HK1191888A - System and method for non-invasive transcranial insonation - Google Patents

Description

System and method for non-invasive transcranial insonation

Cross reference to related applications

This application claims the benefit and priority of U.S. patent application No. 13/209,385 entitled "Non-Invasive transport ultra Apparatus", filed 13/8/2011, which in turn claims priority of 61/453,771 entitled "Non-Invasive transport ultra Apparatus", filed 17/3/2011. This application also claims the benefit and priority of the above-mentioned U.S. provisional application 61/453,771. Each of the above-mentioned patent applications is incorporated by reference herein in its entirety.

Technical Field

The present invention relates to ultrasound devices and methods, and, more particularly, to a portable ultrasound system with stereotactic features configured to ensure that: once the system is placed on the subject's head, a predefined portion of the cerebral vasculature is predictably insonated without feedback from the clinician as is routinely required.

Background

Various devices for ultrasonic irradiation of a subject's head (referred to herein as "ultrasound devices" or "US devices" for simplicity) are known in the art. However, most if not all of the currently available US devices impose certain requirements on the insonation process that limit the efficiency and flexibility of operation of such devices. For example, because the purpose of such US devices is to interrogate a portion of a cerebral blood vessel, these devices must be carefully positioned and oriented by an operator (or clinician) with respect to the head of the subject to ensure that the ultrasound beam produced by the transducer of the US device is correctly directed at the portion of the cerebral blood vessel under consideration. Such localization is often facilitated by preliminary sonographic imaging (e.g., doppler imaging), which lengthens the overall procedure time and produces an image of the cerebral vasculature in relation to a selected spatial coordinate system. From these doppler images, the operator further determines the orientation of the US device with respect to the subject's head. However, the reliance on and reference to doppler images is operator dependent and, inevitably, different operators place the same US device in different locations on the same head, thereby making very significant differences in the reproducibility of the resulting transcranial insonation.

For example, where insonation of a particular clot of a cerebral blood vessel is required, not only the deviations and differences in the three-dimensional (3D) positioning of the US device in the head mentioned above may lead to inaccurate insonation of the clot itself, but also the safety of the insonation process itself may be problematic. To counter these possibilities, operators often need to conduct additional diagnostic studies, which take even more time.

Furthermore, sonothrombolysis (sonothrombolysis) procedures require that the target area be insonated for an extended period of time (in some cases, a minimum of two hours), throughout which conventional US devices for sonothrombolysis require attention from the clinician/operator to remain focused on the subject's head.

Moreover, insonation of the head of a subject is traditionally performed in a clinical setting and, due to the nature of the US equipment used, does not, for example, allow or at least limit the transport of the subject without interfering with the transcranial ultrasound procedure for sonothrombolysis. Accordingly, there remains an unresolved need for a system and method of transcranial insonation that addresses these shortcomings and enables an US device to be repeatably positioned on a subject's head in a pre-fixed orientation with respect to an identified portion of a cerebral vessel, i.e., configured to not constrain transport or otherwise move the subject during insonation, and to remain in a position oriented for optimal insonation without requiring input from an operator.

Disclosure of Invention

Embodiments of the present invention provide an apparatus for transcranial sonothrombolysis of a subject's head comprising a first temporal transducer array cooperating with a first transducer array registration member and an earpiece defining an earpiece plane, an earpiece surface, a front face corresponding to the forehead of the subject's head, and a nasion registration member secured to the earpiece at the front face and projecting transversely of the earpiece plane. In the case of a subject suffering a stroke, the apparatus of an embodiment is adapted for transcranial sonothrombolysis of a clot in a cerebral vessel of the subject. Such an earpiece is adapted to support the first transducer array on a surface of the earpiece (in one embodiment, the inner surface of the earpiece facing the subject's head when the earpiece is positioned on the head for sonothrombolysis). The headset includes anterior and posterior head frame members configured to mate at corresponding ends of these members, for example, to define the headset plane and a circumcranial loop of the headset. The mutual positioning of the anterior and posterior headgear members may be adjustable (optionally, stretchable).

The nasion registration member is configured to rest on the nasion of the subject when the headset is positioned on the subject's head for sonothrombolysis, for example, to ensure that (i) the headset plane is tilted with respect to a reference plane defined by the left otobasion superior (OBS), right OBS and nasion of the subject's head, and (ii) the headset plane passes through the left and right OBS. The angle of inclination between the reference plane and the earphone plane in this position is between about 10 degrees and about 15 degrees and, in one particular embodiment, about 12 degrees. The first transducer array registration means is configured to align the first temporal transducer array with an otobasion point and a sphenoid sinus support (sphenoid shelf) of the subject's head when the headset is positioned on the subject's head for sonothrombolysis, for example, to optimize the extent to which an Ultrasound (US) beam emitted by the first transducer array substantially along the plane of the headset insonates the target central cerebral vasculature. The target central cerebral vessels include at least one of Anterior Cerebral Artery (ACA), Middle Cerebral Artery (MCA), Posterior Cerebral Artery (PCA), Internal Carotid Artery (ICA), Basilar Artery (BAS), and vertebral artery (VER), and the Willis loop. One embodiment of the apparatus additionally includes an occipital transducer fixed on the surface of the earpiece opposite the nasion registration member and configured to emit an US beam toward the target cerebral vasculature substantially along the earpiece plane. An apparatus optionally further comprises a handheld portable remote control unit configured to control operation of at least one of the occipital and first temporal transducer arrays. Such a remote control unit is operatively connected to the headset wirelessly or by means of an umbilical cord (umbilicus). In one embodiment, the apparatus includes a second temporal transducer array cooperating with a second transducer array registration member. In this case, the first and second transducer arrays are fixed to the headset relative to each other such that, when the headset is positioned on the subject's head for transcranial sonothrombolysis, the second transducer array registration member aligns the second temporal transducer array with the supraauricular cardinal point and the sphenoid sinus support of the subject's head, for example, to optimize the extent to which the targeted central cerebral vasculature is insonated by the US beam emitted by the second transducer array substantially along the plane of the headset.

