WO2020157536A1 - Focalisation ultrasonore transcrânienne - Google Patents

Focalisation ultrasonore transcrânienne Download PDF

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Publication number
WO2020157536A1
WO2020157536A1 PCT/IB2019/000185 IB2019000185W WO2020157536A1 WO 2020157536 A1 WO2020157536 A1 WO 2020157536A1 IB 2019000185 W IB2019000185 W IB 2019000185W WO 2020157536 A1 WO2020157536 A1 WO 2020157536A1
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Prior art keywords
usp
event
ultrasound
skull
calibration
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PCT/IB2019/000185
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English (en)
Inventor
Oron Zachar
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Oron Zachar
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Priority to PCT/IB2019/000185 priority Critical patent/WO2020157536A1/fr
Priority to US17/425,347 priority patent/US20220126120A1/en
Publication of WO2020157536A1 publication Critical patent/WO2020157536A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N7/02—Localised ultrasound hyperthermia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08—Detecting organic movements or changes, e.g. tumours, cysts, swellings
    • A61B8/0808—Detecting organic movements or changes, e.g. tumours, cysts, swellings for diagnosis of the brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/44—Constructional features of the ultrasonic, sonic or infrasonic diagnostic device
    • A61B8/4477—Constructional features of the ultrasonic, sonic or infrasonic diagnostic device using several separate ultrasound transducers or probes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/58—Testing, adjusting or calibrating the diagnostic device
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00681—Aspects not otherwise provided for
    • A61B2017/00725—Calibration or performance testing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/54—Control of the diagnostic device
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0004—Applications of ultrasound therapy
    • A61N2007/0021—Neural system treatment
    • A61N2007/0026—Stimulation of nerve tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0056—Beam shaping elements
    • A61N2007/006—Lenses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0078—Ultrasound therapy with multiple treatment transducers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0086—Beam steering
    • A61N2007/0095—Beam steering by modifying an excitation signal

Definitions

  • Embodiments of the present invention relate to systems and methods for ultrasound focusing.
  • various embodiments are directed to efficient methods of focusing a phased array of ultrasound transducer elements, using preparatory measurements to adjust the relative phases of the transducer elements.
  • Ultrasounds are mechanical waves (with a frequency of more than 20 kHz) that travel with alternating compression and rarefaction, thereby transmitting energy by molecular movements.
  • the frequencies used for the transcranial FUS are either mid-frequency (e.g., around 650 kHz) or low frequency (e.g., around 220 kHz).
  • the speed of ultrasound transmission is medium dependent (eg, water and soft tissue are excellent conductors, but air and bone are not). Transmission necessitates a coupling medium (eg, degassed water) between the transducer and biological tissue.
  • FUS Fluorescence-Activated senor
  • a reversible conduction block in peripheral nerves. This conduction block is associated with a mild increase in local temperature (41°C to 45°C) and is mediated by the inactivation of sodium channels. It can produce transient clinical results that may last for a few minutes and are particularly appealing for target localization in functional neurosurgery.
  • FUS can also reversibly open the blood-brain barrier without ablation. Blood-brain barrier opening can be reliably achieved at subthreshold intensities with the use of microbubbles.
  • a recent proof-of-concept study demonstrated localized blood-brain barrier openings of approximately 1 cm3 with very low sonication power (5 W and 230 kHz transducer).
  • FUS creates tissue ablation, the mechanism of which is dependent on frequency.
  • the mid-frequency system 650 kHz
  • the low- frequency system (220 kHz) achieves ablation via cavitation or histotripsy, in which ultrasound interacts with trapped gas bubbles within tissues that leads to the rapid oscillation and collapse of those bubbles.
  • Therapeutic sonications temperature greater than 55°C
  • subthreshold sonications can be a screening tool for target selection for therapeutic interventions, especially in situations where either conventional screening (eg, levodopa challenge) provides insufficient answers (eg, subthalamic nucleus vs VIM for patients with a dual diagnosis of PD and essential tremor) or the most efficacious target for neuromodulation is unclear (eg, subthalamic nucleus vs globus pallidus internus for patients with PD).
  • Thermal ablation as may be accomplished using focused ultrasound, has particular appeal for treating tissue within the brain and other tissue regions deep within the body, because it generally does not disturb intervening or surrounding healthy tissue. Focused ultrasound may also be attractive, because acoustic energy generally penetrates well through soft tissues, and ultrasonic energy, in particular, may be focused towards focal zones having a cross-section of only a few millimeters due to relatively short wavelengths (e.g., as small as 1.5 millimeters (mm) in cross-section at one Megahertz (1 MHz)). Thus, ultrasonic energy may be focused at a region deep within the body, such as a cancerous tumor or other diseased tissue, to ablate the diseased tissue without significantly damaging surrounding healthy tissue.
  • a region deep within the body such as a cancerous tumor or other diseased tissue
  • a piezoelectric transducer may be used that includes a plurality of transducer elements.
  • a controller may provide drive signals to each of the transducer elements, thereby causing the transducer elements to transmit acoustic energy such that constructive interference occurs at a“focal zone”.
  • the focal zone is typically defined as the region of intensity higher than half maximum, and is commonly characterized by a“peak width” in a given direction.
  • the peak width may be anisotropic. In fact, most realized instrumental systems produce an elliptical shaped peak cross-section at half maximum.
  • sufficient acoustic energy may be delivered to generate the desired tissue activation (e.g., heating, necrosis, neural stimulation, etc%) within the focal zone and for a sufficient period until tissue affects occurs.
  • tissue along the path through which the acoustic energy passes (“the pass zone”) outside the focal zone, is affected (e.g, heated) only minimally, if at all, thereby minimizing damaging tissue outside the focal zone.
  • the pass zone tissue along the path through which the acoustic energy passes
  • the pass zone tissue along the path through which the acoustic energy passes
  • the pass zone tissue along the path through which the acoustic energy passes
  • the pass zone is affected (e.g, heated) only minimally, if at all, thereby minimizing damaging tissue outside the focal zone.
  • Phased arrays of ultrasound transducers are well-known as a system for focusing ultrasound energy at target sites inside the body. Constructive and destructive interference of acoustic waves transmitted by multiple transducers can be used to deliver complex spatio
  • phased arrays use tens to hundreds or even thousands of ultrasound transducers distributed spatially on the surface of the body. For instance, a phased array placed on the head can be used to target an area deep in the brain.
  • phased arrays have important limitations for delivering ultrasound transcranially for neuromodulation.
  • Phased arrays use spatially distributed transducers, requiring a larger form factor.
  • large and generally unportable power and control components are required to manage the timing, intensity, phase, and other properties of the ultrasound waves transmitted by each of the transducers.
  • Focused ultrasound i.e., acoustic waves having a frequency greater than about 20 kilohertz
  • ultrasonic waves may be used to ablate tumors, eliminating the need for the patient to undergo invasive surgery.
  • a piezo-ceramic transducer is placed externally to the patient, but in close proximity to the tissue to be ablated (the“target”).
  • the transducer converts an electronic drive signal into mechanical vibrations, resulting in the emission of acoustic waves (a process hereinafter referred to as“sonication”).
  • the transducer may be shaped so that the waves converge in a focal zone.
  • the transducer may be formed of a plurality of individually driven transducer elements whose phases (and, optionally, amplitudes) can each be controlled independently from one another and, thus, can be set so as to result in constructive interference of the individual acoustic waves in the focal zone.
  • a“phased-array” transducer facilitates steering the focal zone to different locations by adjusting the relative phases between the transducers, and generally provides the higher a focus quality and resolution, the greater the number of transducer elements.
  • Magnetic resonance imaging (MRI) may be utilized to visualize the focus and target in order to guide the ultrasound beam.
  • the transducer While the transducer is located external to the patient, it must be in direct contact and tightly coupled with a media that efficiently transmits the high frequency ultrasound waves.
  • the transducer can be positioned in a liquid bath that is capable of efficient transmission of the ultrasound waves.
  • the patient's body must also be wetted and tightly coupled to the transmission media in order to ensure an optimal acoustic wave transmission path from the transducer to the focal zone.
  • tissue homogeneity may vary significantly from patient to patient, and even between different tissue regions within the same patient. Tissue inhomogeneity may decrease intensity of the acoustic energy at the focal zone and may even move the location of the focal zone within the patient's body. Specifically, because the speed of sound differs in different types of tissue, as portions of a beam of acoustic energy travel along different paths towards the focal zone, they may experience a relative phase shift or time delay, which may change the intensity at the focal zone and/or move the location of the focal zone.
  • the speed of sound through fat is approximately 1460 meters per second (m/s)
  • the speed of sound through muscle is approximately 1600 meters per second (m/s).
  • the speed of sound through bone tissue is much faster, for example, approximately 3000 meters per second (m/s) for skull bone tissue.
  • the speed of sound also varies in different organs.
  • the speed of sound in brain tissue is approximately 1570 meters per second (m/s), approximately 1555 meters per second (m/s) in the liver, and approximately 1565 meters per second (m/s) in the kidney.
  • the relative phases (alternatively relative“time shift”) at which the transducer elements need to be driven to result in a focus at the target location depend on the relative location and orientation of the transducer surface and the target, as well as on the dimensions and acoustic material properties (e.g., sound velocities) of the tissue or tissues between them (i.e., the“target tissue”).
  • the relative phases (and, optionally, amplitudes) can be calculated, as described, for example, in U.S. Pat. Nos.6,612,988, 6,770,031, and 7,344,509, the entire disclosures of which are hereby incorporated by reference.
  • the auto-focusing procedure may thus take a substantial amount of time, which may render it impracticable or, at the least, inconvenient for a patient. While the effect of pre-therapeutic sonications may be minimized by employing an imaging technique that requires only low acoustic intensity (e.g., ARFI), it is generally desirable to limit the number of sonications prior to treatment. Accordingly, there is a need for more efficient ways of focusing a phased array of transducer element to create a high-quality ultrasound focus.
  • an imaging technique that requires only low acoustic intensity (e.g., ARFI)
  • Another common technique for focusing ultrasound is by using a shaped lens with an acoustic velocity (i.e. speed of sound) that differs from adjoining air, tissue, or material to bend acoustic waves.
  • Most standard ultrasound focusing lenses employ a single concave lens.
  • a single concave lens focusing system for ultrasound has limitations. Ultrasound lenses comprised of a single concave lens are limited with regard to the range of focal lengths that can be achieved with a lens of a particular cross-sectional area. Short focal lengths cannot be achieved with smaller cross-sectional areas appropriate for systems affixed to the head or skull.
  • Neuromodulation of superficial brain regions with an appropriate transcranial ultrasound system would be advantageous due to the importance of such superficial brain regions (e.g. cerebral cortex) to sensory, motor, higher cognitive function, and other brain functions.
  • transcranial ultrasound neuromodulation requires appropriate ultrasound waveform parameters, including acoustic frequencies generally less than about 10 MHz, spatial-peak temporal-average intensity generally less than about 10 W/cm2 (e.g., between 0.5 and 10 W/cm2), and appropriate pulsing and other waveform characteristics to ensure that heating of a targeted brain region does not exceed about 2 degrees Celsius for more than about 5 seconds.
  • Transcranial ultrasound neuromodulation induces neuromodulation primarily through vibrational or mechanical mechanisms.
  • Noninvasive and nondestructive transcranial ultrasound neuromodulation is in contrast to other transcranial ultrasound based techniques that use a combination of parameters to disrupt, damage, destroy, or otherwise affect neuronal cell populations so that they do not function properly and/or cause heating to damage or ablate tissue.
  • Image quality in transcranial ultrasound remains limited by the deleterious effects of the presence of the skull, including attenuation, aberration, refraction, and mode conversion.
  • An anatomical sources of aberration include layers of bone in the skull (c »2800 m/s, commonly within 15% variation due to difference in bone porosity and thickness) or layers of fat (c » 1450).
  • Fig. 1A shows human anatomy. Shown in Fig. 1A is (i) a skull 150 having a non-uniform thickness; and (ii) brain tissue 98 therein. Skull 150 has two illustrated surfaces which face away from each other: (i) surface 151 of skull 150 is the outer-facing skull surface which faces away from the brain tissue 98 and towards the outside world; and (ii) surface 152 of skull 150 is the inner-facing skull surface which faces inwardly towards the brain tissue 98.
  • outer-facing skull surface is used interchangeably with skull outer surface (or outer skull surface)– the abbreviation SOS may be used and
  • inner- facing skull surface is used interchangeably with skull inner surface (or inner skull surface– the abbreviation SIS may be used.
  • target location 900 is located in space at coordinates (x Target ,y Target ,z Target ).
  • the delivered energy has as‘tight’ of a focus as possible– e.g. most energy is focused at target location 900 within the peak area half-width half-maximum (HWHM).
  • HWHM peak area half-width half-maximum
  • Figs.2A illustrates a hypothetical situation where ultrasound is delivered through a unifom medium.
  • a spherical array of infinitely small ultrasound transducers produces a perfectly coherent peak such that ultrasound waves emitted form different transducers interfere constructively, which results in a perfect focus at target location 900.
  • Fig.2A there is no biological tissue– no skull 150, and no brain tissue 98. In this non-physical hypothetical situation, the focus is perfect.
