the raised rim 118, the locking element on the raised rim 119, the ultrasound transducer 110, the transducer housing unit 108, the connection ports 124 on the transducer housing unit, and the locking plate 106 which secure into the locking element of the raised rim.

[0031 ] FIG. 8D is a schematic of a cross section of the cap opening 116 with the FUS transducer 110. The FUS transducer is made by coupling an Airy beam lens 110 with a flat piezoelectric lead zirconate titanate (PZT) element 122, and a passive cavitation detector (PCD) 120 for microbubble cavitation monitoring and feedback control of FUS sonication. The transducer housing unit has connection ports 124 to connect to the electrical driving system 128, and the PCD data acquisition (DAQ) system 126.

[0032] FIG. 9 is a set of graphs comparing the ultrasound intensity of conventional FUS beam (left) with ultrasharp autofocusing Airy beam (right). The self-bending Airy beam abruptly increases its intensity at the focal point or selected target.

[0033] FIG. 10A is a schematic of an airy beam acoustic lens. The binary Airy beam phase profile (black) was derived from the Airy beam amplitude at the initial plane (orange). The binary (0 and 1 ) design was implemented by 3D printing. Experimental lenses were 3D printed and coupled to a 500 kHz flat transducer.

[0034] FIG. 10B is a set of images of an airy beam lens (bottom left corner) and an image of a generated pressure field in water measured by a hydrophone to showcase the capability of the lenes in ultrasharp focusing.

[0035] FIG. 10C a set of images of an airy beam lens (bottom left corner) and an image of a generated pressure field in water measured by a hydrophone to showcase the capability of the lenes in elongated focusing.

[0036] FIG. 10D a set of images of an airy beam lens (bottom left corner) and an image of a generated pressure field in water measured by a hydrophone to showcase the capability of the lenes in bilateral focusing.

[0037] FIG. 10E a set of images of an airy beam lens (bottom left corner) and an image of a generated pressure field in water measured by a hydrophone to showcase the capability of the lenes in arbitrary pattern focusing (e.g. the letter “W’).

[0038] FIG. 11A is a graph of feedback-controlled FUS sonication in a large animal model (pigs). The targeted cavitation level (TCL) was defined relative to the baseline stable cavitation level obtained at 0.3 MPa in the presence of microbubble. The graph defines three sections: step 1 baseline (left; blue), Step 2 feedback control comprising the ramp-up phase (middle; red) and the maintaining phase (right; green).

[0039] FIG. 11 B is a set of representative contrast-enhance (CE) T1 -weighted MRI images, which show the BBBO under different TCLs (0.25 dB, left; 0.5 dB, middle; 1 dB, left).

[0040] FIG. 11 C is a set of graphs of the CE MRI images (FIG. 11 B) showing the CE volume (top) and percent good pulse rate (bottom).

[0041 ] FIG. 12 is a set of images of acoustic coupling on a head for FUS-BBBO. The columns depict, from left to right, images of a mouse head with the acoustic coupling medium, T2-weighted MRI images at the top of the mouse head, and T1 -weighted CE MRI images of the mouse brain after FUS sonication to show the BB opening outcome. The rows show the type of acoustic coupling medium used and hair vs shaved. The rows from top to bottom show mineral oil on hair, ultrasound gel on a shaved head, and ultrasound gel on hair.

[0042] FIG. 13A is an image of a customized human head phantom, representing the outside of a human head.

[0043] FIG. 13B is an image of a customized human head phantom, representing the inside of a human head.

[0044] FIG. 13C is an image of a customized human head phantom, representing an MRI scan of a human head.

[0045] FIG. 14A is an image of FUS-BBBO procedure in a non-human primate (NHP) with a sonobiopsy device. The sonobiopsy device is positioned using a mechanical arm.

[0046] FIG. 14B is a set of CE MRI image of a NHP showing a successful BBBO at a FUS-targeted brain location (FLIS+; left) compared to a contralateral control (FUS-; right).

[0047] FIG. 15 is a schematic of the sonobiopsy workflow consisting of three stages: pre-procedure sonocap design (left), sonobiopsy procedure (middle), and post-procedure MRI evaluation (right).

DETAILED DESCRIPTION OF THE INVENTION

[0048] The present disclosure is based, at least in part, on the development of a wearable device to allow for a quick and accurate sonobiopsy procedure by integrating an ultrasound transducer into a patient-specific cap.

[0049] One aspect of the present disclosure provides a wearable device for ultrasound-brain interfacing. The current disclosure describes a next-generation wearable device, called sonocap. The sonocap is patient-friendly, easily manufactured, accurate in brain targeting, and safe. The sonocap can transform the diagnosis and treatment of a broad spectrum of brain diseases. The sonocap is a breakthrough wearable ultrasound device that will enhance our technical capability to interface with the brain using ultrasound, thereby providing a platform device for various applications.

[0050] The wearable device 100 consists of a patient-specific cap 102 which can be secured to a patient’s head with a fastener 103, such as a chin strap (FIG. 8A). The cap may have an opening 116 through the outside to the inside of the cap, and the opening may be positioned at any point on the cap. The opening has a raised rim 118 with a locking element 119 to allow for all the components to fit within the opening 116 and be secured in place. The components withing the opening may include a locking plate 106, a transducer housing unit 108, an ultrasound transducer 110, an acoustic coupling medium 114, a detector 120, and a PZT element 122.

[0051 ] The patient-specific cap 102 is designed to conform to the head 104 of an individual based off an image of the individual’s head 104. The image may be a digital 360-degree image of a head or a medical image, including but not limited to an MRI or CT scan. The cap 102 may cover different areas of the patients head as seen in FIG. 6A, FIG. 6B, FIG. 6C, FIG. 7B, FIG. 7C, and FIG. 8A. The cap is secured to patient’s head with a fastener 103, such as a chin strap, an adhesive, a clip, a lock, Velcro-like material, or any other suitable material. In one embodiment, the patient-specific cap may be manufactured through 3D- printing.

[0052] The cap 102 may have an opening 116 position on the cap based on the results of a medical image. The opening 116 may be place on the acoustic axis 112 which is the shortest distance from the transducer to a specific target. The target may be a tumor, may be an area affected by disease, or an area selected for diagnostics. In one embodiment, the specific target may be a glioblastoma (GBM). The opening may have any diameter necessary, as determined by the medical image and the cap function. There may be one or more opening positioned across the cap as determined by one or more acoustic axis and the one or more function of the patient-specific cap, including brain activity detection or reading, modulation of brain activity, and focused/unfocused ultrasound diagnosis or treatment. In one embodiment, there is one opening with a diameter of 15 cm. In another embodiment, there are 5 openings with a diameter of 5 centimeters. In another embodiment, there are 3 openings with a diameter of 5 cm. In another embodiment, there is an array of opening over the surface of the cap. The diameter of the openings may range from 1 cm to 20cm. The diameter of the opening includes 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19 cm, and 20 cm.

[0053] The medical image may provide, but is not limited to, information about the shape and contours of a patient’s head, the location of a target in a patient’s head or brain, and any variability in a patient’s skull, including density and thickness. Herein, the term head may encompass and be interchangeable with an individual’s head, the head including the hair, the skull, the cranium, or the brain.

[0054] The opening of the cap may have a raised rim 118 which may be any height necessary to house all of the components in the opening. The rim 118 contains a locking element 119 which is designed to secure the locking plate 106. This secures all the components of the opening into a fix position and orientation. In one embodiment, the locking element may consist of a slot in the raised rim in which a corresponding tab on the locking plate fits into (FIG. 8B, FIG. 8C). Rotating the locking plate into groves within the raised rim secures the o to the raised rim. In another embodiment the locking element may be a clip which could secure to an indention in the locking plate. The locking plate 106 may be configured to have a hole or slit, from the outside of the locking plate to the inside of the locking plate, such that the components within the opening 116 may be accessible when the locking plate is secured to the rim (FIG. 8A, FIG. 8B).

[0055] The opening 116 may also include a transducer housing unit 108, which is configured to fit inside the opening. In one embodiment, it fits between the locking plate 106 and the ultrasound transducer 110 within the opening 116. The transducer housing unit 108 may have features that fit into the locking element 119 of the rim 118. In one embodiment, the transducer housing unit may have tabs that fit into slots of the locking element of the rim, to secure the transducer housing unit in a fixed position and orientation (FIG. 8B, FIG. 8C). The transducer housing unit may fit over the ultrasound transducer to protect and secure the ultrasound transducer. The transducer housing unit 108 may include one or more ports 124 which allows for the connection of systems outside of the cap to the components with the cap, including the ultrasound transducer. The systems may include, but are not limited to, a data acquisition (DAQ) system, a detector acquisition system, and an electrical driving system.

[0056] The opening 116 of the cap 102 may also include an ultrasound transducer 110. The ultrasound transducer 110 may have features that fit into the locking element 119 of the rim 118. In one embodiment, the ultrasound transducer may have tabs that fit into slots of the locking element of the rim, to secure the ultrasound transducer in a fixed position and orientation (FIG. 8B, FIG. 8C). The ultrasound transducer 110 may include elements, including but not limited to, a focused ultrasound (FUS) transducer, an unfocused ultrasound transducer, a detector 120, and a piezoelectric lead zirconate titanate (PZT) element 122. There may also be connectors 126, 128 which connect the ports 124 of the transducer housing unit 108 to elements within the ultrasound transducer 110. In one embodiment, a connector 126 may connect a passive cavitation detector (PCD) to a PCD DAQ system via the port 124 on the transducer housing unit 110. Another connector 128 may connect the PZT element to an electrical FUS driving system (FIG. 8D). The FUS transducer may be an acoustic lens or any ultrasound transducer that produces a focused ultrasound wave that allows for the specific targeting of the selected target. In one embodiment the acoustic lens may be an Airy lens. In another embodiment the FUS transducer may be a Fresnel lens. The acoustic lens may be configured to target a specific area of the brain based on a medical image. The acoustic lens may be configured to compensate for the variability in an individual’s skull, such as the density and thickness. The FUS ultrasound transducer may comprise one or more acoustic lens. In one embodiment, the acoustic lens may comprise a first face in contact with an acoustic coupling medium 114 and configured to compensate for the variability in the density and thickness of a skull. The acoustic lens may comprise a second face, which is opposite the first face and is configured to focus an ultrasound wave to a specific target. [0057] In one embodiment, the ultrasound transducer may comprise an array of transducer that covers a large area of the head. In another embodiment, the ultrasound transducer may be a detector. In another embodiment, the detector of the ultrasound transducer may monitor blood flow to regions of the brain.