Embodiments of the present invention also provide an apparatus for transcranial sonothrombolysis of a target cerebral blood vessel of a subject's head, the apparatus comprising a set of transducer arrays (in one particular implementation, a temporal transducer array and an occipital transducer array) configured to operate with a hand-held portable remote control unit; and an earphone supporting the array of transducers and mountable to the head of the subject. The headset defines a headset plane and includes a set of mounting registration elements adapted to stereoscopically cooperate with the head of the subject, for example, to (i) align a transcranial acoustic window of the transducer array corresponding to the head of the subject when the headset is placed on the head of the subject for transcranial sonothrombolysis, and (ii) optimize insonation of the target cerebral vasculature through the transcranial acoustic window with a US beam emitted by the transducer array at such stereoscopically cooperating locations. The mounting registration elements are adapted to determine the orientation of the corresponding transducer array emitting the US beam substantially along the headset plane. When the headset is placed on the subject's head for transcranial sonothrombolysis, the headset plane is tilted with respect to a reference plane (defined by the selected external cranial landmarks of the subject's head). In general, the mounting registration element comprises a registration element configured to contact one of a nasion, a left otobasion superior (OBS), a right OBS, an tragus site, a mandible condyle, a zygomatic arch, a alveolar midpoint, and an occipital protuberance when the headset is placed on the subject's head for transcranial sonothrombolysis. In a specific embodiment, the selected external cranial markers include a left otobasion superior (OBS), a right OBS, and a nasion of the subject's head. In one embodiment, mounting the registration elements comprises a nasion registration support protruding from the front of the headset across the plane of the headset and a temporal transducer array registration support slidably mounted on the inner surface of the headset. Such a nasion registration support and temporal transducer array registration support are each configured to be positioned over the nasion of a subject and to engage with an OBS when an earpiece is placed over the subject's head for transcranial sonothrombolysis. In one particular implementation, the registration elements are adapted to ensure that the headset plane passes through the left and right OBS when the headset is placed on the subject's head for transcranial sonothrombolysis.

Optionally, the headset comprises anterior and posterior head frame members configured to mate at corresponding ends of said members, for example to define a circumcranial loop of said headset. The mutual positioning of the anterior and posterior head members is stretch adjustable. One embodiment may additionally comprise a hand-held portable remote control unit configured to power the at least one transducer array, and optionally, an umbilical cord operable to connect the remote control unit to the headset.

Embodiments of the present invention additionally provide an apparatus for transcranial sonothrombolysis of a target vessel of a subject's head, the apparatus comprising one or more transducer arrays, a headset defining a headset plane and supporting the one or more transducer arrays, one or more supports extending outwardly from the headset, wherein different supports are used to position the headset with respect to different external cranial markers of the subject's head. In one case, when the headset is placed on the subject's head for transcranial sonothrombolysis, the headset plane passes through the left and right OBS.

One or more of the mounts of the apparatus are adapted to stereoscopically cooperate with the cranial markers to position the at least one transducer array to optimize insonation of the target cerebral vasculature with an ultrasound beam emitted by the thus positioned at least one transducer array. Furthermore, the at least one stent is adapted to stereotactically align the at least one transducer array for transcranial sonothrombolysis and optimize insonation of the target cerebral vasculature with the US beam through one or more transcranial acoustic windows. In a specific embodiment, the cradle comprises a nasion registration cradle protruding from a front face of the headset and a transducer array registration cradle slidably mounted to an inner surface of the headset, and the external cranial markers comprise a left otobasion superior (OBS), a right OBS, and a nasion of the subject's head. The headset includes front and rear ear mount members configured to mate at corresponding ends of the members, for example to define a circumcranial loop of the headset.

Embodiments of the present invention also include an earphone device for providing transcranial sonothrombolysis of a target cerebral blood vessel of a subject's head. The headset apparatus includes (i) a processor, (ii) a non-transitory tangible computer readable medium having computer readable program code encoded therein, and (iii) an ultrasound device having a headset plane and including a mounting registration bracket and transducer array (defined with respect to corresponding external cranial landmarks of a subject's head). The headset apparatus may be placed on the subject's head such that the mounting registration brackets are in contact with respective corresponding external cranial markers and the headset plane is placed at an angle with respect to a reference plane defined by the external cranial markers. The computer readable program code includes a series of computer readable program steps to effect (a) insonating a target cerebral blood vessel in a plane of the earpiece; and (b) defining an operating scheme for at least one transducer array of the headset device. In one embodiment, the step of insonating comprises insonating with at least one of a temporal transducer array and an occipital transducer array and, additionally or alternatively, the step of defining comprises defining at least one of a time and amplitude sequence of the US beam.

Embodiments of the present invention further provide a method of transcranial sonothrombolysis of a subject's head using an ultrasound US device having a headset defining a headset plane and containing a transducer array and a mounting registration element, wherein the mounting registration element comprises a nasion registration element and at least one temporal registration element. (in one embodiment, the headset contains a temporal transducer array, an occipital transducer array, and a hand-held portable remote control unit with a pre-programmed processor to define an operational scheme for at least one of the temporal and occipital transducer arrays.) in the event that the subject suffers a stroke, the method of one embodiment is adapted for transcranial sonothrombolysis of a clot in the cerebral vasculature of the subject. A method for sonothrombolysis includes positioning an earpiece on a subject's head such that (i) a nasion registration member rests on a nasion of the subject, (ii) an earpiece plane is tilted with respect to a reference plane defined by a left otobasion point (OBS), a right OBS, and the nasion, and (iii) the earpiece plane intersects the reference plane substantially at the left and right OBS. The method further includes insonating a target cerebral blood vessel defined by the headset plane so tilted. The positioning of the headset may include establishing contact between at least one temporal registration member and an OBS and, alternatively or additionally, positioning the headset, for example, with the headset plane tilted at an angle in a range of about 10 degrees to about 15 degrees with respect to the reference plane. Insonating includes insonating at least one of the Anterior Cerebral Artery (ACA), the Middle Cerebral Artery (MCA), the Posterior Cerebral Artery (PCA), the Internal Carotid Artery (ICA), the Basilar Artery (BAS), and the vertebral artery (VER) and Willis loops with a US beam emitted by a transducer array.