  • Some embodiments of the invention relate to providing“feature A’ and/or“feature B” and/or “feature C” and/or“feature D” and/or“feature E” and/or“feature F” and/or“feature G” and/or “feature H” and/or“feature I,” described below in the present section.
  • Embodiments of the present invention relate to systems and methods for ultrasound focusing.
  • various embodiments are directed to efficient methods of focusing a phased array of ultrasound transducer elements, using preparatory measurements to adjust the relative phases of the transducer elements.
  • ultrasound when material (e.g. the skull or brain) is‘irradiated’ with ultrasound, this means that ultrasound is delivered to the material (e.g. the skull or brain).
  • Embodiments of the invention relate to apparatus and methods for generating an ultrasound intensity-peak within a human subject brain around a target peak location in the brain.
  • embodiments of the present invention overcome any defocusing attributable to: (i) differences in the speed of sound between the skull and underlying brain tissue; (ii) the fact that the skull is of non-uniform thickness; and (iii) the fact that the speed of sound within the skull is not uniform.
  • Some embodiments are disclosed and claimed in terms of generating an ultrasound intensity- peak within a human subject brain.
  • the presently disclosed teaching may be employed to produce an ultrasound intensity-peak within a generally round object (e.g. having a representative radius curvature of at (i) at least 7 cm or at least 10 cm and/or (ii) at most 50 cm or at most 40 cm or at most 25 cm)( of having: (i) an outer crust (e.g. including but not only skull/bone) having a lower liquid content (e.g. of non-uniform thickness) and (ii) underlying material (e.g. including brain but not only brain) having a greater liquid content.
  • the ultrasound is delivery from transducers outside of the crust, through the crust, and into the underlying material so as to produce the ultrasound intensity-peak within the underlying material.
  • transducers disposed outside of the head are operated at phase-shifts that are computed by analyzing ultrasound measurement data acquired during a previously-performed calibration stage.
  • the skull or any other crust
  • USP ultrasound skull-probe events
  • UCP ultrasound crust-probe UCP event for the more general case
  • the skull is not a flat plane
  • the skull is a generally round object, and the local surface orientation of the skull (i.e. the vector perpendicular to a local plane of any given location on the skull or other crust).
  • Feature A the skull (or other crust) at a variety of locations (Feature A) which may be distancesd from each other (Feature B), but this entails probing the skull or a variety of different local skull-surface orientations (or orientations of any other crust) (Feature C).
  • an energy flux vector of the ultrasound test signal is substantially perpendicularly incident on the skull (Feature D).
  • Feature E Another feature provided by embodiments of the invention (Feature E) is that ultrasound transducers (i.e. those which participate in the calibration stage as calibration emitters) are held stable for the entirety of the calibration stage.
  • (I) deliver ultrasound for USP (or UCP event) of the calibration stage so that a majority of power of the respective ultrasound test signal is provided from transducers in a relatively small (e.g. a sphere having a radius at most 0.5 cm locale) locale (Feature F); and/or
  • the ultrasound signal of each USP is received by one or more ultrasound transducers.
  • a difference in echo times is computed– for example, (i) a time where a signal reflected from the outer surface 151 of skull 150 may be the ‘first echo time’ and (ii) a time where a signal reflected from the inner surface 151 of skull 150 may be the‘second echo time.’
  • the second echo time may be longer than the first echo time.
  • the ultrasound transducer when measuring the echo time-differences, it is possible to (Feature H) to“re-use” an ultrasound transducer (or a location thereof) which supplies the ultrasound test signal of an USP (or UCP event) by receiving reflected ultrasound back into the same ultrasound transducer or back into another ultrasound transducer displaced therefrom by no more than 0.5 cm. This may be carried out for at least one or at least some or at least a majority of the USP (or UCP events). In some examples, this may increase the accuracy and facilitate computation of face- differences that are useful for achieving a better focus .
  • the ultrasound-intensity peak when producing the ultrasound-intensity peak within the brain beneath the skull (or other material beneath the crust), it may be possible to (Feature I) to “re-use” an ultrasound transducer (or a location thereof) which supplies the ultrasound test signal of an USP (or UCP event) during calibration.
  • an ultrasound transducer or a location thereof which supplies the ultrasound test signal of an USP (or UCP event) during calibration.
  • at least some of the transducers (or some of the locales) deliver may be same as those used to probe the skull during the USP (or UCP) event of calibration.
  • embodiments of the present invention relate to delivery of ultrasound (e.g. non- surgically– i.e. non-invasively).
  • a method for generating an ultrasound intensity-peak within a human subject brain around a target-peak-location, by delivering ultrasound through the skull comprising:
  • AUT ultrasound transducers
  • a respective ultrasound test signal UTSi emitted by one or more transducer(s) of the AUT probes the skull to produce a maximum intensity at a different respective event-specific skull-surface location max_intensity_SOS_LOC(USP-event i ) that is on the skull outer-facing surface and specific for the event USP-eventi;
  • each USP-eventi is defined by a different respective dominant emission- locale DEL(USP-event i ) such that during each USP-event i at least 20% or at least 30% or at least 50% of power of the respective ultrasound test signal UTS i received at the respective skull-surface location max_intensity_SOS_LOC (USP-event i ) on the skull is supplied by transmitter(s) of the AUT whose center(s) is(are) disposed within the dominant emission-locale DEL(USP- event i ), the dominant emission-locale DEL(USP-event i ) being spherical in shape with a radius of at most 0.75 cm or at most 0.5 cm;
  • the dominant emission locales are distributed in space so that no two dominant emission locales (DEL(USP-event j ), DEL(USP-event k )] (j1k) (both j and k are positive integers equal to at most L) are displaced from each other to have a center-center distance of less than 2 cm (alternatively, for every pair of two dominant emission locales (DEL(USP-eventj), DEL(USP-eventk)] (j1k) (both j and k are positive integers equal to at most L, a center-center distance therebetween is at least 2 cm) ; and
  • each USP-eventi having its respective ultrasound test signal UTSi and its respective dominant emission-locale DEL(USP-event i ), respectively receiving ultrasound reflected from the skull during the USP-eventi into a respective one or more of the transducer(s) of the AUT;
  • the electronic processing comprises for each USP-eventi having its respective ultrasound test signal UTSi and its respective dominant emission-locale DEL(USP-event i ), computing a respective measured echo time-difference ETD(USP-event i ) between:
  • AUT ultrasound transducers
  • each USP-eventi is defined by a different respective dominant emission- locale DEL(USP-event i ) such that during each USP-eventi at least 20% or at least 30% or at least 50% of power of the respective ultrasound test signal UTSi received at the respective skull-surface location max_intensity_SOS_LOC (USP-event i ) on the skull is supplied by transmitter(s) of the AUT whose center(s) is(are) disposed within the dominant emission-locale DEL(USP- eventi), the dominant emission-locale DEL(USP-event i ) being spherical in shape with a radius of at most 0.75 cm or at most 0.5 cm;
  • the dominant emission locales are distributed in space so that no two dominant emission locales (DEL(USP-event j ), DEL(USP-event k )] (j1k) (both j and k are positive integers equal to at most L) are displaced from each other to have a center-center distance of less than 2 cm (alternatively, for every pair of two dominant emission locales (DEL(USP-event j ), DEL(USP-event k )] (j1k) (both j and k are positive integers equal to at most L, a center-center distance therebetween is at least 2 cm);
  • step (d) is performed such that:
  • the at least some transducers deliver ultrasound in at relative phases computed from the echo time-differences measured in step (c); and B. the delivering of ultrasound from the at least some transducers generates the ultrasound intensity-peak within the human subject brain around the target-peak-location 900.
  • the respective skull-surface locations max_intensity_SOS_LOC(USP-event i ) on the skull outer-facing surface form a location set SOS_LOC_SET ⁇ max_intensity_SOS_LOC( (USP- event1 ), max_intensity_SOS_LOC( (USP-event 2 )...
  • max_intensity_SOS_LOC( (USP-event L ) ⁇ and wherein the skull-surface locations of the location set SOS_LOC_SET are distributed in space so that no two skull-surface locations (max_intensity_SOS_LOC(USP-event j ), max_intensity_SOS_LOC(USP-event j ) ) on the skull outer-facing surface are displaced from each other by less than disp_numb cm, wherein disp_numb is a positive number whose value is at least 1 or at least 1.5 or at least 2.
  • USP-event i of the L events of ⁇ USP-event 1 USP-event 2 ...
  • USP- event L ⁇ a center of the respective dominant emission-locale DEL(USP-event i ) thereof is displaced from the skull by at most 2.5 cm.
  • a center of the respective dominant emission-locale DEL(USP-event i ) thereof is displaced from the skull by at most 2 cm or at most 1.5 cm.
  • a nearest distance between (i) the target-peak-location 900 in brain tissue 98 beneath the skull and (ii) the skull is at least 2 cm or at least 4 cm or at least 5 cm.
  • each USP-eventi is defined by a different respective dominant emission-locale DEL(USP-event i ) such that during each USP-eventi the at least 50% of power of the respective ultrasound test signal UTSi received at the respective skull-surface location max_intensity_SOS_LOC (USP-event i ) on the skull is supplied by the transmitter(s) of the AUT (i) whose center(s) is(are) each disposed within a dominant emission-locale DEL(USP-event i ) that is spherical in shape with a radius of at most 0.5 cm; and (ii) which each have a width of at most ww cm, wherein 0£ww£1.
  • the dominant emission locales are distributed in space so that a center-center distance between a first DEL(USP-event j ) and a second DEL(USP-event k ) of the dominant emission locales (j1k) (i.e. for two different events) is at least 4 cm or at least 5 cm.
  • at least 30% of ultrasound power of the intensity peak are supplied by transducer(s) disposed with any of the dominant emission-locales ⁇ DEL(USP-event 1 ), DEL(USP-event 2 )...
  • DEL(USP-event L ) ⁇ defined by the at least L ultrasound skull-probe (USP) events ⁇ USP-event 1 , USP-event 2 ... USP-event L ⁇
  • at least 50% (or at least 75%) of ultrasound power of the intensity peak are supplied by transducer(s) disposed with any of the dominant emission-locales ⁇ DEL(USP-event 1 ) , DEL (USP-event 2 )... DEL(USP-event L ) ⁇ defined by the at least L ultrasound skull-probe (USP) events ⁇ USP-event 1 , USP-event 2 ...
  • the ultrasound intensity-peak produced by operating the at least some transducers in the relative phases produces the intensity-peak so that a FWHM full width half maximum thereof in a widest dimension (e.g. of an oval-shaped peak) is at most 5 cm or at most 4 cm.
  • the ultrasound intensity-peak produced by operating the at least some transducers in the relative phases produces the intensity-peak so that a FWHM full width half maximum thereof in a most narrow dimension (e.g. of an oval-shaped peak) is at most 2.5 cm or at most 2 cm or at most 1.5 cm or at most 1 cm.
  • At least a majority of or at least 75% of or all ultrasound transducers employed to transmit ultrasound during calibration mode remain stationary during a time period which begins upon commencement of the operation in the calibration mode and concludes upon generation of the ultrasound intensity-peak. In some embodiments, at least a majority of or at least 75% of or all ultrasound transducers operated according to the relative phases to form the intensity-peak remain stationary during a time period which begins upon commencement of the operation in the calibration mode and concludes upon generation of the ultrasound intensity-peak.
  • a system for generating an ultrasound intensity-peak within a human subject brain around a target-peak-location, by delivering ultrasound through the skull the method comprises:
  • AUT ultrasound transducers
  • a data processing unit for processing output generated by transducer(s) of the AUT in response to ultrasound;
  • control circuitry responsive to output of the data processing unit and configured to control operation of the AUT when the transducers thereof are in proximity of the skull and held relative to each other by the mechanical arrangement at their defined geometry so as to operate the AUT either in calibration-mode or in sub-surface energy-focus (SSEF) mode, wherein:
  • the control circuitry causes at least some transducers of the AUT to subject the skull to at least L ultrasound skull-probe (USP) events ⁇ USP-event 1 , USP-event 2 ... USP-event L ⁇ (L is a positive integer; L35) such that:
  • each USP-event i is defined by a different respective dominant emission- locale DEL(USP-event i ) such that during each USP-event i at least 20% or at least 30% or at least 50% of power of the respective ultrasound test signal UTS i received at the respective skull-surface location max_intensity_SOS_LOC (USP-event i ) on the skull is supplied by transmitter(s) of the AUT whose center(s) is(are) disposed within the dominant emission-locale DEL(USP- event i ), the dominant emission-locale DEL(USP-event i ) being spherical
  • the dominant emission locales are distributed in space so that no two dominant emission locales (DEL(USP-eventj), DEL(USP-eventk)] (j1k) (both j and k are positive integers equal to at most L) are displaced from each other to have a center-center distance of less than 2 cm (alternatively, for every pair of two dominant emission locales (DEL(USP-eventj), DEL(USP-eventk)] (j1k) (both j and k are positive integers equal to at most L, a center-center distance therebetween is at least 2 cm);
  • the data processing unit processes the electrical output to computed therefrom relative phases between different ultrasound transducers
  • the control circuitry causes at least some of the transducers of the AUT to emit simultaneously emit ultrasound according to the relative phases that were computed by the data processing unit so as to generate the ultrasound intensity-peak within a human subject brain around the target-peak-location 900.