[0058] The opening 116 of the cap 102 may also include an acoustic coupling medium 114 which is in contact with the patient’s head 104 and the ultrasound transducer 110. The acoustic coupling medium may be applied to any area of the patient’s head as necessary to successfully operate the wearable device 100. The acoustic coupling medium may be applied to a head without hair or a head with hair. The acoustic coupling medium may be any medium that transfers acoustic energy into the subject and prevents the formation of air bubble. In one embodiment the acoustic medium may be mineral oil, which may be applied to a head with hair, prevent the formation of air bubbles, and result in a clear reading or detection of a signal (FIG. 12; top). In one embodiment, the acoustic coupling medium is applied to the patient’s head before the cap is placed on the patient’s head.

[0059] The cap 102 may also include a plurality of hole through the outside of the cap to the inside of the cap. The plurality of hole may allow acoustic coupling medium 114 to be applied to a patient’s head 104 while the patient is wearing the cap. The plurality of holes may have a diameter of 2 mm. The plurality of hole may range in number from 1 hole to 20 holes. The number of holes may be 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0060] In one embodiment, the cap 102 is used as a sonobiopsy device on glioblastoma (GBM) patients. The targeting accuracy of the device was confirmed in vitro and in vivo, as well as through numerical simulations based on MRI and CT images of GBM patients. This FUS transducer features a small aperture (6.5 cm) and is lightweight (0.24 kg). The ultrasound transducer 110 is a single-element focused ultrasound (FUS) transducer to create microbubbles to open the blood brain barrier (BBB) and release brain tumor-derived biomarkers into the bloodstream for noninvasive and spatially targeted molecular diagnosis of brain tumors.

[0061] One element of the wearable device is a patient-specific cap. Accurate positioning of the ultrasound transducer to target the desired tumor location is crucial for successful ultrasound energy delivery. Existing devices require realtime MRI or optical neuronavigation guidance, which lengthens the procedure and requires additional personnel to operate the guidance systems. Despite recent breakthroughs in developing wearable ultrasound imaging devices, no wearable ultrasound device has been used for brain-blood barrier opening (BBBO). Previous studies proposed the concept of designing a phased-array FUS transducer for BBBO using a patient-specific helmet as a scaffold and developed a skull-conformal 4096-element phased array. However, the phased array design was complex and technically challenging to manufacture. To address the unmet need for wearable ultrasound devices, the current disclosure describes a wearable sonocap by integrating a patient-specific 3D-printed cap with an ultrasound transducer (FIG. 8A, FIG. 8B). One some aspects, the cap can be tailored to an individual patient’s head shape and size based on MRI and CT images for precise registration of the patient’s head in the physical space with the virtual imaging space. In another aspect, the cap has an opening at the accurate location required to guide FUS transducer positioning without requiring complex and bulky robotic/mechanical arms like other devices (Table 1 ). In accordance with another aspect, the patient-specific cap can reduce the procedure time, avoid the need for head fixation and mechanical arms, and enable accurate tumor targeting, thereby offering a patient-friendly FUS procedure.

[0062] In accordance with one embodiment, another element of the device is an Airy beam-enabled FUS transducer. The success of all FUS techniques fundamentally depends on the quality of transcranial ultrasound focusing. The most commonly used approach for ultrasound beam focusing is to use a singleelement concave-shaped transducer. However, this type of transducer has an elongated focal region, limiting its tumor-targeting accuracy and generating off- target BBB openings. For example, a single-element with a full-width-half- maximum (FWHM) focal region size of 6 mm in the lateral direction and 49 mm in the axial direction has an elongated axial FWHM and leads to BBB opening outside the target in NHPs. Our single-element FUS transducer also has an elongated axial FWHM of 27 mm, and BBB opening outside the focal region was observed in our pig studies. Phased arrays are the most widely used approach to improve focusing. For example, ExAblate Neuro has 1024 elements with an axial FWHM of ~7 mm. However, the high cost and complexity of manufacturing limit the scalability of the phased array. 3D-printed acoustic lenses are a disruptive technology for transcranial ultrasound focusing because they can spatially modulate the phase of a transmitted wavefront with submillimeter spatial resolution at extremely low cost. Numerical simulations and phantom experiments demonstrated the great potential of acoustic lenses designed based on time reversal for compensating skull aberrations and generating pressure fields of arbitrary shapes using holograms. These existing approaches for ultrasound beam focusing (using single-element concave-shaped transducers, phased arrays, and acoustic lenses designed based on time-reversal focusing) gradually reshape the ultrasound beam wavefront with smoothly accumulating acoustic intensity (FIG. 9).

[0063] FUS transducers based on abruptly autofocusing Airy beams are developed to achieve spatially precise focusing by coupling Airy beam acoustic lenses with a single-element flat transducer. The Airy function gives rise to Airy beams that laterally shift in the transverse plane along a parabolic selfaccelerating trajectory (i.e., they bend sideways like rainbows) (FIG. 9). Axisymmetric Airy beams exhibit abrupt intensity increases at the focus, which can reach three orders of magnitude larger than the acoustic intensity at the initial source plane. The ultrasharp autofocusing property of Airy beams can reduce the axial FWHM to achieve accurate tumor targeting and minimize off- target effects. The lack of simple devices capable of generating megahertz Airy beams in water has prevented the use of Airy beams in medical ultrasound applications. Several structures for generating Airy beams include the space coiling-up structures and Helmholtz-resonator-like structures. However, these focused on airborne sound waves with long wavelengths and often required the manufacturing of subwavelength units with complicated microstructures, which poses challenges to the fabrication of megahertz ultrasound devices since the wavelength is on the millimeter scale. To address the unmet need for FUS transducers, the device of the current disclosure employs 3D-printable acoustic lenses that can generate megahertz Airy beams and achieve transcranial ultrasharp focusing. This disruptive transducer design is significant for sonobiopsy because it facilitates the development of wearable FUS transducers for targeting brain tumors located at different locations by simply switching the lens, enables the development of spatially accurate sonobiopsy with minimized concerns of off-target effects, and allows easy manufacturing and scaling of these 3D-printable lenses.

[0064] It has been shown that a binary acoustic lens could produce Airy beams in water, and the present disclosure describes a simple-to-design and easy-to- fabricate approach to generate megahertz Airy beams in water using 3D-printed acoustic lenses (FIG. 10A). We designed these lenses by calculating the Airy beam pressure profile at the initial plane using:

where A( ) denotes the Airy function, r is the radial distance, rO is related to the radial position of the main Airy ring, t is a scale factor, and a is a decay factor. The pressure profile was converted to a binary phase of 0 for P0(r) > 0 and n/2 for P0(r) < 0 (FIG. 10A). This design was implemented by 3D printing with two coding bits, a polylactic acid unit (the material commonly used by 3D printers) acting as the bit "1" and a water unit acting as the bit "0". The thickness of the unit "1" was calculated using d = c^ cl/Af c! - c1 ) to produce a phase delay of TV . between unit 1 and unit 0, where f is the frequency and c1 and c2 are sound speed of water and polylactic acid, respectively. The focal depth and FWHM are tunable by adjusting the design parameters, rO and <w, which are scalable by A (A is the wavelength). Several lenses were designed and printed. The lenses were each coupled with a planar ultrasound transducer to generate different focusing patterns. Ultrasharp focusing was achieved with axial FWHM = 2.7A (FIG. 10B). Using the same lens design, the axial FWHM of a 560 kHz transducer is estimated to be 7.4 mm. It was also shown that the focal region size is tunable (FIG. 10C), and superimposing can be used to generate multifocal points, such as bifocal (FIG. 10D) and arbitrary pattern focusing (FIG. 10E). These data demonstrate that Airy beams can be generated by 3D-printed acoustic lenses, and these lenses have great flexibility in ultrasound beam manipulation. [0065] In one embodiment, the device provides PCD for individualized closed- loop feedback control of FUS sonication. A challenge in performing FUS-BBBO in the clinic is the variability of the treatment, leading to inconsistent treatment outcomes. This is caused by variations among patients in the ultrasound pressure and microbubble size distribution and concentration within the FUS focal region. In situ acoustic pressures vary due to skull heterogeneity and variation in the incident angle of the FUS beam relative to the skull. The in situ microbubble concentration distribution in the targeted brain region varies due to differences in factors such as microbubble injection speed, vascular density, vessel size, and blood flow. PCD is a sensitive technique for monitoring microbubble cavitation emissions during FUS sonication (FIG. 5B). The measured stable cavitation level was linearly correlated with BBB opening outcome, and inertial cavitation could be associated with brain tissue damage. To address the limitations of existing approaches, the device uses an individualized closed-loop feedback control algorithm that establishes the TCL based on a “lower threshold” defined with individual variations in ultrasound and microbubble considered. This closed-loop feedback control algorithm has three benefits. (1 ) Improved safety: By defining a lower threshold for the stable cavitation level, the algorithm reduces the risk of reaching levels that may cause inertial cavitation and potentially lead to brain tissue damage. (2) Enhanced consistency: The individualized approach accommodates variations in ultrasound pressure and microbubble concentration, leading to more consistent outcomes among patients. (3) Better control and monitoring: Closed-loop feedback control provides real-time adjustments to FUS parameters and ensures that the desired stable cavitation level is maintained throughout the procedure. Implementing this individualized closed-loop feedback control algorithm will improve the consistency and safety of the sonobiopsy procedure for each patient, ultimately enhancing the clinical translation of sonobiopsy and improving patient outcomes.

[0066] An individualized closed-loop feedback control algorithm was developed and validated its performance was validated in pigs. This algorithm defines TCL based on a lower threshold of the stable cavitation level determined using a "dummy" FUS sonication in the presence of microbubbles. The dummy sonication applied a low acoustic pressure (0.3 MPa measured in free field) for a short duration (5 s) in the presence of intravenously infused microbubbles. Closed-loop feedback-controlled FUS-BBBO in pigs was then achieved through two sonication phases: the ramping-up phase to reach the TCL and the maintaining phase to control the stable cavitation level at the TCL by adjusting the FUS acoustic pressure (FIG. 11 ). Safe and controlled BBB opening was achieved as the TCL increased from 0.25 to 1 dB (FIG. 11 B, FIG. 11 C). The stability of the control algorithm was measured by the good pulse rate, which calculated the percentage of ultrasound pulses with stable cavitation levels within the predefined desired range (i.e. , TCL ± tolerance range). The tolerance range was set to ±0.4 dB to reduce the sensitivity to noise. A high good pulse rate (65-96%) was achieved. These preliminary data demonstrate that it is feasible to perform individualized closed-loop feedback-controlled FUS procedures in large animals.