Embodiments of the present invention additionally provide methods of transcranial sonothrombolysis of a target cerebral vessel of a subject's head using an Ultrasound (US) device having a headset defining a headset plane and including a set of mounted registration elements and a transducer array including a temporal transducer array and an occipital transducer array. The method comprises selecting such external cranial markers associated with the subject's head for defining the location of said target cerebral blood vessel; and defining mounting registration elements on the headset corresponding to the selected external skull marks, respectively. (the definition of mounting the registration elements includes defining a nasion registration support projecting transverse to the plane of the headset and configured to be located at the nasion of the subject when the headset is placed on the subject's head for transcranial sonothrombolysis, and defining a registration member associated with the array of temporal transducers and configured to contact the cardinal point on the ear when the headset is placed on the subject's head for transcranial sonothrombolysis.)

The method additionally comprises positioning a headset on the subject's head in order to establish contact between, for example, the defined mounting registration elements and the respective corresponding external skull markers. The method further includes activating the transducer array to insonate the target cerebral blood vessel substantially along the headset plane, optionally with a hand-held portable remote control unit (either wirelessly or by connecting an umbilical cable or umbilical cord). The process of selecting an external craniological mark includes selecting a craniological mark defining a reference plane across the subject's head and, in one particular implementation, selecting at least three of a nasion, a left otobasion superior (OBS), a right OBS, an tragus point, a mandible condyle, a zygomatic arch, a alveolar midpoint, and an occipital protuberance.

Embodiments of the present invention further provide a computer program product for transcranial sonothrombolysis of a target cerebral vessel of a subject's head using an ultrasound device having a headset (identifying a headset plane and including a set of mounted registration elements defined with respect to corresponding external cranial markers of the subject's head) and a transducer array, wherein the headset is configured to be positionable onto the subject's head such that the mounted registration elements are in contact with the respective corresponding external cranial markers. Such a computer program product comprises a tangible computer usable medium having computer readable program code embodied thereon, the computer readable program having (i) program code for activating at least one transducer array, for example, to optimize insonation of a target cerebral blood vessel substantially in the plane of the headset; and (ii) program code for defining an operating scheme for the at least one transducer array. Further, the program code for defining the operational scenario optionally includes program code for insonating a target cerebral vessel, wherein the peak rarefaction pressure does not exceed 300kPa and the thermal index does not exceed a physiologically compatible thermal index at a predetermined depth within the subject's head. Alternatively or additionally, the program code for defining an operating scheme comprises program code adapted to cause at least one of said transducer arrays to transmit US pulses with a pulse spacing determined to prevent echoes from constructive interference between said US pulses and outgoing pulses. In a specific embodiment, such pulse intervals are between 150 milliseconds and 300 milliseconds.

Drawings

The invention will be more completely understood in consideration of the following detailed description of specific embodiments in connection with the accompanying drawings, in which:

fig. 1 is a perspective view of a US apparatus according to an embodiment of the invention.

Fig. 2A and 2B are side and plan views of an earphone part of an embodiment of the present invention.

Figure 3 is a rendering of a head with a selected cranial landmark having a spatial relationship to the sphenoid sinus support (and the anterior bed process) on which the Willis loop is located. According to one embodiment of the invention, three such landmarks are used to stereoscopically align the array with the acoustic window and the cerebral vasculature.

Fig. 4A is an illustration of the skull and associated cerebral arteries forming a sphenoid sinus stent.

Fig. 4B and 4C are high-level and side views, respectively, of the main cerebral artery and the Willis annulus, which can be seen as tangent to the anterior and posterior bed processes and projecting from the shelf or ledge (leader) formed by the greater and lesser wings of the sphenoid bone (or "sphenoid sinus shelf") which forms the base of the anterior socket and which overlies and is generally coplanar with the orbital canal (orbital track).

Fig. 5A is a diagram illustrating a triangular base (or reference) plane defined by mounting registration markers and used to orient the headset so that the transducer array is positioned and aligned with the cerebral vasculature in optimal registration according to an embodiment of the invention.

Fig. 5B illustrates a fixed tilt of the earpiece relative to the substantial registration plane of fig. 5A, according to an embodiment.

Fig. 6 is a side view of a headset on a user showing one embodiment of the present invention mounted thereon.

Fig. 7A is an internal view of a headset having a radicular registration support and pads configured to align the transducer array with the nasion and sphenoid sinus supports.

Figures 7B and C are perspective views of the temporal transducer array subassembly.

Figure 7D is a cross-sectional view showing details of the temporal transducer array and the transducer array housing.

Fig. 8A depicts an illustrative view of a temporal transducer array cooperating with a temporal acoustic window on the ipsilateral side of the cranium. The view of the target central cerebral blood vessel overlaps the view of the transducer array.

Fig. 8B is a cross-sectional illustration showing an ultrasound beam directed from a temporal transducer array to a target cerebral vessel.

Fig. 9A is a top view of a headset assembly showing temporal and occipital ultrasound beams directed from corresponding transducers toward a target cerebral vessel.

Figure 9B is a side cutaway view of an embodiment of the device depicting an ultrasound beam directed at an occipital transducer array of a target cerebral vessel.

Fig. 9C is a perspective view illustrating a hand-held portable remote control unit for use with an embodiment of the present invention.

Fig. 11A and 11B are graphs illustrating a pulsed operating scheme of a transducer according to an embodiment of the present invention.

FIG. 12A is an example of a meta-pulse (meta-pulse) cycle of operation of an embodiment of the present invention including sixteen US transducers. In conjunction with the traces, the figure represents a pattern of asynchronous ultrasound burst transmissions (i.e., a "meta-pulse cycle") in which each individual crystal is directed to a different anatomical target and transmitted once per cycle.

Fig. 12B is another example of a meta-pulse cycle, here with double, paired transducer firing.

Fig. 12C is another example of an elementary pulsed acoustic action cycle, here with three times the simultaneous transducer transmission.

Figure 13 quantifies the audible sensing of ultrasonic exposure as a function of modulated burst frequency.

FIG. 14A is an illustration of the transducer voltage (V)_p-p) Selected increments of (c), peak sparse pressure (P) as a function of depth_r) A graph of (a).

Fig. 14B is a graph illustrating empirically determined peak sparse pressure versus ICH conversion (%) based on analysis of data from clinical trials.

FIG. 15A is a graph illustrating the table of thickness and thinness of the skull at 1MHz versus peak sparse pressure as a function of depth.

FIG. 15B is the attenuation coefficient for the temporal bone (A)_TempBONE) Curve fitting to frequency.