  • a system for generating an ultrasound intensity-peak within a human subject brain around a target-peak-location, by delivering ultrasound through the skull the method comprises:
  • AUT ultrasound transducers
  • a data processing unit for processing output generated by transducer(s) of the AUT in response to ultrasound;
  • control circuitry responsive to output of the data processing unit and configured to control operation of the AUT when the transducers thereof are in proximity of the skull so as to operate the AUT either in calibration-mode or in sub-surface energy-focus (SSEF) mode, wherein:
  • the control circuitry causes at least some transducers of the AUT to subject the skull to at least L ultrasound skull-probe (USP) events ⁇ USP-event 1 , USP-event 2 ... USP-event L ⁇ (L is a positive integer; L35) such that: (i) during each USP-event i , a respective ultrasound test signal UTS i is emitted by one or more transducer(s) so as to probes the skull to produce a maximum intensity at a different respective skull-surface location max_intensity_SOS_LOC(USP-event i ) on the skull outer-facing surface; (ii) each USP-eventi is defined by a different respective dominant emission- locale DEL(USP-event i ) such that during each USP-eventi at least 20% or at least 30% or at least 50% of power of the respective ultrasound test signal UTSi received at the respective skull-surface location max_intensity
  • the dominant emission locales are distributed in space so that no two dominant emission locales (DEL(USP-event j ), DEL(USP-event k )] (j1k) (both j and k are positive integers equal to at most L) are displaced from each other to have a center-center distance of less than 2 cm;
  • the data processing unit processes the electrical output to computed therefrom relative phases between different ultrasound transducers
  • each USP-eventi respectively defines an event-specific direction of an energy flux vector EFV(USP-event i ) describing the directional energy flux of the USP signal incident upon the skull outer surface to thereby defined an EVF set ⁇ EVF(USP-event 1 ), EVF(USP-event 2 )... EVF(USP- event L ) ⁇ such that all EVF vectors of a sub-set of the EVC set are rotated from each other by at least 15 degrees, a cardinality of the sub-set being at least two.
  • any‘’circuitry’’ or‘’module’’ or“”unit” may be implemented using any combination of hardware (e.g. a general purpose CPU or any other analog or digital hardware) and/or software and/or firmware.
  • a mechanical arrangement may include, for example, a device housing or other components that the skilled artisan would employ after reading the present disclosure.
  • Figs.1-2 relate to prior art
  • FIGS.3-20 illustrate various embodiments of the invention
  • Fig.21 illustrates an embodiment of the invention system.
  • Figs. Fig.22A, 22B, 22C illustrate schematic embodiments of focusing transducer arrays.
  • Fig.22E illustrates a known art system of focusing array
  • Fig.22D illustrate a two-dimensional transducer array.
  • Figs.23A and 23B illustrate steering option of transducer array.
  • Fig.23C illustrates schematic embodiments of focusing transducer arrays.
  • Figs.24A to 24F illustrates flow charts of an embodiment of the invention.
  • Fig.25 illustrates selected functional components of the invention transducer array.
  • Fig.26A illustrates the invention system when operated in a uniform medium.
  • Fig.26B illustrates an embodiment of embodiment of the invention system for intra-cranial focusing with skull aberration calibration.
  • Fig. 26C illustrates the invention system when operated for intra-cranial focusing after aberration calibration.
  • Fig.27 illustrates an embodiment of embodiment of the invention system for intra-cranial focusing with skull aberration calibration.
  • Fig.28 illustrates an embodiment of embodiment of the invention system two-dimensional array of emitter elements and receiver elements.
  • Fig.29 illustrates an embodiment of embodiment of the invention system schematic architecture for intra-cranial focusing with skull aberration calibration.
  • Figs.30A and 30B illustrate aspects of the echo detection mechanism used in the present invention.
  • Fig.31 highlights the switching control module.
  • Fig.32 illustrates an embodiment of selection of receiver sensors association with emitter sensors.
  • Fig.33 illustrates an embodiment of selection of receiver sensors association with emitter sensors.
  • Fig.34 illustrates an embodiment of selection of receiver sensors association with emitter sensors.
  • Fig.35 illustrates basic principles of signal detection from selected surface boundaries.
  • Fig.36 illustrates an embodiment of selection of receiver sensors association with emitter sensors.
  • Fig.37 illustrates schematic representations of the emitter transducer array.
  • Fig.38 illustrates an embodiment of selection of receiver sensors association with emitter sensors.
  • Fig.39 illustrates a 2D array arrangement
  • Figs. 40 to 43 present the planning and data of a numerical simulation realization example of the present invention.
  • Figs.44A - 44D illustrate embodiments of activation patterns of the calibration emitters array.
  • Figs.45A, 45B and 45C illustrate an embodiment where the calibration emitters array and the focusing emitters array are situated at different location with respect to the skull.
  • Fig. 3 illustrates an array of ultrasound transducers (AUT) comprising 10 ultrasound transducers UT 1 -UT 10 .
  • AUT ultrasound transducers
  • the skilled artisan can appreciate that the in different embodiments, more or or fewer ultrasound transducers (AUT) may be provided.
  • the ultrasound transducers are labelled both as UT 1 -UT 10 and as 15501-155010.
  • the transducer 1550 emits an ultrasound test signal which propagates in space, reaches skull 150, and echoes from the skull.
  • the echoed ultrasound may be subsequently detected by the same transducer or by a different transducer.
  • Fig.3 Not shown in Fig.3 are optional and impedance matching material.
  • Fig. 4 illustrates one simple example of an ultrasound test signal and Figs. 5A-5E illustrate reflecting the ultrasound test signal from the skull 150.
  • transducer 1550A emits the ultrasound test signal, which propogates in space and is incident upon outer surface 151 of skull at time tB (see Fig.5B).
  • a first portion of ultrasound energy of the ultrasound test signal reflects back towards transducer 1550A, and a second portion of ultrasound energy of the ultrasound test signal continues through skull 150 towards brain tissue 98.
  • this second porton of ultrasound energy reaches the inner surface 152 of skull 150 at time tC (see Fig.5C)
  • at least some energy of this second portion reflects back towards transducer 1550A.
  • transducer 1550A At time t D , ultrasound energy which was reflected from the outer surface 151 of skull (i.e. at time t B ) is received by transducer 1550A– thus, a first echo of the ultrasound test signal of Fig. 4 is detected at transducer 1550A at a time-delay of (t D – t A ) after the ultrasound test signal is initially emitted by transducer at t A. . This corresponds to the time required for ultrasound to traverse the ‘optical path’ having first and second legs illustrated in Fig.7A;
  • transducer 1550A At time tE, ultrasound energy which was reflected from the inner surface 152 of skull (i.e. at time tC) is received by transducer 1550A– thus, a second echo of the ultrasound test signal of Fig.4 is detected at transducer 1550A at a time-delay of (tE– tA) after the ultrasound test signal is emitted by initially emitted by transducer at tA. This corresponds to the time required for ultrasound to traverse the‘optical path’ having first and second legs illustrated in Fig.7B.
  • the time delay (t E – t D ) (i.e. the delay between receiving of reflected ultrasound in Fig.5D a first echo and the receiving of ultrasound in Fig.5E a second echo) is indicative of a combination of (i) the speed of sound within skull 150; and (ii) the thickness thereof at the location where ultrasound of the ultrasound test signal (i.e. created at time by t A transducer 1550A). In some embodiments, this may be related to an angle between:
  • step P1200 which is a method for generating an ultrasound intensity-peak within a human subject brain around a target-peak-location 900, by delivering ultrasound through the skull 150. This is shown in the last step of Fig. 8 (i.e. step P1200) where a plurality of ultrasound transducers are operated using computed relative phase differences that are computed in earlier steps (e.g. in accordance with the speed of sound in skull tissue and/or brain tissue and/or in accordance with relationship (e.g. ratio) therebetween).
  • a calibration measurement procedure P1110 and a calibration analysis procedure P1150 are first performed.
  • Embodiments of the invention relate to features of the calibration measurement procedure P1110.
  • the measurement procedure is performed using (i) ultrasound transducers (i.e. of an ultrasound array) where the transducers are each very“close” to the surface of skull outer surface 151; and/or (ii) employed to produce a plurality of ultrasound-probe events (discussed below), where for each ultrasound-probe event
  • the term‘very close’ to the skull may be relative to one or more of (i) the size/width of the array used in the calibration measurement procedure P1110 and/or (ii) the radius of curvature (or variations thereof) of the skull and/or of a target portion thereof.
  • each ultrasound skull-probe (USP) event may be performed by delivering ultrasound primarily (i.e. on a per-event basis) from transducer(s) whose respective centers are:
  • each locale may be defined by a sphere having a radius of at most 1 cm or at most 0.5 cm.
  • providing one or both of these features may be useful for delivering ultrasound such that (i) a normal vector at a location of surface 151 where the ultrasound test signal is incident is substantially aligned with (ii) a directional energy flux vector (analogous to a Poynting vector from electricity and magnetism) of the ultrasound test signal used to generate ultrasound skull-probe (USP) event (described below).
  • a normal vector at a location of surface 151 where the ultrasound test signal is incident is substantially aligned with (ii) a directional energy flux vector (analogous to a Poynting vector from electricity and magnetism) of the ultrasound test signal used to generate ultrasound skull-probe (USP) event (described below).
  • USP ultrasound skull-probe
  • the method comprises three steps (each of which is discussed below in greater details):
  • this procedure P1110 may measure an indication of a (i) a thickness of skull 150 as a function of location on the skull and/or (ii) a speed of sound within the skull 150.
  • the physical data acquired during the measurement procedure P1110 is subsequently processed in the calibration ANALYSIS procedure P1150 to compute relative phases used in step P1200 (e.g. for overcoming inhomogeneities in skull thickness and/or in acoustic properties of the skull and/or brain).
  • the calibration MEASUREMENT procedure P1110 may be described with reference to ultrasound skull-probe (USP) events, discussed below.
  • USP ultrasound skull-probe
  • a respective ultrasound test-signal e.g. see Fig.4 ; other examples are in Figs.12A-12B or 18-20.
  • measurement data may be used to determine an echo-time difference.
  • the echo time-difference may be related to the time delay (t E – tD) discussed above with reference to Figs. 4-6. Without limitation, this echo time-difference may describe a combination of (i) the speed of sound within skull 150 or particular portion(s) thereof; and (ii) the thickness thereof at the location at particular location(s).
  • the analysis procedure may also comprise computation of relative phases used in step P1200 (e.g. for overcoming inhomogeneities in skull thickness and/or in acoustic properties of the skull and/or brain).
  • P1200 a sub-surface focus procedure P1200.
  • the relative phases are computed in P1150, they are employed in the focus procedure P1200 where a plurality of ultrasound transducers (i.e. either the same transducers used in P1110 or different transducers) emit ultrasound according to the computed relative phases.
  • P1200 may be performed such that:
  • ultrasound transducers operated in P1200 deliver ultrasound in at relative phases computed from the echo time-differences measured in P1150; and/or (ii). the delivering of ultrasound from the at least some transducers generates the ultrasound intensity-peak within the human subject brain around the target-peak- location 900.
  • USP Events In embodiments of the invention, during P1110 a plurality of Ultrasound probe (USP) events ⁇ USP-event 1 , USP-event 2 ... USP-event L ⁇ are performed. In some embodiments, L35. In some embodiments, L37. In some embodiments, L38. In some embodiments, L310.
  • Each USP event USP-eventi (1£i£L) is characterized by: (i) ultrasound test signal - an ultrasound test signal transmitted to the skull by one or more transmitter(s). As discussed below, the ultrasound test signals may be the same for some or all events or they may be event-specific. (ii) maximum intensity location max_intensity_SOS_LOC(USP-event i ) on the skull outer surface specific for the USP event USP-event i – SOS is an abbreviation for skull outer surface 151. The maximum intensity location max_intensity_SOS_LOC(USP-event i ) is a location on the skull outer surface 151 where the intensity of the ultrasound test signal (i.e.
  • this location is the‘maximum intensity’ location on the skull outer surface.
  • this‘maximum intensity’ location is not necessarily the maximum compared to all locations of space. Rather, the‘maximum intensity’ is compared to only to other locations on the outer surface 151 of the skull 150.
  • This‘maximum intensity location’ is event specific - a different one for each USP event.
  • the set of Ultrasound probe (USP) events ⁇ USP-event 1 , USP-event 2 ... USP-event L ⁇ defined as set of maximum intensity locations ⁇ max_intensity_SOS_LOC(USP-event 1 ), max_intensity_SOS_LOC(USP-event 2 ),.... max_intensity(USP-event L ) ⁇ . More features of the max_intensity_SOS_LOC(USP-event i ) are discussed below.
  • spherical in shape with radius of at most 1 cm or at most 0.75 cm or at most 0.6 cm or at most 0.5 cm. This radius may be considered ‘small’ relative to the radius of curvature of the skull and/or the width of the array of transmitters used to emit ultrasound for P1110.