[0067] The sonobiopsy device has an acoustic coupling medium to avoid hair shaving. Hair is naturally covered in sebum, consisting primarily of lipids and wax produced by glands on the scalp. This layer of lipids contributes to the hydrophobicity of the hair surface, which leads to the formation of air bubbles when the hydrophobic hair surface comes into contact with ultrasound gel (which is mainly water). These air bubbles reflect almost 100% of the ultrasound wave and result in failure or inconsistent delivery of ultrasound energy to the brain. The psychological impact of removing hair could decrease the acceptance of sonobiopsy to patients and physicians as a diagnostic technique. To resolve these challenges, hydrophobic mineral oil can be used as a coupling medium, which avoids trapping air bubbles on the hydrophobic hair surface and facilitates acoustic coupling without hair shaving. The acoustic coupling method is simple, safe, and can be straightforwardly used in patients to avoid hair shaving, which can improve the acceptance of sonobiopsy by patients and physicians.

[0068] The present disclosure also includes methods for performing a sonobiopsy. The methods involve a workflow for performing sonobiopsy using a sonocap and validating the performance of each component of the sonocap. In some aspects, the feasibility and safety of biomarker release under different TCLs to determine the optimal operating parameters that maximize biomarker release without causing tissue damage can be performed. Feasibility of biomarker release can be assessed based on the release of brain-specific proteins [e.g., glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP)] from the brain to the blood.

[0069] Methods to perform a sonobiopsy with the sonocap described in the current disclosure are described. In some aspects, the cap can be fitted to the head of a subject, and the FUS transducer can be inserted into the cap opening through the mineral oil coupling. Definity microbubbles can be continuously infused using a syringe pump. Closed-loop feedback-controlled FUS sonication can then be performed. In an exemplary embodiment, three brain locations at different depths (e.g., cortex, hippocampus, and brainstem) can be targeted to represent variability in the tumor location across patients. In some embodiments, three TCLs (e.g., 0.25, 0.5, and 1 dB) can be evaluated and implemented. In some aspects, sonication parameters can be frequency=650 kHz, pulse repetition frequency=1 Hz, pulse length=10 ms, and total sonication duration=3 min. The procedure time from cap fitting to the end of sonication can be recorded. Blood samples will be collected before and at different time points after FUS sonication (5, 10, and 30 min) to determine the kinetics of biomarker release. The plasma concentrations of brain-specific biomarkers (e.g., GFAP and MBP) can be analyzed using ELISA assays. Repeated sonobiopsy procedures can be performed on each subject. A sample size of 10 repeated measurements allows 80% power to detect a difference of 1 ,72xo- (a denoting pooled standard deviation) in the biomarker concentration based on the 2-sided 2-sample t-test. The total number of experiments is estimated to be 60 for testing three TCLs and three targeting depths.

[0070] Sonobiopsy is a groundbreaking approach for interrogating the brain, providing valuable molecular information that is currently hard to obtain without surgery. Further, the wearable sonocap significantly departs from the status quo designs of clinical FUS devices, which require costly and complex FUS transducers, MRI or neuronavigation for treatment guidance, stereotactic frames or robotic arms for transducer positioning, and hair shaving. In contrast, the innovative sonocap design overcomes these economic and technical barriers to make sonobiopsy accessible, convenient for physicians, and patient friendly. Computing Systems and Devices

[0071] In various aspects, the disclosed ultrasound transducer and detection methods may be implemented using a computing system or computing device. FIG. 1 depicts a simplified block diagram of the system for implementing the computer-aided method described herein. As illustrated in FIG. 1 , the computing device 300 may be configured to implement at least a portion of the tasks associated with the disclosed methods described herein. The computer system 300 may include a computing device 302. In one aspect, the computing device 302 is part of a server system 304, which also includes a database server 306. The computing device 302 is in communication with a database 308 through the database server 306. The computing device 302 is communicably coupled to a user computing device 330 and a FUS-BBBO system 334 through a network 350. The network 350 may be any network that allows local area or wide area communication between the devices. For example, the network 350 may allow communicative coupling to the Internet through at least one of many interfaces including, but not limited to, at least one of a network, such as the Internet, a local area network (LAN), a wide area network (WAN), an integrated services digital network (ISDN), a dial-up-connection, a digital subscriber line (DSL), a cellular phone connection, and a cable modem. The user computing device 330 may be any device capable of accessing the Internet including, but not limited to, a desktop computer, a laptop computer, a personal digital assistant (PDA), a cellular phone, a smartphone, a tablet, a phablet, wearable electronics, smartwatch, or other web-based connectable equipment or mobile devices.

[0072] In other aspects, the computing device 302 is configured to perform a plurality of tasks associated with the disclosed computer-aided methods of performing FUS-BBBO and/or transcranial localization. In some aspects, the computing device 302, user computing device 330, and/or FUS-BBBO system 334 may be operatively connected via a network 350. FIG. 2 depicts a component configuration 400 of computing device 402, which includes database 410 along with other related computing components. In some aspects, computing device 402 is similar to computing device 302 (shown in FIG. 1 ). A user 404 may access components of computing device 402. In some aspects, database 410 is similar to database 308 (shown in FIG. 1 ). [0073] In one aspect, database 410 includes FUS-BBBO data 412, TCL data 418, and PCD algorithm data 420. FUS-BBBO data 412 may include data used to operate a FUS-BBBO system using the individualized closed-loop feedback control of microbubble cavitation as disclosed herein. Non-limiting examples of FUS-BBBO data 412 include various measurements of cavitation signals, any parameters used to control the operation of a FUS-BBBO device, and any parameters defining equations or other algorithms used to implement the individualized closed-loop feedback control of microbubble cavitation as disclosed herein. TCL data 418 may include data used to perform the targeted cavitation levels as disclosed herein. Non-limiting examples of TCL data 418 include measurements of background noise and/or cavitation signals, any parameters defining equations and other algorithms used to implement the transformation of background noise and cavitation signals into targeted cavitation level as disclosed herein and/or any parameters defining equations and other algorithms used to implement the targeted cavitation level using a PCD algorithm method described herein.

[0074] Computing device 402 also includes a number of components that perform specific tasks. In the exemplary aspect, computing device 402 includes a data storage device 430, a PCD algorithm component 440, a focused ultrasound brain-blood-barrier opening (FUS-BBBO) component 450, and a communication component 460. The PCD algorithm component 440 is configured to implement the TCL using an individualized closed-loop feedback control algorithm that establishes the TCL based on a “lower threshold” defined with individual variations in ultrasound and microbubble considered as described herein. The focused ultrasound brain-blood-bamer opening (FUS-BBBO) component 450 is configured to implement the individualized closed-loop feedback control of microbubble cavitation as disclosed herein. The data storage device 430 is configured to store data received or generated by computing device 402, such as any of the data stored in database 410 or any outputs of processes implemented by any component of computing device 402.

[0075] The communication component 460 is configured to enable communications between computing device 402 and other devices (e.g. user computing device 330 shown in FIG. 1 ) over a network, such as a network 350 (shown in FIG. 1 ), or a plurality of network connections using predefined network protocols such as TCP/IP (Transmission Control Protocol/lnternet Protocol).

[0076] FIG. 3 depicts a configuration of a remote or user computing device 502, such as user computing device 330 (shown in FIG. 1 ). Computing device 502 may include a processor 505 for executing instructions. In some aspects, executable instructions may be stored in a memory area 510. Processor 505 may include one or more processing units (e.g., in a multi-core configuration). Memory area 510 may be any device allowing information such as executable instructions and/or other data to be stored and retrieved. Memory area 510 may include one or more computer-readable media.

[0077] Computing device 502 may also include at least one media output component 515 for presenting information to a user 501. Media output component 515 may be any component capable of conveying information to user 501. In some aspects, media output component 515 may include an output adapter, such as a video adapter and/or an audio adapter. An output adapter may be operatively coupled to processor 505 and operatively coupleable to an output device such as a display device (e.g., a liquid crystal display (LCD), organic light-emitting diode (OLED) display, cathode ray tube (CRT), or “electronic ink” display) or an audio output device (e.g., a speaker or headphones). In some aspects, media output component 515 may be configured to present an interactive user interface (e.g., a web browser or client application) to user 501 .

[0078] In some aspects, computing device 502 may include an input device 520 for receiving input from user 501 . Input device 520 may include, for example, a keyboard, a pointing device, a mouse, a stylus, a touch-sensitive panel (e.g., a touchpad or a touch screen), a camera, a gyroscope, an accelerometer, a position detector, and/or an audio input device. A single component such as a touch screen may function as both an output device of media output component 515 and input device 520.

[0079] Computing device 502 may also include a communication interface 525, which may be communicatively coupleable to a remote device. Communication interface 525 may include, for example, a wired or wireless network adapter or a wireless data transceiver for use with a mobile phone network (e.g., Global System for Mobile Communications (GSM), 3G, 4G or Bluetooth) or other mobile data network (e.g., Worldwide Interoperability for Microwave Access (WIMAX)).

[0080] Stored in memory area 510 are, for example, computer-readable instructions for providing a user interface to user 501 via media output component 515 and, optionally, receiving and processing input from input device 520. A user interface may include, among other possibilities, a web browser and client application. Web browsers enable users 501 to display and interact with media and other information typically embedded on a web page or a website from a web server. A client application allows users 501 to interact with a server application associated with, for example, a vendor or business.

[0081] FIG. 4 illustrates an example configuration of a server system 602. Server system 602 may include, but is not limited to, database server 306 and computing device 302 (both shown in FIG. 1 ). In some aspects, server system 602 is similar to server system 304 (shown in FIG. 1 ). Server system 602 may include a processor 605 for executing instructions. Instructions may be stored in a memory area 625, for example. Processor 605 may include one or more processing units (e.g., in a multi-core configuration).

[0082] Processor 605 may be operatively coupled to a communication interface 615 such that server system 602 may be capable of communicating with a remote device such as user computing device 330 (shown in FIG. 1 ) or another server system 602. For example, communication interface 615 may receive requests from a user computing device 330 via a network 350 (shown in FIG. 1 ).

[0083] Processor 605 may also be operatively coupled to a storage device 625. Storage device 625 may be any computer-operated hardware suitable for storing and/or retrieving data. In some aspects, storage device 625 may be integrated into server system 602. For example, server system 602 may include one or more hard disk drives as storage device 625. In other aspects, storage device 625 may be external to server system 602 and may be accessed by a plurality of server systems 602. For example, storage device 625 may include multiple storage units such as hard disks or solid-state disks in a redundant array of inexpensive disks (RAID) configuration. Storage device 625 may include a storage area network (SAN) and/or a network-attached storage (NAS) system.