Fig. 16A and 16B are perspective views of a physical model for attenuation profile analysis as a function of depth for transducers spanning space-time (fig. 16A) and juxtaposed with non-bony sub-occipital acoustic windows (fig. 16B).

FIG. 17 is a flow chart (390) depicting the automated operation of the inventive apparatus wherein the transmit voltage is adjusted to detect the acoustic coupling of each transducer used.

Fig. 18A is a graph depicting the use of phase angle to verify acoustic coupling.

FIG. 18B is a graph of voltage output versus phase angle corresponding to one embodiment of the coupling verification circuit of FIG. 19.

Fig. 19 schematically illustrates a coupling verification circuit (400) that relies on a voltage comparator with the output of fig. 18B.

Fig. 20A and 20B are diagrams depicting a model for vasodilation for the release of endogenous nitric oxide, in which blood shears (fig. 20A) are replaced by non-invasive ultrasound from the device of the invention (fig. 20B).

Detailed Description

In accordance with a preferred embodiment of the present invention, a method and apparatus configured for non-invasive transcranial ultrasound procedures is disclosed, with no imaging-guided placement of a US device in cooperation with a subject's head, as is required by currently employed methods and apparatus in the relevant art. An embodiment of the system of the invention comprises a stereotactic structure and is adapted to be positioned on the head of the subject in a predetermined, reproducibly achievable orientation, which positioning ensures that a specific element of the cerebral blood vessels of the subject is reliably insonated according to the method of the invention.

Reference throughout this specification to "one embodiment," "an embodiment," "a related embodiment," or similar language means that a particular feature, structure, or characteristic described in connection with the referenced embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases "in one embodiment," "in an embodiment," or similar language throughout this specification may, but do not necessarily, all refer to the same embodiment. It should be understood that no portion of this disclosure is intended to provide a complete description of all of the features of the invention, possibly in combination with the accompanying drawings.

Furthermore, the following disclosure may describe features of the invention with reference to the corresponding figures, wherein like reference numerals represent the same or similar elements wherever possible. In the drawings, the structural elements depicted are generally not to scale, and certain features are exaggerated relative to other features for emphasis and understanding. It is to be understood that no single drawing is intended to support a complete understanding of all features of the invention. In other words, a given drawing generally depicts only some, and often not all, features of the invention. In order to simplify a given figure and discussion, a given figure and relevant portion of the disclosure that contains descriptions referencing this figure typically do not contain all of the elements of a particular view or all of the features that may be present in this view, and the discussion is directed to the particular elements that are recited in this figure. One skilled in the relevant art will recognize that the invention may be practiced without one or more of the specific features, elements, components, structures, details, or characteristics, or with other methods, components, materials, and so forth. Thus, although specific details of an embodiment of the invention may not necessarily be shown in each of the figures that describe this embodiment, the presence of such details in the figures may be implied unless the context of the description requires otherwise. In other instances, well-known structures, details, materials, or operations may not be shown in a given figure or described in detail to avoid obscuring aspects of the embodiments of the invention discussed. Furthermore, the described individual features, structures, or characteristics of the invention may be combined in any suitable manner in one or more further embodiments.

Furthermore, the schematic flow chart diagrams included are generally set forth as logical flow chart diagrams. The depicted order and labeled steps of the logical flows, therefore, indicate one embodiment of the presented method. Other steps and methods may be conceived that are equivalent in function, logic, or effect to one or more steps, or portions thereof, of the illustrated method. Additionally, the format and symbols employed are provided to explain the logical steps of the method and are understood not to limit the scope of the method. Although various arrow types and line types may be employed in the flow chart diagrams, they are understood not to limit the scope of the corresponding method. Indeed, some arrows or other connectors may be used to indicate only the logical flow of the method. For instance, an arrow may indicate a waiting or monitoring period of unspecified duration between enumerated steps of the depicted method. The order in which process steps or particular methods occur may or may not strictly adhere to the order of the corresponding steps shown, without loss of generality.

The invention as recited in the claims appended to this disclosure is to be evaluated in light of this disclosure as a whole.

In the united states, approximately 700,000 strokes occur annually, and in more than 150,000 such cases, a stroke happens to be fatal, while in the remaining majority of cases, the stroke debilitates those survivors. Importantly, centralized clinical care centers for stroke currently can only care for about 3% of stroke cases, and mortality and morbidity after advanced diagnosis and treatment-lack of sonothrombolysis-improved by only 20% even for the most advanced care population.

As is known in the art, tools for non-invasive sonothrombolysis are also in the middle of the trial and have not resulted in a change in the basic criteria for stroke care or significantly improved diagnosis of the pathology. The use of existing sonothrombolysis devices suffers from significant inaccuracies in the insonation of the target area of the subject's head (due to the unrepeatable and operator-dependent positioning of such devices during cooperation with the subject's head) and from non-portability (due to the need for a fixed power supply). Accordingly, there is a long felt need for stroke care devices with improved efficacy, non-invasive, non-surgical, and safety.

In general, embodiments of the present invention include US sonothrombolysis devices for transcranial insonation in the form of a headset defining a headset plane (and configured for transcranial mounting) and including a set of registration features (also referred to as a registration system) that facilitate stereotactic (or, in other words, with respect to an external reference frame) positioning of a transducer array of such US devices.