  • Ultrasound Test Signals Each Ultrasound probe (USP) event is associated with a respective ultrasound test signal– i.e. the ultrasound signal emitted by one or more of the transducers which is propagates to the skull (e.g. and is reflected therefrom).
  • USP-event 1 is associated with Ultrasound_test_signal(USP-event 1 )
  • USP-event 2 is associated with Ultrasound_test_signal(USP- event2), and so on.
  • each Ultrasound probe (USP) event is associated with a different ultrasound test signal.
  • the events ⁇ USP-event 1 , USP-event 2 ... USP-event L ⁇ are performed serially.
  • a Discussion of Figs.9A-9D, 10A-10B, 11A-11B, 12A-12B and 13-14 Figs.9A-9D illustrate four example USP events USP-event 1 - USP-event 4 .
  • the events are performed serially– i.e. one after another.
  • Fig.9A corresponding to USP-event 1 , an ultrasound test signal is only provided by a single ultrasound transmitter UT2 while all other ultrasound transmitters UT 1 , UT3- UT 10 are‘OFF.’
  • DEL(USP-event 1 ) is at the center of UT2
  • max_intensity_SOS_Locale(USP-event 1 ) is indicated by the‘X’ in Fig.9A.
  • Fig.9C corresponding to USP-event 3 , an ultrasound test signal is only provided by a single ultrasound transmitter UT 1 while all other ultrasound transmitters , UT 2 - UT 10 are‘OFF.’
  • DEL(USP-event 3 ) is at the center of UT 1 ; and
  • max_intensity_SOS_Locale(USP- event 3 ) is indicated by the‘X’ in Fig.9C.
  • Fig.9D corresponding to USP-event 4 , an ultrasound test signal is only provided by a single ultrasound transmitter UT9 while all other ultrasound transmitters , UT 1 - UT 8 , UT 10 are‘OFF.’
  • DEL(USP-event 4 ) is at the center of UT 9 ;
  • max_intensity_SOS_Locale(USP-event3) is indicated by the‘X’ in Fig.9D.
  • Figs.10A-10B are a close up respectively of USP-event 1 of Fig.9A and USP-event 4 of Fig.9D.
  • the location max_intensity_SOS_Locale(USP-event 1 ) (marked by the‘X’ in Figs.9A and 10A) is simply the location on SOS 151 that is closest to UT 2.
  • the location max_intensity_SOS_Locale(USP- event 4 ) (marked by the‘X’ in Figs.9D and 10B) is simply the location on SOS 151 that is closest to UT 9.
  • FIG. 11A-11B shows the EFV(USP-event 1 ) and EFV(USP-event 4 ) for USP-event 1 and USP-event 4 where EFV is the directional energy flux vector or simply energy flux vector -- analogous to a Poynting vector from electricity and magnetism)
  • Fig.4 showed one example of an ultrasound test signal– other examples are shown in Figs. 12A-12B.
  • Fig.13 shows the echo signals (e.g. received after reflection from the skull) of the example test signal of Figs.12A.
  • Fig.14 shows a system for performed any method disclosed herein.
  • Fig.15 shows the centers of the ultrasound transducers UT 1 - UT 10 (also indicated as 15501- 1550 10 ) of Fig.3– these centers are marked by 5-sided stars.
  • Fig.16 it is possible to‘split’some of the ultrasound transducers into multiple transducers , centers of which are each marked by 5-sided start.
  • the arrangement of Fig.16 may produce effects (i.e. when emitting the ultrasound test signals in P1110) close to the arrangement of Fig.15.
  • UT 1 is split into two transducers
  • UT 2 is split into three transducers
  • UT 1 is not split, and so on.
  • Fig.17 shows some (but not all) transducer centers of Fig.16 as disposed within distinct four emission locales that are each spherical in shape.
  • Figs.18-20 show additional examples of ultrasound test signals.
  • a discussion of Figs.21-45 For ease of reference the following numbers in the figures are meant to refer to as follows
  • focal zone area boundary preferably defined at half maximum peak intensity.
  • 121 uncalibrated focusing focus peak location in the presence an intervening skull-tissue intermediate-layer.
  • intermediate-layer of intervening skull-tissue e.g., skull bone layer
  • 361p or 161p as paired calibration receiver CR(p)– receiver to which reflected ray 371 arrives.
  • 361px– receiver sensor near to the left of emitter.
  • 461p– receiver to which reflected ray arrives when emitted from emitter 341m and reflected from an alternative tilt of skull bone layer.
  • ultrasound propagation“ray” reflected from outer surface of the intermediate skull layer (e.g., skull bone) of incident ultrasound ray 370 according to Snell law.
  • ultrasound propagation“ray” reflected from inner surface of the intermediate skull layer (e.g., skull bone) of incident ultrasound ray 370 according to Snell law. 99– matching medium between the emitter module 110 and the cranial skin surface.
  • the goal of the present invention is to provide a method and apparatus for obtaining phase shift corrections to improve the focus peak within a human skull when ultrasound is produced by an array of emitters outside of the skull.
  • the present disclosure provides a method and apparatus for improving (i.e., reducing the size of) the focal zone in such a situation.
  • the beam of acoustic energy emitted from the focus-emitters array 117 has a relatively wide aperture where it enters the body. Therefore, different parts of the acoustic energy, such as 123 and 124, may pass through different intervening tissue layer thickness between, which may shift the effective relative time delay of acoustic energy transmitted from respective transducer elements upon arrival to the focal zone. This phase shifting may decrease the constructive interference of the acoustic energy at the focal zone, or may even move the focal zone in an unpredictable manner. For example, an intervening skull bone layer thickness difference of 1.5mm may introduce a phase shift of 180° at an ultrasonic frequency of one Megahertz (1 MHz), which would change desired constructive interference at the focal zone into destructive interference.
  • ultrasound frequency lower than 1MHz is used in order to reduce the aberration effect of non-bone tissue inhomogeneity in the brain.
  • the ultrasound wave paths pass through an intervening skull-tissue intermediate-layer bounded by first (outer) and second (inner) boundary surfaces within otherwise same uniform medium 99 in the path from the transducer surface to the resulting focus peak location 131 with resulting focal zone area 139, such that the focal zone area 139 is smaller than the focal zone 129 created when the focusing transducer array 110 is driven with an uncalibrated signal delay set ⁇ FT0(n) ⁇ .
  • the resulting focus peak location 131 is very close to the planned target focus peak location 111 in the sense that the planned target focus peak location is within the resulting focal zone area 139.
  • the key problem is how to determine the calibration set ⁇ CT(n) ⁇ .
  • the present disclosure provides methods and systems for determining the calibration set ⁇ CT(n) ⁇ and thereby creating an improved focus when the focused ultrasound waves path pass through an intervening skull-tissue intermediate- layer 150 bounded by first boundary surface 151 and second boundary surface 152 within otherwise approximately uniform out-of-skull medium 99, and/or similar approximately uniform medium of under-skull brain tissue 98, in the path from the transducer surface to the focus peak.
  • the scanning procedure PROC-1 can be sub-divided into two prominent sub-tasks: (a) physical measurement procedure“MEASURE”, and (b) computational analysis“ANALYSIS” from which the key outcome is the determination of the calibration set ⁇ CT(n) ⁇ .
  • the measurement procedure is an imaging scan followed by an analysis procedure which involves constructing a geometrical 3D image of the skull and assigning phase shift properties to the constructed 3D geometry.
  • the measurement procedure comprises non-imaging non-focusing MEASURE measurements and the calibrated phase shift set elements are computed directly from the MEASURE measurements without going through the construction of a geometrical image of the skull.
  • the calibrated focusing irradiation application procedure“PROC-2” can be sub-divided into two prominent sub-tasks: (a) Input parameters set-up, and (b) irradiation application process.
  • the calibrated focusing irradiation application procedure“PROC-2” is similar to known art. Given the calibration set ⁇ CT(n) ⁇ from PROC-1, the system is activating the focusing emitters array ⁇ FE(n) ⁇ with the corrected set ⁇ FPS(n) ⁇ of input parameter phases. Various other irradiation application process characteristics (intensity, duration, etc.) are determined by clinical goals (e.g., nerve stimulation, tissue ablation, etc.). The innovation is primarily contained in the preparatory measurement MEASURE process in PROC-1 method and apparatus and from it the computation method ANALYSIS from which the core outcome is the values of the calibration set ⁇ CT(n) ⁇ of input parameters that is used to define the corrected set ⁇ FPS(n) ⁇ of phases.
  • semantic functional sets “semantic” meaning is distinguished from“physical”, in the sense that, for example, physically the same component can be operated as a transceiver which is capable of both emitter functionality and receiver functionality.
  • These sets comprising:
  • ⁇ FE(n) ⁇ array 117 of focus-emitters (FEA), ⁇ FE(n) ⁇ ⁇ FE(1), FE(2)... FE(N) ⁇ ;
  • ⁇ CE(m) ⁇ array 112 of calibration-emitters array (CEA), ⁇ CE(m) ⁇ ⁇ CE(1), CE(2)... CE(M) ⁇ ;
  • ⁇ CR(p) ⁇ array 116 of ultrasound calibration-receivers array (CRA), ⁇ CR(p) ⁇ ⁇ CR(1), CR(2)...
  • ⁇ USP(i) set of unfocused ultrasound skull-probe (USP) events ⁇ USP 1 , USP 2 ... USP L ⁇ (1£i£L); ⁇ [CE(j),CR(k1),CR(k2)] ⁇ set of calibration-emitter:calibration-receiver triplets (CECRP); for measuring echo differences; METD(j,k1,k2) between an outer-skull-surface reflection-time received at receiver CR(k1) and an inner-skull-surface reflection-time received at receiver CR(k2) of an ultrasound test signal that is emitted from the calibration emitter CE(j).
  • ⁇ FPS(n) ⁇ set of correction phase-shifts (FPS), ⁇ FPS(n) ⁇ ⁇ FPS(1).... FPS(N) ⁇ ; computed as a function of the time delay set ⁇ TD(m) ⁇ and uncalibrated signal delay set ⁇ FT0(n) ⁇ ; ⁇ TD(j) ⁇ time delay set, computed from measured echo time differences set ⁇ METD(j,k1,k2) ⁇ ;
  • the method and apparatus comprise using arrays (alternately and interchangeably referred to as“sets”) of ultrasound elements comprising:
  • the array 112 of ultrasound calibration-emitters ⁇ CE(m) ⁇ and the array 116 of ultrasound calibration-receivers ⁇ CR(p) ⁇ may physically consist of the same transducer elements, since ultrasound transducers are known in the art to be possible to switch between emitter and receiver functionality.
  • the measurement MEASURE procedure comprises:
  • each USP event is dominated by a different calibration emitter CE(j) to probes a different associated outer surface skull local area LOC[CE(j)] with an ultrasound test signal;
  • test signal emitted from calibration emitter CE(j) has peak intensity within the associated skull local area
  • test signal emitted from any other calibration emitters CE(j ⁇ 1j) which dominate any other of the USP events is having less than 50% of the intensity of the test signal originating from the dominant calibration emitter CE(j) at the skull local area LOC[CE(j)];
  • each USP-eventj an individual calibration emitter CE(j) is activated to emit a test signal while all other calibration emitters CE(j ⁇ 1j) are kept dormant, thereby each USP event is dominated by a different calibration emitter CE(j).
  • the calibration-emitters array (CEA) 112 is positioned in proximity of the skull, as illustrated in Fig.1A, a test signal emitted from calibration emitter CE(j) has peak intensity within the associated limited skull local area close to the emitter CE(j), even when the signal emitted from an individual calibration emitter CE(j) is in itself unfocused in general and unfocused on the skull in particular.
  • test signal we refer to the test signal as“unfocused ultrasound”.
  • a signal from CE(j ⁇ ) will not have a significant intensity in the location of skull local area LOC[CE(j)] associated with calibration emitters CE(j) during the USP-eventj in which the test signal is emitted from CE(j).
  • the analysis ANALYSIS procedure comprises:
  • the calibration analysis comprises
  • the analysis procedure is further comprising of
  • the echo time difference METD(j,k1,k2) is measured between an outer-skull-surface reflection-time and an inner-skull-surface reflection-time of ultrasound test signal that is emitted from the calibration emitter CE(j) of the pair [CE(j), CR(k)], thereby creating a time delay set ⁇ TD(n) ⁇ , the set ⁇ TD(n) ⁇ is computed such that TD(n) is a weighted sum or average of METD(j,k1,k2) elements where CE(j) are geometrically related to calibration-emitters to focus-emitter FE(n).
  • the emitter CE(j) is conceptualized as an ultrasound source of limited extent in space of less 22Cm area, whether made of one or more transducers. In most cost effective embodiments, the emitter CE(j) is consisting of a single transducer. Thereby, for each given calibration-emitter:calibration- receiver triplet [CE(j),CR(k1),CR(k2)] of ⁇ [CE(j),CR(k1),CR(k2)] ⁇ triplets, measuring is performed without generating a geometrical imaging of the skull.