[0084] In some aspects, processor 605 may be operatively coupled to storage device 625 via a storage interface 620. Storage interface 620 may be any component capable of providing processor 605 with access to storage device 625. Storage interface 620 may include, for example, an Advanced Technology Attachment (ATA) adapter, a Serial ATA (SATA) adapter, a Small Computer System Interface (SCSI) adapter, a RAID controller, a SAN adapter, a network adapter, and/or any component providing processor 605 with access to storage device 625.

[0085] Memory areas 510 (shown in FIG. 3) and 610 may include, but are not limited to, random access memory (RAM) such as dynamic RAM (DRAM) or static RAM (SRAM), read-only memory (ROM), erasable programmable readonly memory (EPROM), electrically erasable programmable read-only memory (EEPROM), and non-volatile RAM (NVRAM). The above memory types are examples only and are thus not limiting as to the types of memory usable for the storage of a computer program.

[0086] The computer systems and computer-aided methods discussed herein may include additional, less, or alternate actions and/or functionalities, including those discussed elsewhere herein. The computer systems may include or be implemented via computer-executable instructions stored on non-transitory computer-readable media. The methods may be implemented via one or more local or remote processors, transceivers, servers, and/or sensors (such as processors, transceivers, servers, and/or sensors mounted on vehicle or mobile devices, or associated with smart infrastructure or remote servers), and/or via computer-executable instructions stored on non-transitory computer-readable media or medium.

[0087] The methods and algorithms of the disclosure may be enclosed in a controller or processor. Furthermore, methods and algorithms of the present disclosure can be embodied as a computer-implemented method or methods for performing such computer-implemented method or methods, and can also be embodied in the form of a tangible or non-transitory computer-readable storage medium containing a computer program or other machine-readable instructions (herein “computer program”), wherein when the computer program is loaded into a computer or other processor (herein “computer”) and/or is executed by the computer, the computer becomes an apparatus for practicing the method or methods. Storage media for containing such computer programs include, for example, floppy disks and diskettes, compact disk (CD)-ROMs (whether or not writeable), DVD digital disks, RAM and ROM memories, computer hard drives and backup drives, external hard drives, “thumb” drives, and any other storage medium readable by a computer. The method or methods can also be embodied in the form of a computer program, for example, whether stored in a storage medium or transmitted over a transmission medium such as electrical conductors, fiber optics or other light conductors, or by electromagnetic radiation, wherein when the computer program is loaded into a computer and/or is executed by the computer, the computer becomes an apparatus for practicing the method or methods. The method or methods may be implemented on a general-purpose microprocessor or on a digital processor specifically configured to practice the process or processes. When a general-purpose microprocessor is employed, the computer program code configures the circuitry of the microprocessor to create specific logic circuit arrangements. Storage medium readable by a computer includes medium being readable by a computer per se or by another machine that reads the computer instructions for providing those instructions to a computer for controlling its operation. Such machines may include, for example, machines for reading the storage media mentioned above.

[0088] In some aspects, a computing device is configured to implement machine learning, such that the computing device “learns” to analyze, organize, and/or process data without being explicitly programmed. Machine learning may be implemented through machine learning (ML) methods and algorithms. In one aspect, a machine learning (ML) module is configured to implement ML methods and algorithms. In some aspects, ML methods and algorithms are applied to data inputs and generate machine learning (ML) outputs. Data inputs may include but are not limited to images or frames of a video, object characteristics, and object categorizations. Data inputs may further include sensor data, image data, video data, telematics data, authentication data, authorization data, security data, mobile device data, geolocation information, transaction data, personal identification data, financial data, usage data, weather pattern data, “big data” sets, and/or user preference data. ML outputs may include but are not limited to a tracked shape output, categorization of an object, categorization of a region within a medical image (segmentation), categorization of a type of motion, a diagnosis based on the motion of an object, motion analysis of an object, and trained model parameters ML outputs may further include: speech recognition, image or video recognition, medical diagnoses, statistical or financial models, autonomous vehicle decision-making models, robotics behavior modeling, fraud detection analysis, user recommendations and personalization, game Al, skill acquisition, targeted marketing, big data visualization, weather forecasting, and/or information extracted about a computer device, a user, a home, a vehicle, or a party of a transaction. In some aspects, data inputs may include certain ML outputs.

[0089] In some aspects, at least one of a plurality of ML methods and algorithms may be applied, which may include but are not limited to genetic algorithms, linear or logistic regressions, instance-based algorithms, regularization algorithms, decision trees, Bayesian networks, cluster analysis, association rule learning, artificial neural networks, deep learning, dimensionality reduction, and support vector machines. In various aspects, the implemented ML methods and algorithms are directed toward at least one of a plurality of categorizations of machine learning, such as supervised learning, unsupervised learning, adversarial learning, and reinforcement learning.

THERAPEUTIC METHODS

[0090] Also provided is a process of treating, preventing, or reversing a brain disease in a subject in need of administration of a therapeutically effective amount of a therapeutic agent, so as to treat the brain disease, by facilitating drug delivery to the brain using the wearable ultrasound device described herein.

[0091] Methods described herein are generally performed on a subject in need thereof. A subject in need of the therapeutic methods described herein can be a subject having, diagnosed with, suspected of having, or at risk for developing a brain disease. A determination of the need for treatment will typically be assessed by a history, physical exam, or diagnostic tests consistent with the disease or condition at issue, as well as the sonobiopsy described herein. Diagnosis of the various conditions treatable by the methods described herein is within the skill of the art. The subject can be an animal subject, including a mammal, such as horses, cows, dogs, cats, sheep, pigs, mice, rats, monkeys, hamsters, guinea pigs, and humans or chickens. For example, the subject can be a human subject.

[0092] Generally, a safe and effective amount of a therapeutic agent is, for example, an amount that would cause the desired therapeutic effect in a subject while minimizing undesired side effects. In various embodiments, an effective amount of a therapeutic agent described herein can substantially inhibit a brain disease, slow the progress of a brain disease, or limit the development of a brain disease.

[0093] According to the methods described herein, administration can be intracranial, parenteral, pulmonary, oral, topical, intradermal, intramuscular, intraperitoneal, intravenous, intratumoral, intrathecal, intracranial, intracerebroventricular, subcutaneous, intranasal, epidural, ophthalmic, buccal, or rectal administration.

[0094] When used in the treatments described herein, a therapeutically effective amount of a therapeutic agent can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form and with or without a pharmaceutically acceptable excipient. For example, the compounds of the present disclosure can be administered, at a reasonable benefit/risk ratio applicable to any medical treatment, in a sufficient amount to treat a brain disease.

[0095] The amount of a composition described herein that can be combined with a pharmaceutically acceptable carrier to produce a single dosage form will vary depending upon the subject or host treated and the particular mode of administration. It will be appreciated by those skilled in the art that the unit content of agent contained in an individual dose of each dosage form need not in itself constitute a therapeutically effective amount, as the necessary therapeutically effective amount could be reached by administration of a number of individual doses. [0096] Toxicity and therapeutic efficacy of compositions described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals for determining the LD50 (the dose lethal to 50% of the population) and the ED50, (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index that can be expressed as the ratio LD50/ED50, where larger therapeutic indices are generally understood in the art to be optimal.

[0097] The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the seventy of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration; the route of administration; the rate of excretion of the composition employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts (see e.g., Koda-Kimble et al. (2004) Applied Therapeutics: The Clinical Use of Drugs, Lippincott Williams & Wilkins, ISBN 0781748453; Winter (2003) Basic Clinical Pharmacokinetics, 4th ed., Lippincott Williams & Wilkins, ISBN 0781741475; Sharqel (2004) Applied Biopharmaceutics & Pharmacokinetics, McGraw-Hill/Appleton & Lange, ISBN 0071375503). For example, it is well within the skill of the art to start doses of the composition at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose may be divided into multiple doses for purposes of administration. Consequently, single-dose compositions may contain such amounts or submultiples thereof to make up the daily dose. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by an attending physician within the scope of sound medical judgment.

[0098] Again, each of the states, diseases, disorders, and conditions, described herein, as well as others, can benefit from compositions and methods described herein. Generally, treating a state, disease, disorder, or condition includes preventing, reversing, or delaying the appearance of clinical symptoms in a mammal that may be afflicted with or predisposed to the state, disease, disorder, or condition but does not yet experience or display clinical or subclinical symptoms thereof. Treating can also include inhibiting the state, disease, disorder, or condition, e.g., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof. Furthermore, treating can include relieving the disease, e.g., causing regression of the state, disease, disorder, or condition or at least one of its clinical or subclinical symptoms. A benefit to a subject to be treated can be either statistically significant or at least perceptible to the subject or to a physician.

[0099] Administration of a therapeutic agent can occur as a single event or over a time course of treatment. For example, a therapeutic agent can be administered daily, weekly, bi-weekly, or monthly. For treatment of acute conditions, the time course of treatment will usually be at least several days. Certain conditions could extend treatment from several days to several weeks. For example, treatment could extend over one week, two weeks, or three weeks. For more chronic conditions, treatment could extend from several weeks to several months or even a year or more.

[0100] Treatment in accordance with the methods described herein can be performed prior to, concurrent with, or after conventional treatment modalities for a brain disease. The methods can include enhancing drug delivery to the brain by opening the blood-brain barrier with the sonocap device described in the present disclosure.

[0101] A therapeutic agent can be administered simultaneously or sequentially with another agent, such as an antibiotic, an anti-inflammatory, or another agent. For example, a therapeutic agent can be administered simultaneously with another agent, such as an antibiotic or an anti-inflammatory. Simultaneous administration can occur through the administration of separate compositions, each containing one or more of a therapeutic agent, an antibiotic, an antiinflammatory, or another agent. Simultaneous administration can occur through the administration of one composition containing two or more of a therapeutic agent such as a chemotherapy, an Alzheimer’s Disease therapeutic agent, a Parkinson’s disease therapeutic agent, an antibiotic, an anti-inflammatory, or another agent. A therapeutic agent can be administered sequentially with an antibiotic, an anti-inflammatory, or another agent. For example, a therapeutic agent can be administered before or after administration of an antibiotic, an antiinflammatory, or another agent.

ADMINISTRATION

[0102] Agents and compositions described herein can be administered according to methods described herein in a variety of means known to the art. The agents and composition can be used therapeutically either as exogenous materials or as endogenous materials. Exogenous agents are those produced or manufactured outside of the body and administered to the body. Endogenous agents are those produced or manufactured inside the body by some type of device (biologic or other) for delivery within or to other organs in the body.