Registration system for external skull markers

Figures 1, 2A and 2B provide a general description of an embodiment of the US ultrasonic thrombolysis apparatus of the present invention. For example, FIG. 1 is a perspective view 100 of such an ultrasonic thrombolytic device. As shown, embodiment 100 includes a headset (headset) or headset assembly 101 defining a headset plane and configured for circumcranial positioning in cooperation with a subject's head, a remote control unit 102 having a power supply unit in a pocket-sized housing, and a cable or umbilical cord 103 operatively and optionally detachably connecting headset 101 with remote control 102. (in a related embodiment, not shown, remote control unit 102 may be operatively connected to headset 101. in another related embodiment, elements of the remote control unit described below cooperate with or are integrated into elements of headset assembly 101.) remote control unit 102 is provided with appropriate operating elements, such as, for example, on/off or pause actuators or buttons 107 and status indicator strip 108. The earpiece 101 is designed for an extended wearing period and weighs less than 500 grams, and the entire embodiment 100 weighs less than 1 kg. The embodiment 100 is shown to include three transducer arrays (two temporal transducer arrays 105a, 105b and one occipital transducer array 106) repositionably affixed to the inside of the headset 101, but more generally includes a different number of multiple transducer arrays. For example, in one implementation, embodiment 100 includes 6 transducers in each temporal transducer array 105a, 105b and 4 transducers in the occipital array 106. Each transducer array 105a, 105b, 106 comprises a plurality of piezoelectric crystals, each about 1cm in diameter, which are optionally individually powered and operated, typically in the range of about 500kHz to about 3500kHz, and, in particular embodiments, between about 1MHz and about 2 MHz. In one implementation, the structural housing and/or support elements of the earphone assembly 101 are constructed of a radiation transparent plastic material having a low Hounsfield density. Examples of such plastic materials include polycarbonate, acrylonitrile-butadiene-styrene (ABS), styrene-acrylonitrile, polystyrene, nylon, polyethylene, acrylates, and the like. For example, Bayblend (Bayer MaterialScience, Dusseldorf, germany) may be used in the construction of the headset of the present invention, although not limited thereto. The CT translucency of various plastics has been described, for example, by Henrikson (in CT evaluation of plastic intraepithelial papers, am. J. neuron injection, 8: 378-39, 1987).

Fig. 2A and 2B provide side and top views of the headset assembly 101 of fig. 1, showing elements of a stereotactic registration or positioning system (e.g., a nose and ear registration cradle) configured to align the transducer of this embodiment with a target acoustic window and a target cerebral blood vessel in the skull bone when the headset 101 is in cooperation with the subject's head, as discussed below. The above mentioned headphone plane defined by the headphone 101 is the plane 230 extending along the headphone 101 and intersecting the plane of fig. 2A along the dotted line shown. In particular, the earphone assembly 101 comprises an arcuate front headgear member 101a adapted to fit the front of a subject's head and having two open ends configured to receive corresponding ends of an arcuate, flexible rear headgear member 101 b. As shown, members 101a and 101b are paired, in that the ends of member 101b are inserted into the corresponding ends of member 101a, so as to define, in the mated position, the plane of headset 101 and the circumcision of the skull of headset 101 to fit around the subject's head. The mutual positioning of members 101a and 101b and the size of the loop of earphone 101 can be adjusted by a clasping mechanism or knob 119 located within the body of front head frame member 101 a. As shown, the knob 119 is located on the front of the headset 101 (which corresponds to the forehead of the subject's head), but may generally be located in a different position. Fastening is achieved by tightening posterior head member 101b and does not alter or otherwise affect the cranium placement of anterior head member 101a with the registration stent, thereby ensuring that stereotactic alignment with respect to the cerebral vasculature is not disturbed. The headset 101 also includes a set of registration system elements (discussed in detail below), one of which is a nasion registration cradle 120. A mount 120 is mounted on the medial anterior portion of the headgear 101 and supports a nose pad 104, the nose pad 104 being adapted to cooperate with and to rest against the nasal root on the nasal bridge of the subject.

As mentioned, according to the inventive concept, the structure of the registration system of the US device of the invention is designed to ensure that, once an embodiment of the device cooperates with the head of the subject, the transducer of this embodiment is reliably positioned and oriented in a certain predetermined spatial relationship with the cranial features in a single movement, thereby enabling the transducer to predictably emit ultrasound waves towards the target cerebral artery most commonly associated with stroke. This is in sharp contrast to prior art solutions which require repeated, operator-related reorientation of the array to obtain optimal positioning of the array on the subject's head and thus delay initiation of the insonation process. One arterial target of insonation includes, for example, the cerebral artery, commonly referred to as the Circle of Willis (Circle of Willis), whose cerebral vascular tree produces redundancy or collateral processes in the cerebral circulation. (the Willis loop may be interchangeably referred to herein as the cerebral arterial loop (cerebral arterial nexus)), in particular, if a portion of the loop becomes blocked or narrowed (stenosed) or one of the arteries supplying the loop is blocked or narrowed, then blood flow from the other vessels will often keep the brain perfused well enough to avoid the signs of ischemia. Also, statistically, many strokes are found to be strokes of the cerebral arteries associated with the Willis loop. Thus, (i) defining the orientation of the Willis's loop in relation to the external cranial marker, and (ii) configuring the registration system of the US device in relation to the same external cranial marker to set the spatial location of the US device in dependence on such defined orientation, ensures that the transducer of the US device is unambiguously, passively (i.e. without requiring or using any feedback from the clinician or machine characterizing the accuracy of such location) and repeatedly (i.e. whenever the US device cooperates with the subject's head) positioned for insonation of the Willis's loop and the associated cerebral arteries.

The registration system of embodiments of the present invention is defined by external skull markers associated with a person's head. This reuse of the saved external skull marks eliminates the need for a trained clinician and/or sonographer to adjust and readjust the earphones of the device on the subject's head. According to an embodiment of the invention, the external reference frame for sonothrombolysis comprises an external skeleton, wherein the cranial reference frame is based on one or more cranial markers of the head, such as the nasion, left otobasion, right otobasion, tragus point, mandible condyle, zygomatic arch, alveolar midpoint and occipital protuberance. In one embodiment, for example, a triangular frame of reference is used to define the registration system of the US device. The reference frame for such a triangle includes at least three markers, such as the nasion and right (Rt) and left (Lt) supraaural base markers. The selection of this triangular frame of reference establishes unambiguously the relative positions of (i) the temporal and sub-occipital acoustic windows in the subject's skull, (ii) the sphenoid sinus "shelf" formed by the large and small wings of the sphenoid, (iii) the anterior and posterior bed processes, (iv) the saddle back, and (v) the Willis loop, which has the cerebral arterial loop, the bifurcation of the internal carotid artery that unites the anterior, middle and posterior cerebral arteries, and the junction of the basilar artery with the communicating cerebral and vertebral arteries. A conventional frame of reference (e.g., a reference plane) to the subject's head, selected in the related art, is defined to determine the orientation of the US device with respect to a vertical plane or a horizontal plane. The elements of the cerebral vessels targeted by the system and method of the present invention, such as the Willis's rings, define planes that are neither vertical nor horizontal, but rather are inclined with respect to the horizontal. Thus, the conventionally defined sonication process or US apparatus, the operation of which is defined with respect to a conventional reference frame, is not configured to reproducibly target and sonicate, for example, the Willis's circle. Accordingly, the reference frame defined by embodiments of the present invention has proven empirically to be more reliable than the conventional Broca reference plane (also known as the "neuroeye plane" or NOP), and more preferable than the Frankfurt-Virchow plane, which is tilted from and below the target anatomy. Although the NOP following the orbital canal is slightly below and parallel to the Willis's loop, its use requires a measurement of 3.3cm above the tragus point and is not readily available to unskilled persons. In contrast, the use of the reference frame defined by the embodiments of the present invention does not require any guidance and/or preparation by clinical personnel. As will be further discussed, the desired spatial orientation of the device with respect to the predefined reference plane is pre-set by the design of the headset geometry.