  • the number of calibration emitters in the set ⁇ CE(m) ⁇ and the number of focus emitters in the set ⁇ FE(n) ⁇ may be different, and hence also the number of measured echo time difference METD(j,k1,k2) elements in the set ⁇ METD(j,k1,k2) ⁇ may be different than the number of focus emitters in the set ⁇ FE(n) ⁇ . Therefore, in computing the may incorporate weighted averages of several measured echo time difference METD(j,k1,k2) elements within a given neighborhood of a local on the skull.
  • the measurement MEASURE procedure comprises:
  • the analysis ANALYSIS procedure comprises: v. having a pre-determined uncalibrated signal delay set ⁇ FT0(n) ⁇ for focusing ultrasound with the array of focus-emitters ⁇ FE(n) ⁇ in a uniform medium;
  • the arrays ⁇ FE(n) ⁇ and ⁇ CE(m) ⁇ may overlap spatially.
  • the sets ⁇ FE(n) ⁇ and ⁇ CE(m) ⁇ may intersect (i.e., share elements). In fact, from cost, performance and simplicity considerations, an embodiment is one in which the arrays ⁇ FE(n) ⁇ and ⁇ CE(m) ⁇ are physically the same elements.
  • the array 112 and array 117 are one and the same), or one is a subset of the other (e.g., ⁇ CE(m) ⁇ is a subset of ⁇ FE(m) ⁇ , such that only a portion of the emitters are used for the calibration process. Therefore, some of the figures and embodiment examples are drawn as such. i.e, there is one array (112,117) of physical ultrasound emitters that serves both for the purpose of MEASURE procedure (in PROC-1) and for focusing (in PROC-2). Yet this should not be understood as limiting.
  • the triplet [CE(j),CR(k1),CR(k2)] may be regarded as composed of two calibration-emitter:calibration- receiver pairs: the pair [CE(j),CR(k1)] for measuring the outer-skull-surface reflection-time received at receiver CR(k1) of an ultrasound test signal that is emitted from the calibration emitter CE(j); and the pair [CE(j),CR(k2)] for measuring the inner-skull-surface reflection-time received at receiver CR(k2) of an ultrasound test signal that is emitted from the same calibration emitter CE(j).
  • the intermediate skull layer e.g., skull bone layer
  • the problem is how to determine the skull properties and geometry non-invasively.
  • we define the intermediate skull layer geometry by knowledge of first boundary surface 151 shape function Z1(x,y) and the second layer 152 shape function Z2(x,y).
  • the skull bone layer geometry is determined from MRI or CT imaging.
  • the MEASURE sub-task measurement procedure PROC-1 is an imaging procedure done by MRI or CT scanning, from which various skull parameters are determined by supplemental external information. e.g., from multiple slices of MRI images a full 3D skull bone section shape is reconstructed.
  • external information concerning speed of sound in the bone is supplemented to predict and determine the supposed time shifts created by the skull bone on ultrasound. i.e., the MRI or CT scanning is NOT by itself directly measuring ultrasound phase shift or time shift due to passage through the skull layer.
  • each phase shift correction CT(n) to be applied to individual emitter En is determined by going through a geometrical reconstruction of the intermediate skull layer shape and considering the particular path of the ultrasound from the emitter En to the intended focus location.
  • the present invention uses ultrasound emitters array not only for the irradiation PROC- 2 procedure, but also for the measurement PROC-1 procedure, thereby eliminating completely the need for non-ultrasound MRI or CT at any step of the full procedure (PROC-1 and PROC-2) method and apparatus; (ii) what is measured is not geometrical imaging of the skull shape, but the direct ultrasonic shift effects of the skull. It is conjectured that the measurement is somehow capturing a measure that is proportional to the real focusing path without actually being the focusing path or focused at all; and (iii) the ultrasound MEASURE procedure method in the present invention is different from what is commonly understood as“ultrasound scanning” in known art of medical ultrasound imaging.
  • known art medical ultrasound scanning is an imaging procedure using focused ultrasound, thereby, skull scanning and/or imaging is done by focusing ultrasound array onto the skull.
  • only individual calibration-emitter elements CE(m) are activated, without focusing on the skull or any brain tissue, during the MEASURE process of PROC- 1.
  • the focusing emitters array elements ⁇ FE(q) ⁇ are activated simultaneously only during the irradiation-focusing PROC-2 procedure, and not on skull tissue.
  • the calibration-emitters are not producing a focused beam in general and specifically not focused on the skull surface.
  • the present invention MEASURE sub-task is characterized by that: (i) the array ultrasound elements are operated serially in time, such that individual array element (or small groups of elements the majority of which consisting of less than 10% of the number array elements) are operated on after the other, and preferably after the previous element signal reflection have been measured; (ii) the ultrasound beam is not focused; (iii) target area Measurement is performed by NOT by steering a beam focus, but instead by way of each individual array element (or small group of elements) measuring the small section of the intermediate skull layer (e.g., skull bone) closest to it.
  • the array ultrasound elements are operated serially in time, such that individual array element (or small groups of elements the majority of which consisting of less than 10% of the number array elements) are operated on after the other, and preferably after the previous element signal reflection have been measured; (ii) the ultrasound beam is not focused; (iii) target area Measurement is performed by NOT by steering a beam focus, but instead by way of each individual array element (or small group of elements) measuring the
  • each phase shift correction CT(n) to be applied to individual emitter En is determined directly from the associated individual emitter En MEASURE step, without going through a geometrical reconstruction of the intermediate skull layer shape and without considering the particular path of the ultrasound from the emitter to the intended focus.
  • CT(n) (V2/V1 - 1) * TD(n)/2
  • FPS(n) FT0(n) + (V2/V1-1)*TD(n)/2, where V1 is an assumed pre-determined average speed of sound in the interior brain tissue (preferably within 10% accuracy), and V2 is an assumed pre-determined average speed of sound in the intermediate skull layer (e.g., skull bone), preferably within 20% accuracy (and more preferably within 10% accuracy).
  • the time TD(n) is determined from the time difference between the reflected signals 171 from the intermediate skull layer first surface 151 and the reflected signals 172 from the intermediate skull layer second surface 152.
  • ANALYSIS sub-task is more conventionally performed, such that each phase shift correction CT(n) to be applied to individual emitter En is computed by going through a geometrical reconstruction of the intermediate skull layer shape and considering the particular path of the ultrasound from the emitter En to the intended focus location. Yet, in the present invention the geometrical reconstruction of the intermediate skull layer shape and thickness are determined in a novel way.
  • individual emitter 141m as calibration emitter CE(m) is emitting a signal while all other emitters (or at least nearby emitters) are not activated.
  • the reflected echo signal 171 from the intermediate skull layer first surface 151 and the reflected echo signal 172 from the intermediate skull layer second surface 152 are each detected at the same receiver sensor 161p as paired calibration receiver CR(p) (in practice the physical receiver sensor 161p as paired calibration receiver CR(p) can be the same as the emitter source 141m as calibration emitter CE(m)), and the time difference TD(n) between them is determined (e.g., the time difference between the maximum peaks of the received echo signals).
  • such MEASURE steps are serially performed in time on other emitters (preferably most of the emitters, or all of the emitters), thus generating the echo time difference set ⁇ TD(n) ⁇ .
  • each measured TD(n) is an estimation of the local time difference of ultrasound to so twice across the local skull bone thickness nearest to the emitter element En.
  • the calibration elements CT(n) forming the calibration set ⁇ CT(n) ⁇ are each a function of TD(n), V1 and V2.
  • CT(n) (V2/V1 - 1) * TD(n)/2.
  • amplitude corrections can be determined from the reflected test signals from individual emitters.
  • a step of frequency-test scan is added to be performed prior to treatment application PROC-2, or prior to the MEASURE procedure.
  • the goal is to find the frequency of maximum transmission through the intermediate skull layer in order to minimize loss of intensity at the focus (due to reflection from the intermediate bone layer) and in order to minimize heat deposition within the intermediate bone layer.
  • the reflected signal intensity is measured while changing the emitter activation frequency range around a central work frequency, e.g., within 10% deviation from the central work frequency. For example, if the work frequency is chosen to be 500KHz, a scan of frequency range between 450KHz and 550KHz is performed. Minimum local of reflected signal intensity indicates maximum local transmission at the associated frequency.
  • the frequency scan is performed for the array activation as a whole (rather than for local regions).
  • the amplitude of reflected beams received by receiver array is not used in the procedures disclosed herein except for (a) using the timing of peak amplitudes in reflected signals in order to acquire the time delays to be used for phase corrections (or phase shifts) for each emitter, and (b) as described in the preceding paragraphs, for optimizing the measurement frequency in order to maximize the transmitted intensity of the focused ultrasound radiation during the subsequent PROC- 2 procedure.
  • the amplitude of reflected beams is an important element of producing images or digital representations of the scanned tissues.
  • step (a) is performed so that for the total set of ultrasound emitters TSUE that is the union ⁇ CE(m) ⁇ U ⁇ FE(n) ⁇ of the sets of ultrasound calibration-emitters and ultrasound focus- emitters, the measuring is performed so that each calibration-emitter CEi , of the given calibration-emitter:calibration-receiver triplet (CEi, CRj), is operated when it’s nearest 20 neighbors in the TSUE are substantially dormant.
  • each individual emitter of the focus-emitters array produces ultrasound radiation which is unfocussed, in the sense that it is does not generate on its own a focused peak maximum on the skull bone layer.
  • the invention introduces a method for generating an ultrasound intensity-peak within a human subject brain around target-peak-location 131, by delivering ultrasound through the skull 150, the skull having an outer surface 151 and inner-facing second boundary surface 152, the method comprising first performing an ultrasound-based calibration procedure and subsequently forming an ultrasound peak around the target-peak location 131 using phase-shift data acquired during the calibration procedure, wherein:
  • the calibration procedure comprises subjecting the skull to a series of unfocused ultrasound skull-probe (USP) events such that:
  • each of the at least 10 different USP events probes the skull with unfocused ultrasound at a different maximum-intensity location
  • the ultrasound calibration-emitters are transceivers which can be operated also as receivers. Therefore, in some embodiments the array of calibration-emitters is comprising the same physical elements as the calibration-receivers. Hence these elements activation is switched between emitter and receiver functionality.
  • TD(n) as a function of the measured echo time difference set ⁇ METD(j,k1,k2) ⁇ is such that, for the majority of n, TD(n) is a weighted average of the subset ⁇ METD(j,k1,k2) ⁇ including the calibration-emitters CE(m) nearest and next-nearest to the focus-emitter FE(n).
  • TD(n) may be equal to the average of selected METD(j,k1,k2) associated with nearest neighbors CE(m) calibration emitters.
  • the time delay set ⁇ TD(n) ⁇ is computed such that TD(n) is a weighted sum of METD(j,k1,k2) elements associated with the subset of calibration-emitters ⁇ CE(j),n ⁇ which are geometrically related to focus- emitter FE(n).
  • the focus-emitter array ⁇ FE(n) ⁇ is positioned at the same location or in great proximity to the location of the calibration-emitters ⁇ CE(j) ⁇ .
  • the geometrical association is essentially an identity.
  • the focus-emitters array ⁇ FE(n) ⁇ is positioned at a different location from the calibration-emitters ⁇ CE(j) ⁇ , the geometrical association is more involved, as discussed below with respect to Figs 45A,45B,45C.
  • the value of TD(n) is a function of the measured echo-difference set ⁇ METD(j,k1,k2) ⁇ such that contributions from METD(j,k1,k2) ⁇ values are weighed higher where CE(j) is a nearer calibration-emitter to the location to the focus-emitter FE(n).
  • the value of TD(n) is a function of the measured echo-difference set ⁇ METD(j,k1,k2) ⁇ such that contributions from METD(j,k1,k2) ⁇ is weighed highest where CE(j) is a nearest calibration-emitter to the location to the focus-emitter FE(n).
  • the value of TD(n) is set equal to METD(j,k1,k2) ⁇ , where CE(j) is a nearest calibration-emitter to the location to the focus- emitter FE(n).
  • the value of TD(n) is a weighted sum of the elements of the measured echo- difference set ⁇ METD(j,k1,k2) ⁇ such that contributions from METD(j,k1,k2) ⁇ is weighed highest where CE(j) is a nearest calibration-emitter to the location to the focus-emitter FE(n).
  • CE(j) is a nearest calibration-emitter to the location to the focus-emitter FE(n).
  • the value of TD(n) is set equal to the weighted average of two METD(j,k1,k2) ⁇ associated with the two nearest calibration-emitters to the location to the focus-emitter FE(n), with the weight proportional to their distance from the focus-emitter FE(n).
  • FPS(n) (FT0(n) + CT(n)), where CT(n) is a function of TD(n)/2 and where ⁇ FT0(n) ⁇ is a delay set used for a uniform-space focusing of said ultrasound array.
  • the complete set of ultrasound emitters is the sum of ultrasound calibration-emitters ⁇ CE(m) ⁇ and the set of ultrasound focus-emitters ⁇ FE(n) ⁇ .
  • a dormant emitter is considered to be an emitter whose simultaneous intensity is less than 80% of the intensity of the highest intensity active emitter.
  • a dormant emitter is considered to be an emitter whose simultaneous intensity is less than 50% of the intensity of the highest intensity active emitter.