[0103] As discussed above, administration can be parenteral, pulmonary, oral, topical, intradermal, intratumoral, intranasal, inhalation (e.g., in an aerosol), implanted, intramuscular, intraperitoneal, intravenous, intrathecal, intracranial, intracerebroventricular, subcutaneous, intranasal, epidural, intrathecal, ophthalmic, transdermal, buccal, and rectal.

[0104] Agents and compositions described herein can be administered in a variety of methods well-known in the arts. Administration can include, for example, methods involving oral ingestion, direct injection (e.g., systemic or stereotactic), implantation of cells engineered to secrete the factor of interest, drug-releasing biomaterials, polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, implantable matrix devices, mini-osmotic pumps, implantable pumps, injectable gels and hydrogels, liposomes, micelles (e.g., up to 30 pm), nanospheres (e.g., less than 1 pm), microspheres (e.g., 1-100 pm), reservoir devices, a combination of any of the above, or other suitable delivery vehicles to provide the desired release profile in varying proportions. Other methods of controlled-release delivery of agents or compositions will be known to the skilled artisan and are within the scope of the present disclosure.

[0105] Delivery systems may include, for example, an infusion pump which may be used to administer the agent or composition in a manner similar to that used for delivering insulin or chemotherapy to specific organs or tumors. Typically, using such a system, an agent or composition can be administered in combination with a biodegradable, biocompatible polymeric implant that releases the agent over a controlled period of time at a selected site. Examples of polymeric materials include polyanhydrides, polyorthoesters, polyglycolic acid, polylactic acid, polyethylene vinyl acetate, and copolymers and combinations thereof. In addition, a controlled release system can be placed in proximity of a therapeutic target, thus requiring only a fraction of a systemic dosage.

[0106] Agents can be encapsulated and administered in a variety of carrier delivery systems. Examples of carrier delivery systems include microspheres, hydrogels, polymeric implants, smart polymeric carriers, and liposomes (see generally, Uchegbu and Schatzlein, eds. (2006) Polymers in Drug Delivery, CRC, ISBN-10: 0849325331 ). Carrier-based systems for molecular or biomolecular agent delivery can: provide for intracellular delivery; tailor biomolecule/agent release rates; increase the proportion of biomolecule that reaches its site of action; improve the transport of the drug to its site of action; allow colocalized deposition with other agents or excipients; improve the stability of the agent in vivo; prolong the residence time of the agent at its site of action by reducing clearance; decrease the nonspecific delivery of the agent to nontarget tissues; decrease irritation caused by the agent; decrease toxicity due to high initial doses of the agent; alter the immunogenicity of the agent; decrease dosage frequency, improve taste of the product; or improve shelf life of the product.

[0107] A control sample or a reference sample as described herein can be a sample from a healthy subject. A reference value can be used in place of a control or reference sample, which was previously obtained from a healthy subject or a group of healthy subjects. A control sample or a reference sample can also be a sample with a known amount of a detectable compound or a spiked sample.

[0108] Compositions and methods described herein utilizing molecular biology protocols can be according to a variety of standard techniques known to the art (see e.g., Sambrook and Russel (2006) Condensed Protocols from Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, ISBN-10: 0879697717; Ausubel et al. (2002) Short Protocols in Molecular Biology, 5th ed., Current Protocols, ISBN-10: 0471250929; Sambrook and Russel (2001 ) Molecular Cloning: A Laboratory Manual, 3d ed., Cold Spring Harbor Laboratory Press, ISBN-10: 0879695773; Elhai, J. and Wolk, C. P. 1988. Methods in Enzymology 167, 747-754; Studier (2005) Protein Expr Purif. 41 (1 ), 207-234; Gellissen, ed. (2005) Production of Recombinant Proteins: Novel Microbial and Eukaryotic Expression Systems, Wiley-VCH, ISBN-10: 3527310363; Baneyx (2004) Protein Expression Technologies, Taylor & Francis, ISBN-10: 0954523253).

[0109] Definitions and methods described herein are provided to better define the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art.

[0110] In some embodiments, numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the present disclosure are to be understood as being modified in some instances by the term “about.” In some embodiments, the term “about” is used to indicate that a value includes the standard deviation of the mean for the device or method being employed to determine the value. In some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the present disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the present disclosure may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. The recitation of discrete values is understood to include ranges between each value.

[0111] In some embodiments, the terms “a” and “an” and “the” and similar references used in the context of describing a particular embodiment (especially in the context of certain of the following claims) can be construed to cover both the singular and the plural, unless specifically noted otherwise. In some embodiments, the term “or” as used herein, including the claims, is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive.

[0112] The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended.

For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and can also cover other unlisted steps. Similarly, any composition or device that “comprises,” “has” or “includes” one or more features is not limited to possessing only those one or more features and can cover other unlisted features.

[0113] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the present disclosure and does not pose a limitation on the scope of the present disclosure otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the present disclosure.

[0114] Groupings of alternative elements or embodiments of the present disclosure disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0115] All publications, patents, patent applications, and other references cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present disclosure.

[0116] Having described the present disclosure in detail, it will be apparent that modifications, variations, and equivalent embodiments are possible without departing from the scope of the present disclosure defined in the appended claims. Furthermore, it should be appreciated that all examples in the present disclosure are provided as non-limiting examples.

EXAMPLES

[0117] The following non-limiting examples are provided to further illustrate the present disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent approaches the inventors have found function well in the practice of the present disclosure, and thus can be considered to constitute examples of modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure.

EXAMPLE 1 - WEARABLE SONOCAP FOR ULTRASOUND-BRAIN INTERFACING

INTRODUCTION

[0118] Brain tumor diagnosis primarily relies on neuroimaging, such as magnetic resonance imaging (MRI), followed by surgical resection or stereotactic biopsy for histological validation. However, invasive tissue biopsy is associated with significant risks, is not ideal for repeated sampling to monitor tumor progression and treatment response and may not be feasible for surgically inaccessible tumor locations or medically inoperable patients. Approximately 700,000 patients in the United States have a primary central nervous system tumor, and nearly 200,000 new cases of brain metastases are diagnosed annually. Brain tumors severely threaten human health due to their fast development and poor prognosis. For example, glioblastoma (GBM), the most common primary brain tumor in adults, has a median survival time of ~1 year. The current standard of care relies on MRI and CT to identify suspicious tumor lesions, followed by surgical resection or stereotactic biopsy for histological confirmation. However, invasive brain tumor biopsy carries a 5-7% risk of major morbidity and may not be feasible for medically inoperable patients or those with tumors in surgically inaccessible locations. Repeated tissue biopsies to assess treatment response and recurrence are not feasible due to the increased risk of complications and morbidity. These challenges limit the timely diagnosis and selection of treatment options, hinder a better understanding of the disease, and impair the development of effective treatment approaches. There is an urgent need for developing noninvasive techniques to care for brain tumor patients.

[0119] Blood-based liquid biopsies provide noninvasive, rapid, and cost-effective methods for obtaining crucial information about tumors, showing promise for the diagnosis, molecular characterization, and monitoring of brain tumors by detecting circulating tumor-derived biomarkers (e.g., DNA, RNA, and proteins shed by tumor cells). Blood-based liquid biopsy-guided personalized therapy has entered clinical practice to treat several cancers; however, extending its application to brain cancer remains challenging. First, the blood-brain barrier (BBB), which restricts the release of brain tumor biomarkers into the peripheral circulation, resulting in extremely low concentrations of circulating tumor biomarkers. Second, conventional blood-based liquid biopsy methods do not provide information on tumor location. Third, many tumor biomarkers have short half-lives in blood, e.g., circulating tumor DNA’s half-life is 16 min to 2.5 h.

[0120] Low-intensity focused ultrasound (FUS) combined with intravenously injected microbubbles can achieve noninvasive, spatially targeted, and reversible BBB opening (BBBO), referred to as FUS-BBBO. FUS noninvasively penetrates the skull and focuses on a small focal region. Microbubbles, used in the clinic as ultrasound contrast agents, are administered by intravenous injection and are subsequently confined to the vasculature due to their relatively large sizes (1-10 pm). Microbubbles amplify and localize FUS-mediated mechanical effects on the vasculature through FUS-induced cavitation (i.e. , microbubble expansion, contraction, and collapse). Microbubble cavitation generates mechanical forces on the vasculature and increases the BBB permeability. The opened BBB usually closes within several hours. This technique has been used for the delivery of therapeutic agents from blood circulation to the brain, and its feasibility and safety have been established in patients with various brain diseases, including GBM, Alzheimer’s disease, and Parkinson’s disease.

[0121] However, the existing platform for sonobiopsies has several limitations. It must be performed in a neurosurgery suite and requires head fixation and hair shaving. While the total elapsed procedure time from when the patient was placed on the surgical table to the end of FUS sonication was only about 30 min, the neuronavigation guidance to align the FUS transducer focus to the planned tumor target took more than half of that time (FIG. 5A). Passive cavitation detector (PCD) provided real-time monitoring but not real-time feedback control of FUS sonication, which is necessary to ensure procedure consistency and safety. Thus, there is a need for a device to advance the clinical translation of sonobiopsy.

BACKGROUND

[0122] Patient-specific cap. A next-generation FUS device to substantially advance the clinical translation of sonobiopsy. This device should meet the following six criteria: (1 ) affordable, (2) no head fixation required, (3) no hair shaving required, (4) short procedure time, (5) high accuracy in targeting tumors, and (6) real-time feedback control of FUS sonication. To address this unmet need, we propose to develop the sonocap (FIG. 7B, FIG. 7C, FIG. 8A), which meets these criteria which are not meet by other devices (Table 1 ).

[0123] Accurate positioning of the FUS transducer to target the desired tumor location is crucial for successful FUS energy delivery. Existing devices require real-time MRI or optical neuronavigation guidance (Table 1 ), which lengthens the procedure and requires additional personnel to operate the guidance systems. Despite recent breakthroughs in developing wearable ultrasound imaging devices, no wearable FUS device has been used for BBBO. Previous studies proposed the concept of designing a phased-array FUS transducer for BBBO using a patient-specific helmet as a scaffold and developed a skull-conformal 4096-element phased array. However, the phased array design was complex and technically challenging to manufacture. To address the unmet need for sonobiopsy FUS devices, we developed the wearable sonocap by integrating a patient-specific 3D-printed cap with a FUS transducer (FIG. 8A). The cap will be tailored to an individual patient’s head shape and size based on MRI and CT images (FIG. 7A) for precise registration of patient’s head in the physical space with the virtual imaging space. The cap will have an opening at the accurate location required to guide FUS transducer positioning without requiring complex and bulky robotic/mechanical arms like other devices (Table 1 ). The patient-specific cap will reduce the procedure time, avoid the need for head fixation and mechanical arms, and enable accurate tumor targeting, thereby offering a patient-friendly FUS procedure.