To facilitate an understanding of the spatial cooperation of embodiments of the present invention with the subject's head, fig. 3, 4A, 4B and 4C provide a mutual orientation of a target portion of the cerebrovascular system and an external skull marker system, wherein the external skull marker system defines the registration system of embodiments of the present invention. In particular, fig. 3 is a pictorial view providing a rendering of a head having characteristic external cranial markers of the head in spatial relationship to a sphenoid sinus support (marked by an anterior bed process, see fig. 4A) on which the main portion of the Willis loop is located. Among the external craniological marks chosen to define the registration system of the device of the present invention according to embodiments of the present invention are the nasion 130, the supraauricular cardinal point or OBS (one shown, right OBS 131), the tragus point 132, the ear canal (with central auricular point 133), brema 134, and the mandibular condyle, the zygomatic arch, the alveolar midpoint, brema, or occipital protuberance (OCP) (not shown). Fig. 4A is a perspective expanded view of the skull 140 showing the general location of the cranial apex 141, bones forming anatomical features referred to herein as "sphenoid sinus supports" 143 (e.g., the large and small wings of the sphenoid bone), and the major cerebral arteries 142, 144. Fig. 4B and 4C are high-level and side views of the major cerebral arteries and the Willis's annulus 144. Shown are the Anterior Cerebral Artery (ACA), Middle Cerebral Artery (MCA), Posterior Cerebral Artery (PCA), Internal Carotid Artery (ICA), Basilar Artery (BAS), and vertebral artery (VER) and their connections to Willis's loop (144). Referring again to fig. 4A, the Willis loop 144 is shown partially positioned over the sphenoid sinus stent 143, with the sphenoid sinus stent 143 forming the base of the anterior fossa of the overlying orbital canal and generally co-located with the Alleman plane.

In accordance with the concepts of the present invention, at least three external registration markers are used to stereoscopically align the earpiece (e.g., earpiece 101 of fig. 1) and corresponding transducer array (e.g., arrays 105, 105b, 106 of fig. 1) of an embodiment of the US device with the acoustic window in the skull and the target cerebral vasculature. In one implementation, for example, the selected indicia include the nasion 130 and left and right OBS. To this end, fig. 5A shows a diagram illustrating a reference plane P (the xz plane in fig. 5A, also referred to herein as the Alleman plane) containing selected registration markers (the nasion 130, the left OBS131a, and the right OBS131 b). The isosceles triangle T defined by the markers 130, 131a, 131b has a base line connecting the left and right OBSs 131a, 131b and bisected by the straight middle line 136. The midline 136 extends in an anterior-posterior direction through the cranial apex, is generally tangent to the sphenoid sinus stent 143 of fig. 4A and is parallel to and slightly above the orbital canal of the subject (not shown), and defines the cerebral hemisphere. According to an embodiment of the present invention, the reference Alleman plane defined by triangle T is the external guide to the location of the cerebral vessels most prone to stroke.

As shown in fig. 5B, for example, in one implementation, once the headset is placed on the subject's head, the headset of the US device is configured to tilt about the Alleman plane P (as shown, the line "headset tilt" 138, further referring to fig. 2A, in this position of the headset 101, this line substantially coincides with the headset plane 230). For example, the inclination is provided by structurally offsetting the front headpiece member 101a of the headset above the nasion 130, e.g., by a distance h₁To be realized. It should be appreciated that the height of the glabella of an adult is about 0.7cm to about 1.6 cm. Therefore, if the structure is offset by a distance (height) h₁Chosen to be about 2cm, the front member 101a of the headset crosses the eyebrows of the wearer. The rear headband member 101b is structurally adapted to be positioned below the occipital protuberance by a distance h₂. When so tilted, the earpiece continues to rest against the external registration mark. The angle of inclination θ is selected to be between about 10 to about 15 degrees, and preferably about 12 degrees. Fig. 6 is a side view of the embodiment 100 of fig. 1, the embodiment 100 being positioned on a subject's head 600 and cooperating with selected external registration markers according to the spatial relationship described with reference to fig. 3, 4A and 4B. Thus, the temporal transducer arrays 105a, 105B of embodiment 100 may be slidably positioned on the head over the temporal acoustic window 137 of the skull as shown in fig. 5B.

To enable and achieve this desired tilt and offset with respect to the external skull markers, embodiments of the present invention include a mechanical mount with appropriate surfaces configured to engage selected external markers when the headset of this embodiment is placed on the subject's head. Fig. 7A, 7B, 7C, and 7D provide illustrations of portions of the headset 101 of fig. 1 in which elements of the registration system are configured to enable predetermined positioning of the US device of the present invention with respect to registration markers (discussed with reference to fig. 3, 4A, 4B, and 6).

One element of the registration system of the present invention, the nasion registration bracket 120, is shown in a back elevation view of the front frame member 101a in fig. 7A and in the views of fig. 7B-7D. Specifically, two additional elements of the registration system, the lateral registration OBS holder, are represented by the lateral registration OBS holder 154 of the right subassembly 700 that includes the temporal transducer array 105 b. The lateral registration OBS holder 154, in the form of an earpiece (earpiece), includes a surface 153 for aligning the temporal transducer array with the supraaural base point and the sphenoid sinus holder 143 of fig. 4A. The slider foot 153 of the sub-assembly 600 is suitably sized to be insertable into the right rail 152 of the headgear member 101a and slidably and securely fit, thereby allowing for suitable positioning of the transducer array 105B in front of the subject's ear such that, when the fully assembled headset 101 is positioned on the subject's head, the transducer array engages the temporal acoustic window 137 of fig. 5B. Referring again to fig. 5A, this positioning defines the fore-aft adjustment of the subassembly 700 about the midline and base of the triangle T. (the equivalent of subassembly 700 is configured similarly to subassembly 600, containing the second transducer array 155a, and is adjusted anteroposteriorly on the other side of the subject's head with respect to the midline and base of the triangle T, in cooperation with the head frame 101a of FIG. 7A via a second slide rail on the left side of the head frame 101 a. for simplicity of illustration, this equivalent subassembly is not shown.)