  • a dormant emitter is considered to be an emitter whose simultaneous intensity is less than 20% of the intensity of the highest intensity active emitter.
  • a dormant emitter is considered to be an emitter whose simultaneous intensity is less than 10% of the intensity of the highest intensity active emitter.
  • the position of the array 117 of focus-emitters ⁇ FE(n) ⁇ and array 112 of calibration-emitters ⁇ CE(n) ⁇ during the focusing is the same as during the measurement procedure. In some embodiments, the position of the array 112 of calibration-emitters ⁇ CE(n) ⁇ remains the same throughout the measurement procedure.
  • the invention introduces a system for focusing ultrasound into a target brain tissue when having an intervening skull-tissue 150 intermediate-layer bounded by first 151 and second 152 boundary surfaces, using unfocused ultrasound sensing, the system comprising:
  • a delay module 114 for creating a delay set ⁇ F(n) ⁇ , and a control facility 160 configured to set relative phases of the signal between the focus-emitters ⁇ FE(n) ⁇ transducer elements according to delay set ⁇ F(n) ⁇ ; the delay module capable of producing a base- delay set ⁇ FT0(n) ⁇ used for a uniform-space focusing of said ultrasound array on a target location in hypothetical uniform target tissue;
  • control system 160 further capable for selectively activating sub-sets of calibration-emitters ⁇ CE(m) ⁇ ;
  • a detection module 170 in communication with the calibration-emitters ⁇ CE(m) ⁇ and the calibration-receiver elements ⁇ CR(p) ⁇ and in communication with the control module 160;
  • the detection module 170 enabling receiver control and analysis, for identifying and processing ultrasound echo test signals reflected by said intermediate-layer first 151 and second 152 boundary surfaces - using a selectively activated calibration-emitter element CE(m) and a paired selected associated calibration-receiver element CR(p);
  • the detection module 170 serially performing a measurement of such echo signals from a plurality of selected array calibration-emitters elements (e.g., majority of array calibration-emitter elements), thereby generating a corrected delay set ⁇ FPS(n) ⁇ ;
  • control system 160 and delay module 114 capable of driving the transducer array 117 of focus-emitter elements ⁇ FE(n) ⁇ at the corrected delay set ⁇ FPS(n) ⁇ , so as to generate an improved the ultrasound focus compared with the case where the relative phases where ⁇ FT0(n) ⁇ .
  • control module 160 is configured for a series of unfocused ultrasound skull-probe (USP) events such that:
  • each of the at least 10 different USP events probes the skull with unfocused ultrasound at a different maximum-intensity location
  • the control module for selectively activating sub- sets of calibration-emitters ⁇ CE(m) ⁇ is selectively activating individual array elements CE(m)) while maintaining other array elements in a dormant state.
  • the system is such wherein the detection system serially performing a measurement of such echo signals from a plurality of selected array calibration-emitters elements, is serially performing the measurement on a majority of array calibration-emitter elements,
  • system is further comprising a positioning module capable of maintaining the position of the emitter phased array with respect to the target tissue.
  • the system is having at least two modes of activation, (i) a focusing beam mode at which the majority of the emitter array elements are simultaneously emitting ultrasound to create a focus peak, and (ii) an calibration mode at which only a minority of emitter elements are simultaneously activated and at least one receiver element is sensing the reflected signals and transmitting them for analysis to the computation module.
  • the minority of emitter array elements is less than 10% of the array elements, or less than 1% of the array elements.
  • the minority of emitter array elements is an individual single element.
  • Fig.22E illustrates a known art embodiment where the focusing emitter module 11 is complemented by a receiver module 12 which is significantly distanced in space from large portion of the emitter module. It will be argued that such geometric combination of emitter and receiver modules are ieffective for realization of the present invention.
  • embodiments of the present invention comprise a distributed array of receiver array elements which is roughly paralleling in space the distribution of emitter array element, as exemplified in Fig.8.
  • the coupling medium is deformable, such as a liquid or gel, in order to be able to conform to the skin contour.
  • the coupling medium has speed of sound similar to the skin tissue.
  • Figs. Fig.22A, 22B, 22C illustrate schematic embodiments of focusing transducer emitter arrays ⁇ E(n) ⁇ , representing alternative embodiments realizations of the basic transducer array as is known in the professional literature to achieve focusing of ultrasound. It is not meant to be limiting, but to the contrary to exemplify the variety of technical possibilities and combinations for the basic transducer array arrangement which is not core to the inventive step of the present invention.
  • Fig.222C illustrates a flat transducer emitter array ⁇ E(n) ⁇ with variable relative phase delay between the array element.
  • the focusing transducer 110 is certain related aspects of the focusing transducer 110, such as the focus peak location 111 which is also the focal center of the focusing transducer in uniform medium 99, the emitter array 112 component of the focusing transducer, focusing transducer surface 113, and the focal zone 119 area boundary, preferably defined at half maximum peak intensity.
  • Fig.22D illustrates schematically a two-dimensional (2D) array of emitter elements. This is meant to highlight the fact that the illustrations in other figures herein, although look graphically like lines, stand to represent 2D and/or 3D arrangements of ultrasound transducer arrays. Hence the simplified graphical representation of other figures is only for the purpose of visual simplicity and not meant to be limiting.
  • Figs.23B and 23C illustrate the ability to steer the focus peak location to more than one location in space using appropriate time delay set for the transducer array, as is well known in the art of ultrasound transducer arrays.
  • Fig.25 highlights additional features of an embodiment of the invention system.
  • a base-signal generator 115 produces base signal f0107.
  • the base-signal f0 is input to and manipulated by a delay-module 114.
  • the delay-module 114 generates a set ⁇ F(n) ⁇ of time shifted signals 116 each shifted by a time delay F(n) with respect to the input base-signal f0.
  • also and amplitude modification of the base-signal amplitude may be generated for each time shifter signal ⁇ f(n) ⁇ .
  • Optimal focusing is obtained when all signals of the set ⁇ f(n) ⁇ arrive in-phase to a particular focus peak point 111 at which they have maximum constructive interference.
  • Figs.26A, 26B, 26C illustrate a principal problem and goal of the present invention.
  • Fig.26A illustrates the focus of ultrasound created by transducer 110 when driven by signal delay set ⁇ FT0(n) ⁇ , where the ultrasound waves propagate in uniform medium 99 throughout the path from the transducer surface to the focus peak 111 with focus zone area 119.
  • the calibration emitters array has a characteristic size CS(CEA). To achieve good focus at depth of about 26Cm, the calibration array needs to be of about the same size. Hence the CEA characteristic size is at least 5cm, preferably between 26Cm to 10cm. For completeness, since stray elements are of little effect, we shall define the characteristic size CS(CEA) as a diameter of the smallest sphere which includes a 80% of the emitters calibrations emitters array.
  • Each member CE(j) of the calibration emitters array is displaced from the skull by DISPL[CE(j)].
  • the calibration emitters should be in proximity of the skull.
  • the majority of calibration emitters are within 23Cm of the skull skin surface, better within 22Cm of the skull skin surface, better within 1cm of the skull skin surface.
  • a ratio between DISPL(CE(j) ) and CE(CEA) is at most 1/2, preferably at most 1/3, preferably at most 1/4.
  • the uniform medium 99 is the matching medium between the transducer 110 and the skull.
  • the intracranial skull medium 98 is typically non-uniform. It is preferred, and common in the art, to select a matching medium 99 which is of uniform ultrasound properties and which is characterized by speed of sound which the same (e.g., within less than 10% difference of) as or close to (e.g., within less than 10% difference of) the average speed of sound of the intracranial brain tissue 98.
  • Fig.26B illustrates the focus of ultrasound created by transducer 110 when driven by the same signal delay set ⁇ FT0(n) ⁇ as in Fig.26A, but where the ultrasound wave paths pass through an intervening skull-tissue intermediate-layer bounded by first 151 and second 152 boundary surfaces within otherwise same uniform medium 99 in the path from the transducer surface to the focus peak 121 with focal zone area 129. Due to the intervening layer, a non-optimal interference is creating the focus peak 129 with focal zone area 129 larger than the uniform medium focal zone 119 and in many cases both shifted focus peak location 121 and more than one focus peak location.
  • the delay set electronic control facility is configured to set relative phases of the signal between the focus-emitters ⁇ FE(n) ⁇ transducer elements according to delay set ⁇ F(n) ⁇ ; the delay module capable of producing a base-delay set ⁇ FT0(n) ⁇ used for a uniform-space focusing of said ultrasound array on a target location in hypothetical uniform target tissue
  • the key problem is how to determine the calibration set ⁇ CT(n) ⁇ .
  • the present invention provides a method and system for determine the calibration set ⁇ CT(n) ⁇ and thereby creating an improved focus when the focused ultrasound waves path pass through an intervening skull-tissue intermediate-layer bounded by first and second boundary surfaces within otherwise approximately uniform medium 99 in the path from the transducer surface to the focus peak.
  • the measurement procedure PROC-1 can be sub-divided into two prominent sub-tasks: (a) physical measurement procedure“MEASURE”, and (b) computational analysis“ANALYSIS” from which the key outcome is the determination of a time-set ⁇ TD(n) ⁇ from which is determined the calibration set ⁇ CT(n) ⁇ , where each element CT(n) is a function of corresponding TD(n).
  • the calibrated focusing irradiation application procedure“PROC-2” can be sub-divided into two prominent sub-tasks: (a) Input parameters set-up, and (b) irradiation application process.
  • the system is activating the emitters array with the corrected set ⁇ FPS(n) ⁇ of input parameters phases.
  • the irradiation application process itself is determined by clinical goals (e.g., nerve stimulation, tissue ablation, etc.).
  • the innovation is primarily contained in the preparatory measurement process PROC-1 method and apparatus and from it the core outcome is the values of the calibration set ⁇ CT(n) ⁇ of input parameters that is used to define the corrected set ⁇ FPS(n) ⁇ of phases.
  • Fig. 27 illustrates an embodiment of the present invention.
  • a test signal is emitted from an individual emitter 141m as calibration emitter CE(m) as calibration emitter CE(m) selected from the transducer emitters array ⁇ CE(m) ⁇
  • These reflections can be detected in any one of possible receiver sensors of the receiver array 116.
  • receiver sensors 161p as paired calibration receiver CR(p) as paired calibration receiver CR(p), or 162p, to be paired with emitter 141m as calibration emitter CE(m).
  • TD(n) time difference between the signal reflection from boundary surface 151 and surface 152.
  • the specific time difference TD(n) is due primarily to the extra path travel within the intermediate skull layer 150 for the signal reflection from boundary surface 152.
  • the reflected signal path 172 arriving to receiver sensor 161p as paired calibration receiver CR(p) is different from the path of the reflected signal path 174 arriving to receiver sensor 162p.
  • the sound wave passes once through the intermediate skull layer 150 width.
  • the reflected test signals, 172 and 174, from boundary 152 each passes twice through the intermediate skull layer 150 width (corresponding to the incident and reflected portions of the path within the layer 150). Therefore, half of the reflected test signals time difference TD(n), i.e., (TD(n)/2), is a good approximation to the time shift contribution of the intermediate skull layer 150 to the total travel time of the focused beam from the particular emitter 141m as calibration emitter CE(m) to the focus peak location 111.
  • adjusting the relative time shift by subtracting (TD(n)/2) from FT0(n) substantially eliminates the phase shift contribution of the intermediate skull layer 150 to the total travel path from the emitter 141m as calibration emitter CE(m) to the focus peak 111.
  • One preferred approximation, as illustrated for the path 172, is a test signal path for which at least the incident portion of the test signal path to be the same as the focused beam path 170 to the focus peak 111.
  • fast switching needs to be operated to switch the emitter transducer to receiver mode of operation within the duration of the reflection time.
  • ray 370 defined to be the ultrasound propagation“ray” from emitter 341m as would be in the selected uniform medium 99 traversing the focus peak 111
  • the path of ray 370 through the intermediate skull layer 150 is very close to the real path of ultrasound ray from emitter 141m as calibration emitter CE(m) to the focus peak 111.
  • Another preferred embodiment approximation is one for which the same physical transducer array element is used for both test signal emitter and as receiver sensor.
  • Another preferred embodiment approximation is one for which, as illustrated for the path 171, for a given emitter 141m as calibration emitter CE(m) the associated receiver sensor 161p as paired calibration receiver CR(p) is a neighboring (e.g., nearest neighbor) transducer sensor element 161p as paired calibration receiver CR(p).
  • a question in such embodiments is which direction of neighbor to choose as sensor placement relative to the emitter element. For example, should it be one to the left or to the right of the emitter element.
  • the better approximation depends on the relative curvature of the entry boundary 151 of the intermediate skull layer 150 compared with the curvature of the focus beam at that boundary surface. For example, as illustrated in Fig. 27, if the boundary surface 151 is flatter than the better approximation is to have for emitter element 141m as calibration emitter CE(m) the associated test receiver sensor 161p as paired calibration receiver CR(p) to the right of it. The opposite choice, of a receiver sensor to the left would be preferred if the boundary surface 151 would be of higher curvature than the focused beam.