[0124] Airy beam-enabled FUS transducer. The success of all FUS techniques fundamentally depends on the quality of transcranial ultrasound focusing. The most commonly used approach for ultrasound beam focusing is to use a single-element concave-shaped transducer. However, this type of transducer has an elongated focal region, limiting its tumor-targeting accuracy and generating off-target BBB openings. Our single-element FUS transducer has an elongated axial FWHM of 27 mm, and BBB opening outside the focal region was observed in our pig studies. Phased arrays are the most widely used approach to improve focusing. For example, ExAblate Neuro has 1024 elements with an axial FWHM of ~7 mm. However, the high cost and complexity of manufacturing limit the scalability of the phased array. 3D-printed acoustic lenses are a disruptive technology for transcranial ultrasound focusing because they can spatially modulate the phase of a transmitted wavefront with submillimeter spatial resolution at extremely low cost. Simulations and phantom experiments demonstrated the great potential of acoustic lenses designed based on time reversal for compensating skull aberrations and generating pressure fields of arbitrary shapes using holograms. These existing approaches for ultrasound beam focusing (using single-element concave-shaped transducers, phased arrays, and acoustic lenses designed based on time-reversal focusing) gradually reshape the ultrasound beam wavefront with smoothly accumulating acoustic intensity (FIG. 9).

[0125] The FUS transducers we developed is based on abruptly autofocusing Airy beams to achieve spatially precise focusing by coupling Airy beam acoustic lenses with a single-element flat transducer. The Airy function gives rise to Airy beams that laterally shift in the transverse plane along a parabolic selfaccelerating trajectory (i.e., they bend sideways like rainbows) (FIG. 9). Axisymmetric Airy beams exhibit abrupt intensity increases at the focus, which can reach three orders of magnitude larger than the acoustic intensity at the initial source plane. The ultrasharp autofocusing property of Airy beams can reduce the axial full-width-half-maximum (FWHM) to achieve accurate tumor targeting and minimize off-target effects. The lack of simple devices capable of generating megahertz Airy beams in water has prevented the use of Airy beams in medical ultrasound applications. Several structures for generating Airy beams have been manufactured, including the space coiling-up structures and Helmholtz-resonator-like structures. However, these studies focused on airborne sound waves with long wavelengths and often required the manufacturing of subwavelength units with complicated microstructures, which poses challenges to the fabrication of megahertz ultrasound devices since the wavelength is on the millimeter scale.

[0126] To address the unmet need for FUS transducers, we designed a 3D- printable acoustic lenses that can generate megahertz Airy beams and achieve transcranial ultrasharp focusing. This disruptive transducer design facilitates the development of wearable FUS transducers for targeting brain tumors located at different locations by simply switching the lens, enables the development of spatially accurate sonobiopsy with minimized concerns of off-target effects, and allows easy manufacturing and scaling of these 3D-printable lenses.

[0127] PCD for individualized closed-loop feedback control of FUS sonication. A critical challenge in performing FUS-BBBO in the clinic is the variability of the treatment, leading to inconsistent treatment outcomes. This is caused by variations among patients in the ultrasound pressure and microbubble size distribution and concentration within the FUS focal region. In situ acoustic pressures vary due to skull heterogeneity and variation in the incident angle of the FUS beam relative to the skull. The in situ microbubble concentration distribution in the targeted brain region varies due to differences in factors such as microbubble injection speed, vascular density, vessel size, and blood flow. PCD is a sensitive technique for monitoring microbubble cavitation emissions during FUS sonication (FIG. 5B). The measured stable cavitation level was linearly correlated with BBB opening outcome, and inertial cavitation could be associated with brain tissue damage. To address the large variability associated with the procedure, Exablate Neuro calibration required ramping up the pressure to an “upper threshold” and then maintaining the pressure at a fixed percentage of the upper threshold (e.g., 50%). The need to reach the upper threshold for the calibration increases the risk of generating inertial cavitation, and the system becomes an open loop after reaching the threshold. While other strategies do not consider the variations in microbubbles because TCL was defined without microbubbles being injected.

[0128] To address the limitations of existing approaches, we developed an individualized closed-loop feedback control algorithm that establishes the TCL based on a “lower threshold” defined with individual variations in ultrasound and microbubble considered. This closed-loop feedback control algorithm has three benefits. (1 ) Improved safety: By defining a lower threshold for the stable cavitation level, the algorithm reduces the risk of reaching levels that may cause inertial cavitation and potentially lead to brain tissue damage. (2) Enhanced consistency: The individualized approach accommodates variations in ultrasound pressure and microbubble concentration, leading to more consistent outcomes among patients. (3) Better control and monitoring: Closed-loop feedback control provides real-time adjustments to FUS parameters and ensures that the desired stable cavitation level is maintained throughout the procedure. Implementing this individualized closed-loop feedback control algorithm improves the consistency and safety of the sonobiopsy procedure for each patient, ultimately enhancing the clinical translation of sonobiopsy and improving patient outcomes.

[0129] Acoustic coupling medium to avoid hair shaving. An important component in any ultrasound therapy system is the method for coupling the acoustic energy into the patient. Achieving optimal acoustic coupling can be challenging and is often the hardest step in the procedure. This is because hair is naturally covered in sebum, consisting primarily of lipids and wax produced by glands on the scalp. This layer of lipids contributes to the hydrophobicity of the hair surface, which leads to the formation of air bubbles when the hydrophobic hair surface comes into contact with ultrasound gel (which is mainly water). These air bubbles reflect almost 100% of the ultrasound wave and result in failure or inconsistent delivery of ultrasound energy to the brain. Therefore, hair is shaved in all reported clinical FUS-BBBO studies. The psychological impact of removing hair could decrease the acceptance of sonobiopsy to patients and physicians as a diagnostic technique

[0130] To resolve these challenges, we used hydrophobic mineral oil as a coupling medium, which avoided trapping air bubbles on the hydrophobic hair surface and facilitated acoustic coupling without hair shaving. Mineral oil has previously been used as an acoustic coupling medium for therapeutic ultrasound applications but has not been used for coupling through hair. The acoustic properties of mineral oil were thoroughly characterized and reported to be only slightly different from those of water and ultrasound gel, especially when only a thin layer was used. Our acoustic coupling method is simple, safe, and can be straightforwardly used in patients to avoid hair shaving, which can improve the acceptance of sonobiopsy by patients and physicians.

RESULTS

[0131 ] Airy beam lens for ultrasound beam focusing. A binary acoustic lens can produce Airy beams in water; thus, we invented a simple-to-design and easy-to-fabricate approach to generate megahertz Airy beams in water using 3D-printed acoustic lenses (FIG. 10A). We designed these lenses by calculating the Airy beam pressure profile at the initial plane using P_0 (r)=Ai((r_0- r)/w)exp['”i(a (r_O-r)/co), where Ai (■) denotes the Airy function, r is the radial distance, r_0 is related to the radial position of the main Airy ring, co is a scale factor, and a is a decay factor. The pressure profile was converted to a binary phase of 0 for P_0 (r)>0 and n/2 for P_0 (r)<0 (FIG. 10A). This design was implemented by 3D printing with two coding bits, a polylactic acid unit (the material commonly used by 3D printers) acting as the bit "1" and a water unit acting as the bit "0". The thickness of the unit "1" was calculated using d=(c_1 c_2 4f(c_2-c_1 )) to produce a phase delay of TI/2 between unit 1 and unit 0, where f is the frequency and c_1 and c_2 are sound speed of water and polylactic acid, respectively. The focal depth and FWHM are tunable by adjusting the design parameters, r_0 and co, which are scalable by A (A is the wavelength). We designed and printed several lenses and coupled them with a planar ultrasound transducer to generate different focusing patterns. We achieved ultrasharp focusing with axial FWHM = 2.7A (FIG. 10B). Using the same lens design, the axial FWHM of a 560 kHz transducer is estimated to be 7.4 mm. We also showed that the focal region size is tunable (FIG. 10C), and superimposing can be used to generate multifocal points, such as bifocal (FIG. 10D) and arbitrary pattern focusing (FIG. 10E). These data demonstrate that Airy beams can be generated by 3D-printed acoustic lenses, and these lenses have great flexibility in ultrasound beam manipulation.

[0132] Individualized closed-loop feedback control is feasible in large animals. We developed an individualized closed-loop feedback control algorithm and validated its performance in pigs. This algorithm defines TCL based on a lower threshold of the stable cavitation level determined using a "dummy" FUS sonication in the presence of microbubbles. The dummy sonication applied a low acoustic pressure (0.3 MPa measured in free field) for a short duration (5 s) in the presence of intravenously infused microbubbles. Closed-loop feedback- controlled FUS-BBBO in pigs was then achieved through two sonication phases: the ramping-up phase to reach the TCL and the maintaining phase to control the stable cavitation level at the TCL by adjusting the FUS acoustic pressure (FIG.

11 A). Safe and controlled BBB opening was achieved as the TCL increased from 0.25 to 1 dB (FIG. 11 B, FIG. 11 C). The stability of the control algorithm was measured by the good pulse rate, which calculated the percentage of ultrasound pulses with stable cavitation levels within the predefined desired range (i.e. , TCL ± tolerance range). The tolerance range was set to ±0.4 dB to reduce the sensitivity to noise. A high good pulse rate (65-96%) was achieved.

[0133] Mineral oil for acoustic coupling medium for hair. We demonstrated that mineral oil could be used for coupling through mouse hair, leveraging oil’s high affinity to hair due to its inherent hydrophobicity. We compared FUS-BBBO outcomes in mice (n=5 per group) under three coupling approaches (FIG. 12): (1 ) new approach with oil and no shaving (FIG. 12; top), (2) conventional approach using ultrasound gel and hair shaving (FIG. 12; middle), and (3) comparison group using ultrasound gel and no shaving (FIG. 12; bottom). For the new approach, mineral oil was applied to the mouse's head. Then, additional oil was added on top of the hair for coupling with a FUS transducer that was attached to a water bladder. For the conventional approach, hair was removed using depilatory cream, and the scalp was thoroughly cleaned using alcohol pads. Degassed ultrasound gel was then applied to couple with the FUS transducer. For the comparison group, hair was first cleaned using alcohol pads. Degassed water was added to the hair, and ultrasound gel was applied to the wetted hair. The quality of the coupling was evaluated by T2-weighted MRI to detect air bubbles in the coupling medium. We found that oil achieved high- quality coupling without trapping air bubbles, similar to gel with shaving. In contrast, bubbles were detected in the ultrasound gel with the hair group. FUS- BBBO outcomes using mineral oil were not significantly different from that of the conventional approach but higher than ultrasound gel with hair.