Fig. 7D is a diagram showing embodiment 700 in perspective view with a cross section through the piezoelectric crystals of transducers 155b, 155c of temporal array 105 b. The transducers 155a, 155b, 155c (shown arranged in an array of six cells) are optionally contained in a housing 156a and covered by a base plate 156b that cooperates with the slider feet 154. The housing includes a thin covering layer 157 adapted to act as a coupling layer for more efficiently coupling the acoustic output of the transducers 155a, 155b, 155c to the skull. The covering 157 may comprise polyurethane, polyethylene, silicon, rubber, and similar materials that are relatively soft and compliant and have a durometer value between that of the transducer and that of the skull. Alternatively or additionally, cover layer 157 may include a couplant gel as known in the art. Referring again to fig. 6, when the headset with front headset member 101a carries subassembly 700 on its interior surface and its counterpart is placed on the subject's head, subassembly 700 and its counterpart are generally aligned with and above the upper boundary of the zygomatic arch such that the corresponding transducers 155a, 155B, 155c are in contact with the head and acoustically coupled to temporal acoustic window 137 of fig. 5B by thin covering layer 157. Temporal acoustic window 137 is defined by a location in the skull that has a portion of bone that is relatively thin compared to bone in another portion of the skull.

Fig. 8A depicts temporal transducer array 105 (of temporal transducer arrays 105a, 105 b) adapted to interface with a temporal acoustic window on the same side of the skull as seen from the superimposed view of the transducer array and the central cerebral vasculature (BAS and Willis ring 144 can be seen). Also shown is the pillow transducer array 106 anchored below the OCP. The operation of nasion registration riser or cradle 120' with beveled pad 104, posterior head frame member 101b fixed under the OCP, and stretching knob 119 facilitates stabilization of the headset 101 with respect to a unique and well-defined anatomical position of the selected cranial landmarks. By having the earpiece 101 oriented in this manner, the head can be bent forward to open the occipital acoustic window without losing the stereotactic positioning of the right (Rt) and left (Lt) temporal transducer arrays 105a, 105 b. Fig. 8B is a perspective illustration depicting the orientation of the unfocused ultrasound beams (schematically shown as 160a, 160B) emitted by the Rt temporal transducer array 105B with respect to the internal anatomy of the target cerebral vasculature. The acoustic beam propagates through a temporal acoustic window 137 (shown in fig. 5B) and on 161 through the main (nexii) cerebral vessels, including the MCA, ACA, ICA, and Willis ring 144. In one implementation, Rt and Lt temporal transducer arrays 105a, 105b are configured to alternately transmit ultrasound waves to radiate/insonify substantially equally the hemisphere of the brain.

Fig. 9A, 9B provide additional illustration of one implementation of mechanical registration between an embodiment of the present invention and a target cerebral vessel through the use of selected external cranial markers. For example, fig. 9A depicts a top view of a headset assembly cooperating with a subject's head (not shown) using stereotactic positioning via the above-described registration system and using temporal and occipital unfocused ultrasound beams 160, 162 emitted from two directions 161, 163 to a target central cerebral vessel 161. In this embodiment, the occipital transducer array 106 is shown as including four occipital transducers 166. Figure 9B is a "through" side view showing how the ultrasound beams 162a, 162B of the occipital transducer array 106 are directed toward the internal cerebral vasculature. When the stereo registration system utilizing embodiments of the present invention is properly angled and positioned, the transducers in the occipital array are oriented toward the junction of the basilar and vertebral arteries and the internal carotid and anterior/posterior traffic arteries of Willis's loop 144, as discussed above.

Examples of auxiliary elements and operating characteristics of embodiments of the invention

In one embodiment, and with further reference to fig. 1, 2B, 7A-7D, for example, the transducer assemblies (105 a, 105B, 106) are configured to be detachable from the header member 101 a. In such an embodiment, the transducer array may be sold as a disposable module with a pre-installed "ready-to-use" gel couplant pad. The transducer module optionally has wiring terminals that plug into a female socket in the mounting socket (the portion of head frame member 101a surrounding slider 154), thereby enabling embodiments of the present invention to perform a functional self-check before beginning the insonation process using integrated watchdog circuitry. Optionally, the apparatus may also verify the acoustic coupling by performing a self-check before initiating transmission of the cyclic element pulse, for example using phase comparator circuitry described later in this description.

Embodiments of the present invention preferably employ unfocused transducers, i.e., producing waves that diverge as they propagate and are more acoustically activeA transducer for a beam of the target area. For an unfocused transducer, the near field length, beam spread angle and beam diameter may be calculated as L = D²f_c/4c, where L is the near field length, D is the diameter or aperture of the element, f_cIs the frequency and c is the speed of sound in the medium.