  • the difference between left and right sensors are minuscule, and an embodiment is to have a fixed pre-determined association of a given emitter sensor 141m as calibration emitter CE(m) to s fixed receiver sensor 161p as paired calibration receiver CR(p).
  • receiver element 261n can serve for test signal from several nearest neighboring emitter elements marked by the dashed circle, such as 241n and 241m.
  • the emitter and receiver sets are physically distinct. In some other embodiments, the emitter and receiver sets are overlapping. For example, referring to Fig.8, the array of receiver element marked by shaded fill cells may be distinct from the array of emitter elements marked by white fill cells. Alternatively, the shaded fill cells can mark a sub-set of the transducer elements which may be switched between acting as emitter and receiver functionality.
  • the emitter and/or receiver elements are able to selectively activate individual emitter and/or receiver elements from the physical arrays sets. For example, for test signal and calibration procedures, one is preferably activating the array emitter elements serially or in sub-sections (i.e., not all together as for focus creation), and respectively receiving and/or analyzing the echo received signals only of the associated receiver sensors. That is relevant both for embodiments where the emitter and receiver sets are physically distinct and for embodiments where they are overlapping.
  • the switching control and activation of the emitter 112 and/or receiver 116 arrays are managed by a controller module 255.
  • Fig. 29 illustrates an embodiment the invention system for focusing ultrasound into a target tissue when having an intervening skull-tissue intermediate-layer 150 bounded by first 151 and second 152 boundary surfaces, using ultrasound sensing, the system comprising:
  • a focusing transducer 110 comprising an emitter phased array ⁇ E(n) ⁇ 112 of ultrasound transducer elements for generating an ultrasound focus in the target tissue. At least most transducer elements having means connected thereto for variably setting a delay for that emitter transducer E(n), including a delay module for setting delay set ⁇ F(n) ⁇ of signals delay to associated emitter elements ⁇ E(n) ⁇ .
  • a receiver array 116 comprising a plurality of ultrasound receiver elements ⁇ R(n) ⁇ associated with emitter elements ⁇ E(n) ⁇ ; The receiver array 116 is connected to and controlled by a receiver control module 170.
  • a transmit/receive controller“T/R controller” module 255 for directing the activation and switching of individual elements of the emitter and receiver arrays.
  • the T/R module 255 comprising connections to the emitters array 112, to the receiver array 116, to the signal generator module 140 and to the control & computation module 160.
  • An emitter mux module 145 receives input signal from the signal generator 140, the associated activation delay set ⁇ TD(n) ⁇ from control module 160, and the array elements activation directed by T/R module 255.
  • the emitter mux 145 transmit the activation signals to the emitter array 112 elements ⁇ E(n) ⁇ .
  • a minority, preferably one, of the emitter elements E(n) is activated at a time, preferably with a distinct“test-signal”, which may be preferably different from the action-signal.
  • the test signal reflected echo-signal is received at an associated“paired” receiver element of the receiver set 116 and transmitted for analysis to receiver control module 170. It is expected that the received reflected signal would include multiple reflections from various material boundaries such as skin surface, fatty tissue, and the intermediate skull bone layer 150.
  • the receiver control module extracts the from the received signal the echo component associated with reflections from the first and second boundary surfaces 151 and 152 of the intermediate skull layer 150.
  • the time difference between these reflection signals is determined by the time-shift determiner module 172 to create the reflection time difference TD(n). Repeating the process serially for multiple, preferably most or preferably all, of the emitter elements, lead to obtaining a reflection time difference ⁇ TD(n) ⁇ .
  • the positioning module 165 maintains the transducer module 110 at a fixed orientation relative to the target tissue for both the calibration procedure and the focusing mode activation.
  • Fig.30A and Fig.30B highlight some aspects of the extraction of the reflected signals and calculation of the reflection delay time TD(n).
  • Fig.30A highlights the multiple layers of tissue on the path from the transducer emitter outside of the head to the focus peak within the skull.
  • Fig. 30B illustrates schematically the reflection of emitted test-signal 155, first reflected signal 156 from boundary surface 151 is received at the receiver sensor, and later the reflected signal 157 from the boundary surface 152 of the intermediate skull layer 150 is received at the receiver sensor. The arrival time difference between signal 156 and 157 corresponds to the detected test-signal delay TD(n).
  • the focusing-axis 310 is defined as the line from the focus peak to geometrical center of the transducer array in uniform medium.
  • a better matching of is obtained if the distance D1 between the emitter 341m and associated calibration-receiver 361p is larger than the distance D2 between the emitter 342m and associated calibration-receiver 362p.
  • the difference between D1 and D2 can be a factor of two or more.
  • ray 370 defined to be the ultrasound propagation“ray” from emitter 341m as would be in the selected uniform medium 99 traversing the focus peak 111
  • the path of ray 370 through the intermediate skull layer 150 is very close to the real path of ultrasound ray from emitter 141m as calibration emitter CE(m) to the focus peak 111.
  • Reflected ultrasound propagation “ray” 371 is reflected from outer surface of the intermediate skull layer (e.g., skull bone) of incident ultrasound ray 370.
  • Reflected ultrasound propagation“ray” 372 is reflected from inner surface of the intermediate skull layer (e.g., skull bone) of incident ultrasound ray 370.
  • the preferred associated calibration-receiver for optimal path matching is not fixed for all intermediate skull layers, but is dependent on the orientation of the intermediate tissue boundary layers relative to the transducer focusing-axis 310.
  • the preferred associated calibration-receiver for optimal path matching may depend on the skull orientation with respect to the transducer array focusing-axis 310. For example, for layer orientation 450a the better optimal receiver is 361p, while for layer orientation 450b the better optimal receiver is 461p.
  • the sensing of the skull orientation with respect to the transducer can also be detected using the ultrasound emitter array 112 and the receiver array 116. i.e., in embodiments of the method of the present invention, prior to the test signal procedure there is a calibration procedure for determining the orientation of the intermediate tissue boundary layers with respect to focusing-axis 310.
  • the aberration effect of the scalp layer is small compared with just the skull bone layer, because (a) the speed of sound in the scalp is very close to the speed of sound in brain tissue and/or the coupling medium 118, and (b) the scalp is relatively uniform in thickness across the surface area of the scalp contact with the device.
  • the focus of our discussion is on detection and correction of reflections between the first skull boundary entry surface 151 and the second skull bone boundary exit surface 152. Yet, this is not meant to be limiting.
  • the inclusion of the scalp layer 155 is a simple extension of the entry reference to the skin surface 153 entry instead of the bone entry surface 151.
  • the first reflection delay count would be from the path 173, which is identifiable as known in the art to select among the series of echo received signals.
  • the reflection times may be different. Therefore, the selection of receiver sensors at which time of reflected beams is measured is affecting the time delay correction calibration. i.e., for each calibration-emitter CE(m) there is an associated“paired” calibration-receiver CR(p) at which the echo signal is measured, thus defining the pair [CE(j),CR(k1),CR(k2)]. Different pairing may lead to different measurement and hence different calibration outcome. Some of the difference between various embodiments relates to the method or protocol of selecting the pairing of the calibration-emitter CE(m) there is an associated“paired” calibration-receiver CR(p) at which the echo signal is measured for the calibration ANALYSIS.
  • Fig. 36 illustrates a preferred method of receiver sensor selection.
  • better focusing calibration would be obtained if the test signals path through the intermediate tissue layer is better matching (i.e., closer) to the path through the intermediate skull layer of focusing beam to the focus peak location.
  • a test pulse is emitted from an individual emitter 341m, there is a sufficient time gap to distinguish between arrival at the receiver array 116 of the reflection beam signal 571 from first surface (outer surface) 151 and of reflection beam signal 572 from second surface (inner surface) 152 of the intermediate skull layer 150.
  • the reflected beam signal 571 may be arriving at each receiver of the receiver array 116 at a different time and also at a different intensity with a spatial distribution 563 of intensity which is measured by the receivers array.
  • the reflected beam signal 572 may be arriving at each receiver of the receiver array 116 at a different time and also at a different intensity with a spatial distribution 564 of intensity which is measured by the receivers array.
  • the sensor for timing T1 of the arrival of reflection 571 is timed at receiver 561p at which reflected beam 571 is detected at peak intensity.
  • the sensor for timing T2 the arrival of reflection 572 is timed at receiver 562p at which reflected beam 572 is detected at peak intensity. Repeating the test process for each emitter E(n) we obtain the reflected signals arrival times T1(n) and T2(n).
  • Fig. 38 illustrates a preferred method of receiver sensor selection.
  • better focusing calibration would be obtained if the test signals path through the intermediate tissue layer is better matching (i.e., closer) to the path through the intermediate skull layer of focusing beam to the focus peak location.
  • a test pulse is emitted from an individual emitter 341m, there is a sufficient time gap to distinguish between arrival at the receiver array 116 of the reflection beam signal 571 from first surface (outer surface) 151 and of reflection beam signal 572 from second surface (inner surface) 152 of the intermediate skull layer 150.
  • the reflected beam signal 571 may be arriving at each receiver of the receiver array 116 at a different time and also at a different intensity with a spatial distribution 563 of intensity which is measured by the receivers array.
  • the reflected beam signal 572 may be arriving at each receiver of the receiver array 116 at a different time and also at a different intensity with a spatial distribution 564 of intensity which is measured by the receivers array.
  • the intended depiction in Fig.38 is that the selection of receiver sensor at which reflection time is measured is based on a geometrical determination method.
  • the skull section 155 of intermediate skull layer 150 external surface 151 geometry and orientation at the section 155 facing the transducer is assumed to be given or measure by some known method.
  • the external shape of the skull boundary surface 151 is easy to determine with a variety of well known methods. It is the inner boundary surface 152 which is mostly unknown. Given the surface section 155, the geometrical ray 370 from each emitter element 341m to the intended focus peak 111 is traced. The ray is taken as reflected following classical law of reflection that the incident ray, the reflected ray, and the normal to the surface of the mirror all lie in the same plane. Furthermore, the angle of reflection is equal to the angle of incidence. Thereby, for a target focus location 111, the associated paired receiver for each emitter is selected.
  • the sensor for timing T1 of the arrival of reflection 571 is timed at receiver 561p at which reflected beam 571 is detected at peak intensity. In embodiments, the sensor for timing T2 the arrival of reflection 572 is timed at receiver 562p at which reflected beam 572 is detected at peak intensity. Repeating the test process for each emitter E(n) we obtain the reflected signals arrival times T1(n) and T2(n).
  • phase corrections i.e., time delays
  • amplitude corrections are determined in embodiments.
  • the fractional intensity which is collected at the receiver peak (and optionally including the intensity of the nearest neighbors receivers also) for both the first boundary reflection and second boundary layer reflected echo signal is indicative of the remaining transmitted intensity that reaches the focus peak.
  • Higher reflected fraction RI(n) means lower transmitted intensity fraction“TI(n)” contributing to the focus peak.
  • the amplitude correction A(n) for each emitter En of the set ⁇ En ⁇ is a function of TI(n), e.g., proportional to 1/TI(n).
  • the intensity emitted from emitter En is set to be [1/TI(n)]*A0, where A0 is the intended average intensity of the transducer emitters array.
  • a step of frequency-test scan is performed prior to treatment application.
  • Typical skull bone thickness ranges between 4mm to 12mm.
  • Typical ultrasound treatment frequency ranges between 0.25MHz to 2MHz, which at average speed of sound in bone of 3000 m/s translates to a range of wavelength between 1.5mm to 12mm.
  • 1 ⁇ 4 wavelengths range in size between 0.375mm to 3mm.
  • the 2D surface area of the transducer emitter array 212 is subdivided into a set of two or more sub-sections ⁇ 21Fig.22A, 2122B, etc... ⁇ .
  • the optimal frequency W1 is determined independently for each sub-section. Then, the treatment is delivered with each sub-section driven at its own local optimal frequency, in parallel or serially with other sub-sections of the transducer array.
  • the key in the preparatory MEASURE process is to get separate measurements of individual emitters En (or small local group of emitters).
  • the signals from sufficiently distant emitters do not mix or interfere at the small distance of the MEASURE reflection measurements. Therefore, in embodiments, the MEASURE process can be performed simultaneously on multiple emitters sub-set of the full array set ⁇ En ⁇ such that the distance between the array elements is larger than the distance between each array element and the intermediate skull layer 151.
  • Figs 40– 43 describe a computer simulation which illustrates the method and elements of the apparatus according to embodiments. While the simulation was conducted in 2D, its extension to 3D is straight forward to experts of the art.
  • the emitters array 112 consists of 20 identical elements emitting ultrasound at frequency of 500KHz. Each element width is 4mm, the elements are ordered tightly along an arc of radius of curvature 80mm. The array elements perform both as emitter and receiver sensors at the same location and thus it is representing also the receivers array 116.
  • the intermediate curved layer 150 representing a skull bone element, is bounded by a front/outer boundary surface curve 151 in the shape of a smooth arc and back/inner boundary surface 152 in the shape of a curved step. Thereby, the intermediate payer 150 has asymmetric thickness going from 10mm width on one side to 6mm with on the other side.