METHODS AND EXPERIMENTAL DESIGN Cap design and construction

[0134] The cap will be designed using the following process. (1) Acquire patient head MRI and CT data and process the data using 3D Slicer to segment the scalp, skull, brain, and tumor. (2) Generate a 3D model of the patient’s head using software such as Blender. (3) Design a cap that matches the patient’s head shape and securely fits the head. (4) Design an opening for the FUS transducer. A desired tumor target location will be selected based on the MRI scan. A line that connects the selected tumor location with its nearest skull location will be used to define the acoustic axis of the FUS transducer (FIG. 9A). The shortest distance is selected to minimize exposure of brain tissues to FUS sonication. The FUS transducer position will be determined as perpendicular to the acoustic axis and in contact with the scalp. The opening will have two slots on the side to guide the positioning of the acoustic lens to ensure proper orientation relative to the skull. It also will have two slots on the back for securing the locking plate (FIG. 9B, FIG. 9C). (5) Print the cap using a large-volume highspeed 3D printer (Liquid Crystal Magna, Photocentric Ltd). We will distribute small holes (e.g., 10 holes with 2-mm diameter each) on the cap and fill them with Vaseline. These holes will serve as fiducial markers for assessing the registration accuracy of the cap by measuring the offset between the intended and actual locations of the fiducial markers.

Phantom evaluation

[0135] Customized human head phantoms from True Phantom Solutions Inc. (FIG. 13A, FIG. 13B, FIG. 13C) were used. These phantoms were made based on MRI and CT images of 10 GBM patients. We have obtained these images from 54 patients for our previous evaluation of the neuronavigation-guided sonobiopsy device. We selected images from 10 patients (5 male and 5 female) to cover both sexes and different ages. Each phantom consists of three components: (1) An anatomically correct brain phantom with an implant to represent the tumor; (2) A skull phantom with acoustic properties matching those estimated from the CT scans; (3) A soft skin tissue phantom created based on MRI scans to represent the soft tissue on the head. The 3D-printed cap is fitted on the phantom. MRI was performed to measure spatial registration accuracy using the average offset of the fiducial markers on the cap. We attached real human hair wigs to the head phantom; 3 male and 3 female hair types were selected to represent different racial groups (Caucasian, African, and Asian) and evaluate the impact of hair type on the cap’s registration accuracy.

[0136] We designed Airy beam lenses based on the MRI and CT scans of each human head phantom (n=10, 5 male and 5 female). The top piece of the skull phantom is detachable (FIG. 13B). We designed the FUS transducer for sonicating through this piece of the skull. A skull positioner will be designed to hold the lens at the exact location relative to the skull. We then measure the acoustic pressure fields using a hydrophone in a water tank and quantify the transcranial targeting accuracy by the offset between the intended and actual FUS focus location and the FWHM focal region size. We also design and print time-reversal lenses and compare their performance with the designed Airy beam lenses.

[0137] The performance of the algorithm is evaluated using the top piece of the human skull phantom (n=10, 5 male and 5 female), which will be placed above a tube (5-mm diameter) for infusing microbubbles in a water tank. The skull holder is used to hold the skull and the FUS transducer. We will evaluate algorithm performance by measuring the good pulse rate under three TCLs (0.25, 0.5, and 1 dB above the lower threshold).

Airy beam lens design pipeline

[0138] Designing the Airy beam lens followed a three-step process. Step 1: The initial design of the Airy beam lens. The FUS transducer position on the patient’s head is determined as described above. The FUS frequency is 650 kHz. The transducer aperture starts at 6 cm and can later be optimized based on simulation. We designed the acoustic lens using the superimposing method. One side of the lens that faces the skull is designed using time reversal to compensate for skull aberrations, and the other side is designed to generate the Airy beam. Mineral oil is used as the coupling medium when designing the lens. Briefly, skull density and thickness information obtained from CT scans is used to estimate sound speed for numerical simulations of ultrasound pressure fields inside the skull using the k-Wave MATLAB toolbox. Numerical simulations are performed to calculate the acoustic field back propagated from the selected tumor target to the transducer surface, and the lens is designed using phaseconjugation to compensate for skull phase aberrations. Step 2: Evaluate the designed lens using forward simulation. We performed numerical simulations by coupling the designed lens with a flat 650 kHz transducer to simulate the pressure field distribution inside the skull. We evaluate the designed lens by calculating (1 ) the FWHM of the focal region and (2) the transcranial targeting accuracy using the offset between the simulated focus location and the selected tumor target location. Step 3: Perform iterative optimization of the lens design. We repeat the above two steps with different lens design parameters (aperture, r₀ , and co) until the following three design criteria are met. (1) Transcranial targeting offset will be <5 mm to achieve accurate tumor targeting. Our previous numerical simulation using GBM patient MRI and CT images determined that the transcranial targeting offset of a single-element concave-shaped FUS transducer was 5.5 ± 4.9 mm. The Airy beam-enabled FUS transducer is expected to perform better than this. (2) Axial FWHM will be <7 mm, comparable to that of the Exablate Neuro, to demonstrate the capability of the Airy beam in achieving ultrasharp focusing. (3) Lens diameter will be <6 cm to minimize the weight of the transducer.

FUS transducer construction

[0139] The designed lenses are printed using a high-resolution 3D printer (Ultimaker S5) and polylactic acid filament to ensure a well-defined print and smooth surface finish that prevents unwanted sound attenuation and reflection (FIG. 10A). After printing, these lenses will be coupled with a planar piezoelectric lead zirconate titanate (PZT) element with air backing. PZT is commonly used in ultrasound transducers due to its high transmission efficiency. Two wires will be soldered to the positive and negative electrodes of the element and connected to a function generator via a power amplifier. An electric impedance matching network will be designed to optimize transmission efficiency.

PCD sensor

[0140] The PCD sensor needs to meet the following design criteria: (1) small size (<6 mm diameter) to minimize impacts on acoustic lens performance; (2) sensitive to detect cavitation emissions through the skull; (3) wide directivity to detect cavitation emissions over a large volume. The PCD sensor is a circularshaped planar ultrasound transducer with a center frequency of 2.25 MHz, a 6- dB bandwidth of 1.39 MHz, and an aperture of 6 mm. We integrated this sensor with the FUS transducer by inserting the PCD sensor through a hole in the middle of the flat ultrasound transducer (FIG. 8C). The PCD will be connected to a digital oscilloscope (Picosocpe) and a computer for real-time data acquisition and processing.

Cavitation feedback control algorithm

[0141] The algorithm developed in our preliminary study is promising in pigs with the pig age and targeted brain location kept consistent (FIG. 11 A). However, when translating it to human subjects, we encounter a challenge due to the large variations in skull properties and targeted brain locations among patients. When using the same low pressure (0.3 MPa in free field) to perform the dummy sonication to define the lower threshold for the feedback control algorithm, the in situ pressure in the targeted brain regions varies. This variability limits the algorithm’s ability to ensure consistent and safe FUS sonication among patients. We overcame this weakness by utilizing a new method for defining the lower threshold. We will ramp up the ultrasound pressure from 0 at a step size of 0.01 MPa in the presence of continuously infused microbubbles until the stable cavitation level is significantly higher than the background noise level measured when the pressure was 0. The stable cavitation level will be measured by the amplitude of the 4^th harmonics of the FUS (2.24 MHz), which is selected for its proximity to the center frequency of the PCD and its detectability only in the presence of microbubbles (2^nd and 3^rd harmonics can be generated by FUS sonication without microbubbles, according to our clinical PCD data). Once the lower threshold is reached, the pressure will continue to increase step by step until the stable cavitation level reaches the TCL defined in reference to the lower threshold. The control algorithm will then switch to the maintaining phase, where the acoustic pressure will be adjusted to maintain the stable cavitation level within the target range (i.e. , TCL ± tolerance range of 0.4 dB) until the end of the sonication. If the stable cavitation level falls outside the target range, the FUS output pressure of the next pulse will immediately decrease or increase by the step size (0.01 MPa). Other sonication parameters: pulse repetition frequency=1 Hz, pulse length=10 ms, duration= 5 s at each step, and total duration=3 min. FUS sonication will stop when inertial cavitation is detected to avoid tissue damage.

Acoustic coupling method

[0142] After placing the cap on the patient’s head, we add mineral oil to the cap opening (FIG.8A, FIG. 8B), allowing oil to saturate the hair and reach the scalp. Additional oil will be added to the opening, which serves as an oil reservoir. We coat the Airy beam lens surface with oil and slide it into the opening along with the flat transducer. The locking plate will rotate in and push the FUS transducer against the hair to squeeze out air bubbles, if there are any, in the coupling medium.

[0143] We test the coupling method using human hair wigs. The coupling quality will be evaluated by T2-weighted MRI scans (FIG. 12). The acquired images are processed to quantify the number of voxels that contain bubbles.

Sonobiopsy workflow using the sonocap

[0144] The sonocap will be designed for rhesus macaques (n=4, 2 male and 2 female, 5-12 kg) and will be used for sonobiopsy following the workflow summarized in FIG. 15. The cap and FUS transducer will be scaled down from human to NHP size. During the sonobiopsy procedure, the NHP will be under anesthesia (anesthesia is not needed for human patients). The cap will be fitted to the NHP head, and the FUS transducer will be inserted into the cap opening through the mineral oil coupling. Definity microbubbles will be continuously infused using a syringe pump. Closed-loop feedback-controlled FUS sonication will then be performed. Three brain locations at different depths (e.g., cortex, hippocampus, and brainstem) will be targeted to represent variability in the tumor location across patients. Three TCLs (e.g., 0.25, 0.5, and 1 dB) will be evaluated. All other sonication parameters will be kept the same as our clinical study (FIG. 5A): frequency=650 kHz, pulse repetition frequency=1 Hz, pulse length=10 ms, and total sonication duration=3 min. The procedure time from cap fitting to the end of sonication will be recorded. Blood samples will be collected before and at different time points after FUS sonication (5, 10, and 30 min) to determine the kinetics of biomarker release. The plasma concentrations of brain- specific biomarkers (e.g., GFAP and MBP) will be analyzed using ELISA assays. Repeated sonobiopsy procedures will be performed on each animal. No more than one procedure will be performed on each animal per month to minimize any potential stress to the animal. A sample size of 10 repeated measurements will allow 80% power to detect a difference of 1 ,72X<J (<J denoting pooled standard deviation) in the biomarker concentration based on the 2-sided 2-sample f-test. The total number of experiments is estimated to be 60 for testing three TCLs and three targeting depths.