  • a difference of 4mm in passage length through the intermediate skull layer would cause a relative phase shift of 1 ⁇ 2 wavelength and result with destructive interference at the intended focus peak location instead of the intended constructive interference needed to create the peak as would be in uniform media 98.
  • the curvature of the emitters array 112 and the intermediate skull layer outer surface 151 are not concentric, the distance between elements En of the array 112 and the intermediate skull layer surface 151 is not uniform, but it is roughly around 10mm.
  • Fig.41 illustrates the MEASURE step performed on one emitter element, labeled“s1”.
  • the signal is excited on S1 element, and measured on the same S1 element and two adjacent neighbors.
  • the first peak at ⁇ 12 micro-sec corresponds to the front reflection 371 from the intermediate skull layer outer boundary surface.
  • the second peak at ⁇ 17.5 micro-sec corresponds to the back layer reflection 272 from the inner boundary surface.
  • the measurement is a signal-selection process, which in the this simulation is decided by the sensor on which the first reflected echo signal 171 was the strongest intensity.
  • the measurement of the second echo reflected signal 172 was chosen to be measured on the same receiver sensor irrespective of its strength.
  • the reflected signals were also measured on the same element E1. This happens to be the case since the array 112 is positioned close to the layer surface 151 and also because the curvature of the array is very close to concentric with the curvature of the intermediate skull layer.
  • the array 112 is positioned close to the skull, hence close to the skull boundary surface 151.
  • the curvature of the array is very close to concentric with the generic curvature of the human skull layer, typically between 26Cm and 122Cm radius of curvature.
  • different areas of the skull have some difference in curvature, and also there is a range of curvature differences between human individuals. Therefore, in some preferred embodiments, instead of fixed array curvature, the array curvature used in a particular instance can be modifiable to better match to the area of the skull that is irradiated in practice. i.e., prior to the start of PROC-1 as discussed above, there is an initial“curvature adjustment” step.
  • the MEASURE procedure in the simulation consisted of serially performing the same MEASURE step on all the 20 emitters forming the emitters array 112 set ⁇ En ⁇ .
  • Fig. 42 illustrates the ANALYSIS procedure portion of PROC-1.
  • the first column (#1) numbers the emitters ⁇ En ⁇ where“n” goes from 1 to 20.
  • Column #2 indicates the emitter on which the first reflected signal from the intermediate skull layer outer (front) boundary surface 151 surface (which was emitted from that line“n”th emitter) was the largest intensity.
  • Column #3 indicates the emitter on which the reflected signal from the intermediate skull layer inner (back) boundary surface 152 surface (which was emitted from that line“n”th emitter) was the largest intensity.
  • Column #4 lists the Front- Reflection-Time set ⁇ TFRn ⁇ of measured time period which took the first reflected signal from the intermediate skull layer outer (front) boundary surface 151 surface counted from when it was emitted from that line“n”th emitter.
  • Column #5 lists the Back-Reflection-Time set ⁇ TBRn ⁇ of measured time period which took the first reflected signal from the intermediate skull layer inner (back) boundary surface 152 surface counted from when it was emitted from that line“n”th emitter.
  • Column #6 lists the resulting set ⁇ TD(n) ⁇ of time difference TD(n) between the two reflected times. This is the main component of the ANALYSIS procedure, from which all else it derived by various estimation approximations.
  • Figs.223A, 223B, 223C illustrates the PROC-2 process simulation outcome of performing the calibrated focusing irradiation application procedure.
  • the system is activating the emitters array with the corrected set ⁇ FPS(n) ⁇ of input parameters phases.
  • Fig.423A shows a train of several wave crests, a short time after being emitter from the emitters array ⁇ En ⁇ of 20 emitters and before arriving at the front boundary surface 151 of the intermediate skull layer 150. There is a visible time delay between the two sides of the array– one facing the narrow side of the intermediate skull layer 150 and the other side facing the wider side of the intermediate skull layer 150– creating creates a non-circular wave-front.
  • Fig. 423B shows a train of several wave crests, a short time after emerging off the back-boundary surface 152 of the intermediate skull layer 150.
  • the wave-front is emerging with a well-coordinated circular wave-front between the two sides of the array– one facing the narrow side of the intermediate skull layer 150 and the other side facing the wider side of the intermediate skull layer 150, apart from a small and weak misalignment at the central area.
  • Fig.423C shows the waves converging properly to a concentrated peak with the intended peak width 139 and at the intended peak location 131 within few millimeters deviation.
  • Fig.44 illustrates a flow chart of an embodiment of the method of invention.
  • Figs. 44A - 44D illustrate embodiments of activation patterns of the calibration emitters array 112. Elements of the receivers array 116 are marked by dotted hexagons, and the remaining elements are emitters. In this embodiment, the same physical emitters serve for both the calibration emitters array 112 and the focusing emitters array 117. Activated emitter elements are marked by line-filled hexagon (as element 241a in Fig.44A) and dormant emitters are marked by white filled hexagons. Thus, the activation state illustrated in Fig.44A is one wherein only emitter element 241a is activated and all other emitters are dormant. Fig.44B is one wherein only emitter element 241b is activated and all other emitters are dormant.
  • Fig.44C is one wherein only emitter element 241c is activated and all other emitters are dormant.
  • Fig. 44D is one wherein both emitter elements 241a and 241d are activated and all other emitters are dormant.
  • the system serially activates configurations of the calibration emitters. In order to prevent interference of test signals from different emitters, in some configurations only a single calibration emitter is activated while all other emitters are dormant. Yet, if emitters are sufficiently distant from one another that interference is minimal enough to not disturb the test signal proper detection then it may be possible in some embodiments to simultaneously activate more than one calibration emitter (e.g., as illustrated in Fig.44D) during the calibration process.
  • the key outcome, of this modified embodiment of the calibration ANALYSIS procedure, is the construction of a fictitious-skull geometry and associated phase shifts distribution.
  • the PROC-2 irradiation focussing process is then performed as if the irradiated intermediate skull layer object is of the properties of the fictitious-skull rather than the real patient skull.
  • the array 112 of the emitters used for calibration-emitters function, can be both geometrically and physically different from the array 117 of the emitters used for the focus- emitters function. From the calibration procedure outcome, it is the data of the fictitious-skull geometry and phase shifts which is the input in to the focusing procedure.
  • the focusing array configuration can in principle be independent of the configuration of the calibration array used for producing the phase shifts input data.
  • the PROC-1 MEASURE-Trace process implements serial activation of an array of ultrasound probes, each placed at an associated probing-location relative to the skull.
  • the PROC-1 MEASURE-Trace process implements the serial activation of an array of ultrasound probes to trace, at discrete locations, the shape of the external skull and measure an effective local ultrasound time delay phase shift directly.
  • An effective fictitious skull model shape and thickness model is produced as an outcome of the PROC-1 MEASURE-Trace process.
  • the focus-emitters array 117 which can be placed at any geometrical position and orientation relative to the traced external skull geometry, is activated for focusing at any location within the skull, while computing the focusing phase shifts with respect to the effective fictitious skull model, taking the effective fictitious skull model external surface as coinciding with the human subject skull, using known in the art methods for focusing through a known layer geometry. An assumed speed of sound properties of the skull layer is also taken into consideration as is known in the art.
  • Figs. 45A, 45B illustrate an embodiment where the PROC-1 MEASURE process and the PROC-2 irradiation process where performed with the emitters array 112 at the different relative position with respect to the intermediate skull layer 150.
  • Fig.45B due to the location of the intended focus relative to the layer 150, it may be preferable to perform the PROC-2 irradiation process with the emitters array 112 relatively at bigger distance from the intermediate skull layer 150.
  • the problem is that the path of emitted wave from a given emitter to the intended focus location 131 is not passing through the same intermediate skull layer section (e.g., skull bone section) in both cases.
  • the path 370 in Fig.45A from emitter E1 to the intended focus 131 is passing through a different location in the intermediate skull layer 150 from the path 970 in Fig.45B from emitter E1 to the intended focus 131.
  • the VIRTUAL LAYER CONSTRUCTION outcome is a geometrical construction which overlap a portion of the intermediate skull layer which is facing the emitters array 112 during the MEASURE process.
  • the time delays set ⁇ TD(n) ⁇ is generated as a function of the geometrical-surface-time-difference value function GSTD(x,y,z).
  • the coordinate system (x,y,z) axis are fixed relative to the geometry of the emitters array ⁇ CE(j) ⁇ . Thereby, positioning of the focusing emitters array ⁇ FE(n) ⁇ can be determined by knowledge of the relative positioning of the focusing emitters array to the emitters array ⁇ CE(j) ⁇ . In some embodiments the coordinate system (x,y,z) axis are fixed relative to the geometry of the skull first boundary layer 151. Thereby, positioning of the focusing emitters array ⁇ FE(n) ⁇ can be determined by knowledge of the relative positioning of the focusing emitters array to the skull first boundary layer 151.
  • the value of GSTD(x,y,z) is a function of the measured echo-difference set ⁇ METD(j,k1,k2) ⁇ such that contributions from METD(j,k1,k2) ⁇ values are weighed higher where CE(j) is a nearer calibration-emitter to the location to the geometrical point (x,y,z).
  • the value of GSTD(x,y,z) is a function of the measured echo-difference set ⁇ METD(j,k1,k2) ⁇ such that contributions from METD(j,k1,k2) ⁇ is weighed highest where CE(j) is a nearest calibration-emitter to the location to the geometrical point (x,y,z).
  • the value of GSTD(x,y,z) is set equal to METD(j,k1,k2) ⁇ is weighed highest where CE(j) is a nearest calibration- emitter to the location to the geometrical point (x,y,z).
  • the value of GSTD(x,y,z) is a weighted sum of the elements of the measured echo-difference set ⁇ METD(j,k1,k2) ⁇ such that contributions from METD(j,k1,k2) ⁇ is weighed highest where CE(j) is a nearest calibration-emitter to the location to the geometrical point (x,y,z).
  • the value of GSTD(x,y,z) is set equal to the weighted average of two METD(j,k1,k2) ⁇ associated with the two nearest calibration-emitters to the location to the geometrical point (x,y,z), with the weight proportional to their distance from the geometrical point (x,y,z).
  • the geometrical-surface-time-difference value function GSTD(x,y,z) geometry is an approximation of the outer boundary surface 151 of the skull.
  • the timing of first echo from a calibration emitter CE(j) serves to determine the geometrical distance of the outer skull surface from the geometrical location of the emitter CE(j).
  • ⁇ TD(n) ⁇ is associated with the focus-emitters array ⁇ FE(n) ⁇
  • All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the patent specification, including definitions, will prevail.
  • the materials, methods, and examples are illustrative only and not intended to be limiting.

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Abstract

Des modes de réalisation de l'invention concernent un procédé et un système pour focaliser de l'énergie ultrasonore à travers un tissu crânien intermédiaire dans un site cible à l'intérieur d'une région tissulaire cérébrale cible sous le crâne, comprenant un réseau d'émetteurs de transducteurs, un réseau de récepteurs de transducteurs, un processeur recevant des signaux d'écho en provenance du récepteur pour déterminer des facteurs de correction pour les éléments transducteurs pour compenser la réfraction se produisant en raison du tissu intermédiaire. Les facteurs de correction peuvent comprendre des facteurs de correction de phases, et les phases de signaux d'excitation fournis aux éléments transducteurs peuvent être étalonnées par focalisation sur la base des facteurs de correction de phases pour focaliser l'énergie ultrasonore sur le tissu au niveau du site cible.
PCT/IB2019/000185 2017-02-23 2019-01-31 Focalisation ultrasonore transcrânienne WO2020157536A1 (fr)

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FR3114032A1 (fr) * 2020-09-15 2022-03-18 Commissariat A L'energie Atomique Et Aux Energies Alternatives Méthode de génération d’un front d’onde acoustique à travers une paroi

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US20180177491A1 (en) * 2016-12-22 2018-06-28 Sunnybrook Research Institute Systems and methods for performing transcranial ultrasound therapeutic and imaging procedures
US20180360420A1 (en) * 2017-06-20 2018-12-20 Kobi Vortman Ultrasound focusing using a cross-point switch matrix
US20190030375A1 (en) * 2017-02-23 2019-01-31 Oron Zachar Transcranial ultrasound focusing

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US20080177180A1 (en) * 2004-08-17 2008-07-24 Technion Research & Development Ultrasonic Image-Guided Tissue-Damaging Procedure
US20160106395A1 (en) * 2013-05-03 2016-04-21 Sunnybrook Health Sciences Center Systems and methods for super-resolution ultrasound imaging
US20180177491A1 (en) * 2016-12-22 2018-06-28 Sunnybrook Research Institute Systems and methods for performing transcranial ultrasound therapeutic and imaging procedures
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US20180360420A1 (en) * 2017-06-20 2018-12-20 Kobi Vortman Ultrasound focusing using a cross-point switch matrix

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210219958A1 (en) * 2020-01-22 2021-07-22 Samsung Medison Co., Ltd. Ultrasound diagnostic apparatus and method of controlling the same, and computer program product
FR3114032A1 (fr) * 2020-09-15 2022-03-18 Commissariat A L'energie Atomique Et Aux Energies Alternatives Méthode de génération d’un front d’onde acoustique à travers une paroi

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