MRI evaluation

[0145] Immediately after the last blood collection, the anesthetized animal will be transported to a clinical 3T MRI scanner (Simens) to obtain the following scans using standard-of-care sequences. T1 -weighted images of the head with the cap will be obtained for quantifying cap registration accuracy by calculating the average offset of fiducial markers on the cap between the planned and the actual locations. T2-weighted scans of the coupling medium will be obtained to quantify the coupling quality by calculating the number of voxels that contain bubbles. T 1 - weighted MRI scans pre- and post-administration of the MR contrast agent will be obtained to assess the location of BBB opening for evaluating the FUS targeting accuracy by calculating the offset between the planned target location and the centroid of BBB opening. The safety of FUS sonication will be assessed using the following measures: (1) acute brain tissue damage will be identified by changes in the diffusion-weighted images, (2) local edema will be detected by increased signals in the FLAIR images, and (3) bleeding at the targeted site will be detected by changes in the T2* susceptibility imaging. After the MRI scans, the animal will be monitored until they recover from anesthesia. Daily observational neurological examinations will be performed by veterinarian staff to assess mentation and posture, ambulation of all four limbs, fine motor movements, appetite, and interest in enrichment.

Claims

CLAIMS What is claimed is:

1 . A wearable mounting device for facilitating a focused ultrasound procedure in a patient, the device comprising a cap custom-fitted to a shape and size of at least a portion of a head of the patient, the cap comprising: a. an outer surface and a contact surface opposite the outer surface, wherein the contact surface comprises a contact contour conforming with a corresponding outer contour of the at least a portion of the head of the patient; b. at least one circular opening defined through the cap, each opening configured to receive and retain at least one ultrasound probe at a predetermined position and orientation relative to the head of the patient; c. at least one attachment fitting, each attachment fitting comprising a rim outwardly protruding from the outer surface of the cap and attached at a perimeter of each opening, each attachment fitting further comprising a locking element to retain the at least one ultrasound probe in the at a predetermined position and orientation; and d. at least one locking plate, each locking plate comprising a disc sized to fit within each opening, wherein each disc further comprises an insertion element formed on at least a portion of a perimeter of the disc, wherein each locking plate is configured to insert over the ultrasound probe positioned within each opening and lock in place by interaction of the attachment element with the locking element of the attachment fitting.

2. The device of claim 1 , further comprising a fastener attached to the outer surface of the rim in at least two positions, wherein the fastener is configured to hold the cap securely in place on the head of the patient.

3. The device of claim 2, wherein the fastener comprises a chin strap.

4. The device of claim 1 , further comprising at least one additional opening formed through the cap, wherein each additional opening is configured to provide: a. an inlet to facilitate the introduction of an acoustic coupling medium between the inner surface of the cap and an underlying portion of the head of the patient; b. a fiduciary marker to confirm that the cap is positioned correctly; and c. any combination thereof.

5. The device of claim 1 , further comprising at least two alignment fittings formed within an inner surface of the collar and extending to an exposed surface of the collar, wherein each alignment fitting is configured to receive a locking plate alignment tab projecting radially outward from a perimeter of the locking plate and a probe alignment tab projecting radially outward from the ultrasound probe, wherein the at least two alignment fittings are configured to align the locking plate and the ultrasound probe in the predetermined position and orientation when positioned within the attachment fitting.

6. The device of claim 5, wherein: a. the locking element comprises at least one radial set screw advanced though a threaded bore defined through the rim of the attachment fitting toward the center of the opening and the locking element comprises an indentation within at least a portion of the perimeter of the locking plate, wherein the indentation is configured to receive a tip of the set screw advanced into the opening through the threaded bore; b. the locking element comprises a threaded fitting formed within an inner surface of the collar and the circumference of the locking plate comprises circumferential threads configured to thread into the threaded; or c. the locking element comprises at least two spiral channels formed within the inner surface of the collar, each spiral channel extending circumferentially from one alignment fitting and ending, wherein the at least two spiral channels are configured to receive at least alignment tabs of the locking plate or ultrasound probe when twisted into the collar of the attachment fitting.

7. The device of claim 1 , wherein the inner surface of the cap is contoured to match the corresponding outer contour of the head of the patient as measured using at imaging method selected from MR imaging methods, CT imaging methods, 3D scanning methods, and 3D optical scanning methods.

8. The device of claim 7, wherein the medical imaging method is MR imaging method, wherein the use of MR imaging method ensures that an ultrasound coordinate system of the at least one ultrasound probe is registered to an MR coordinate system.

9. The device of claim 1 , wherein the focused ultrasound procedure is selected from focused ultrasound-aided opening of the brain-blood barrier for sonobiopsy or delivery of therapeutic agents to a brain of the patient, passive cavitation imaging, ultrasound imaging, and any combination thereof.

10. A system for facilitating a focused ultrasound procedure in a patient, the device comprising a cap custom-fitted to a shape and size of at least a portion of a head of the patient and at least one ultrasound probe mounted to the cap, wherein: a. the cap comprises: i. an outer surface and a contact surface opposite the outer surface, wherein the contact surface comprises a contact contour conforming with a corresponding outer contour of the at least a portion of the head of the patient; ii. at least one circular opening defined through the cap, each opening configured to receive and retain at least one ultrasound probe at a predetermined position and orientation relative to the head of the patient; iii. at least one attachment fitting, each attachment fitting comprising a rim outwardly protruding from the outer surface of the cap and attached at a perimeter of each opening, each attachment fitting further comprising a locking element to retain the at least one ultrasound probe in the at a predetermined position and orientation; iv. at least one locking plate, each locking plate comprising a disc sized to fit within each opening, wherein each disc further comprises an insertion element formed on at least a portion of a perimeter of the disc, wherein each locking plate is configured to insert over the ultrasound probe positioned within each opening and lock in place by interaction of the attachment element with the locking element of the attachment fitting, a transducer housing unit configured to contain the ultrasound transducer; and b. each ultrasound probe is configured to deliver ultrasound energy to a predetermined region of interest within a brain of the subject, wherein each ultrasound probe comprises an ultrasound transducer selected from a focused ultrasound transducer, an unfocused ultrasound transducer, and an unfocused ultrasound transducer acoustically coupled in series with an acoustic lens configured to focus the ultrasound energy to the predetermined region of interest; wherein the ultrasound probe is positioned within the opening of the attachment fitting over an underlying portion of the head and locked into place at the predetermined position and orientation by the locking plate inserted and locked into the opening of the attachment fitting over the ultrasound probe.

11 . The system of claim 10, further comprising a fastener attached to the outer surface of the rim in at least two positions, wherein the fastener is configured to hold the cap securely in place on the head of the patient.

12. The system of claim 11 , wherein the fastener comprises a chin strap.

13. The system of claim 10, further comprising at least one additional opening formed through the cap, wherein each additional opening is configured to provide: a. an inlet to facilitate the introduction of an acoustic coupling medium between the inner surface of the cap and an underlying portion of the head of the patient; b. a fiduciary marker to confirm that the cap is positioned correctly; and c. any combination thereof.

14. The system of claim 10, further comprising at least two alignment fittings formed within an inner surface of the collar and extending to an exposed surface of the collar, wherein each alignment fitting is configured to receive a locking plate alignment tab projecting radially outward from a perimeter of the locking plate and a probe alignment tab projecting radially outward from the ultrasound probe, wherein the at least two alignment fittings are configured to align the locking plate and the ultrasound probe in the predetermined position and orientation when positioned within the attachment fitting.

15. The system of claim 10, wherein: a. the locking element comprises at least one radial set screw advanced though a threaded bore defined through the rim of the attachment fitting toward the center of the opening and the locking element comprises an indentation within at least a portion of the perimeter of the locking plate, wherein the indentation is configured to receive a tip of the set screw advanced into the opening through the threaded bore; b. the locking element comprises a threaded fitting formed within an inner surface of the collar and the circumference of the locking plate comprises circumferential threads configured to thread into the threaded; or c. the locking element comprises at least two spiral channels formed within the inner surface of the collar, each spiral channel extending circumferentially from one alignment fitting and ending, wherein the at least two spiral channels are configured to receive at least alignment tabs of the locking plate or ultrasound probe when twisted into the collar of the attachment fitting.

16. The system of claim 10, wherein the inner surface of the cap is contoured to match the corresponding outer contour of the head of the patient as measured using at imaging method selected from MR imaging methods, CT imaging methods, 3D scanning methods, and 3D optical scanning methods.

17. The system of claim 16, wherein the medical imaging method is MR imaging method, wherein the use of MR imaging method ensures that an ultrasound coordinate system of the at least one ultrasound probe is registered to an MR coordinate system.

18. The system of claim 10, wherein the focused ultrasound procedure is selected from focused ultrasound-aided opening of the brain-blood barrier for sonobiopsy or delivery of therapeutic agents to a brain of the patient, passive cavitation imaging, ultrasound imaging, and any combination thereof.

19. The system of claim 10, further comprising an amount of an acoustic coupling medium between the ultrasound probe and the head of the subject, wherein the acoustic coupling medium comprises mineral oil.

20. The system of claim 10, wherein the ultrasound probe comprises a flat transducer coupled to the acoustic lens, the acoustic lens comprising an acoustically transmissive material configured to spatially modulate the ultrasound energy produced by the flat transducer to produce a uniform ultrasound beam through the predetermined region of interest.

21 . The system of claim 20, wherein the acoustic lens is selected from an Airy lens and a Fresnel lens.

22. The system of claim 21 , wherein the acoustic lens comprises a first surface contacting the flat transducer and a second surface contacting the underlying portion of the head of the patient, wherein the first surface defines a plurality of phase modulation features configured to focus the acoustic beam produced by the flat transducer into a uniform ultrasound beam through the predetermined region of interest of the patient.

23. The system of claim 22, wherein the second surface of the acoustic lens defines a plurality of additional phase modulation features configured to compensate for non-homogeneous tissue types present in the underlying portion of the head of the patient between the head surface and the predetermined region of interest, wherein the non- homogeneous tissue types are selected from skin tissue, bone tissues, circulatory vessels, grey matter, white matter, cerebrospinal fluid, and any combination thereof.

24. The system of claim 10, wherein the ultrasound probe further comprises a passive cavitation detector (PCD).

25. The system of claim 10, wherein the ultrasound probe further comprises at least one port configured to electrically connect the ultrasound transducer to at least one additional system selected from a data acquisition (DAQ) system, a detector system, and an ultrasound transducer driving system.

26. The system of claim 25, further comprising at least one of the additional systems operatively coupled to the at least one ports of the ultrasound probe.