Fig. 9c is a perspective view illustrating the hand-held portable remote control unit 102 of fig. 1 with a housing 112 and a cover 111. As shown, the remote control unit 102 includes a printed circuit board 116 having a microcontroller 115 that is preprogrammed to enable operation of the US device and, optionally, to obtain and store data associated with such operation and/or insonation of the subject's head. For example, the remote control unit 102 optionally contains sensors (not shown) for collecting data and for generating feedback to the processor 115 in order to adjust at least some operating parameters of the US device (e.g., output energy, transducer firing sequence, or pulse interval). Remote control unit 102 also includes suitable electronic circuitry (not shown) including tangible computer-readable storage media. The electronic circuitry is configured to enable at least operation of the transducer and, optionally, obtain data associated with such operation. Mounted on the cover 111 is a battery power source 113 (e.g., three AAA batteries 114). Also shown is an on-off/pause switch 107 and at least one status indicator 108, such as an LED-based indicator (or, alternatively, another suitable status indicator, such as a buzzer or a liquid crystal display). The printed circuit board 116 has leads to a junction 117 forming a power and data bus that is routed through the umbilical 103 to the headset 100 of fig. 1. The power supply 113 may be equipped with a plurality of commercially available small batteries that can deliver about 200mAmp-hr, and if desired 400mAmp-hr, at an operating voltage of about 1.5 to about 4VDC, more preferably about 3.5 + -1 VDC, but alternatively about 9-12VDC, without charging for up to about 12 hours. Thus, the battery will have a capacity of 0.6 to 15 watt-hours and preferably has a weight of less than 250 grams, more preferably less than about 100 grams, and most preferably less than about 50 grams. The battery may be generally a rechargeable battery, an insertable battery, a lithium ion polymer battery, a lithium ion phosphate battery, a lithium-sulfur battery, a lithium-titanate battery, a nickel-zinc battery, a nickel-iron battery, a NiCd battery, a NiMH battery, an alkaline battery, a 9V battery, a cell phone battery, or at least one AA or AAA battery (as shown, 114), among others. Preferably, the power source is rechargeable and/or replaceable, and, where rechargeable, optionally includes a control circuit having a "fuel gauge," such as that available from Benchmark (BQ 2040) for charging the battery pack. The cell phone battery is typically about 3.7V and can deliver a power factor of about 1Amp-hr or about 20 to 40 Amp-hr/gm or more. For example, a device of the present invention operating in continuous mode for 2 hours at a maximum power draw of 400mAmp-hr and then in batch mode for 10 hours at 200mAmp-hr would require a battery of approximately 2.8Amp-hr capacity. A device with a maximum power draw of 200mAmp-hr would only require 400mAmp-hr for operation over a 2 hour cycle and therefore can operate with three AAA batteries in series providing approximately 4V. By way of example, a fresh battery may be installed if desired, and the total weight of the battery pack is 50 grams or less. Advantageously, this allows for portable, expandable procedures, such as ambulatory transcranial ultrasound.

In one embodiment, the US transducer transmits ultrasound waves in pulses, optionally grouped into pulse groups, which in turn may be modulated in time and/or spatial location with the processor 115. It has been empirically determined that such modulation of the operation of the transducer reduces the acoustic wave action intensity and power draw from the power source, while improving the operating efficiency of embodiments of the US device. The efficiency or rating factor for each transducer crystal, stored in a tangible (and, optionally, computer readable) memory unit associated with the US device, may be accessed by microcontroller 115 during start-up of the insonation process and used to vary the voltage applied to each crystal of the headset independently of the operation of the other crystal, thereby compensating for variations in the manufacturing process of the transducer array. This achieves an advantageous reduction in intra-headset variability of ultrasound therapy.

The frequency, pulse repetition pattern, and pulse element cycle (metacycle) rate are factors in the efficacy and safety of the US apparatus according to embodiments of the present invention. Thus, the operating scheme of the transducer and the corresponding patterned waveform can be changed using the pre-programmed processor 115. The dominant frequency selected for operation of the apparatus of the present invention is in the range of about 0.5 to about 3.5 MHz. As the operating frequency increases, the Mechanical Index (MI) of the tissue subjected to the insonation decreases, but the Thermal Index (TI) of the tissue subjected to the insonation conversely increases. (MI is an indication of the likelihood of non-thermal biological effects in tissue, and is defined as the peak sparse pressure or degraded peak pressure at negative amplitude divided by the square root of the ultrasound frequency,as MI increases, the likelihood of biological effects in the tissue increases. Accommodation limits typically allow mechanical indices up to 1.9 for most tissues other than ophthalmology. At low acoustic powers, the acoustic response is typically linear. TI is an estimate of the temperature increase calculated as the tissue absorbs ultrasound, determined by the ratio of the total acoustic energy to the acoustic power required to raise the tissue temperature by 1 ℃. Some devices further subdivide TI based on the tissue being insonated: a soft tissue thermal index TIS for soft homogeneous tissue, a skull thermal index TIC for bone at or near the surface, and a bone thermal index TIB for bone after the beam has penetrated the soft tissue. More generally, the temperature of the tissue subjected to the acoustic wave increases with increasing intensity and increasing frequency. ) An operating rate range of from about 0.8 or 0.9MHz to about 3.0MHz is preferred. And more preferably about 0.8MHz and about 1.2 MHz. In operation, the pulse width, intensity, and pulse repetition frequency are selected to be, for example, an integrated I of no more than about 720mW/cm2_spta.3And (4) limiting. (conventionally, spatio-peak temporal mean intensity, or I_sptaA value representing the temporal average intensity of the point in the acoustic field where the intensity is at a maximum. For example, I_spta.0Is calculated in such a way that the calculation,wherein PD is the pulse duration, P_rIs the peak sparse pressure, defined as the absolute value of the half-amplitude of the sound pressure penetrating the tissue. ) The acoustic pressure and/or intensity is controlled by adjusting the pressure (V) applied to a given transducer_p-p) To be realized.

In defining the operating scheme of the transducer of the US device according to an embodiment of the present invention, the processor 115 of the remote control unit 102 is optionally pre-programmed to cause the transmission of the US in various pulse forms (including meta-pulses with a cyclic meta-pulse repetition frequency (or MCRF)) and duty cycles, so as to limit power consumption and allow heat dissipation through passive devices, such as conductive and convective cooling from the external surfaces of the earpiece and transducer, and configured not to overload the cooling capacity of the wearer. MCRF is the frequency transmitted from the multiple transducers of the headset over a complete pulse cycle, such that each transducer independently transmits ultrasound waves in a predetermined sequence and is isolated from the other transducers. Eliminating the need for active cooling greatly reduces the overall power draw of the device and is an advance in the art. For example, FIG. 11A illustrates a typical US pulse 340, consisting of a primary frequency f_cIs provided, is provided by the sinusoidal sound waves 339. Each pulse 340 includes approximately 12 sound waves. At a primary frequency of 2MHz, for example, this type of pulse has a pulse width of about 6 microseconds. Although not limited thereto, as an example, a series of pulses 340 may be emitted by the transducer of the US device of the present invention, with a pulse repetition frequency or PRF of about 6KHz, which corresponds to a pulse interval PI of 167 microseconds and a duty cycle of about 3.6%. The duty cycle may vary from 0.1-10%, more preferably 3-5%, and most preferably about 3.5 ± 0.5%. In other embodiments, pulse amplitude modulation or pulse frequency modulation may also be used. The PI value is selected such that the time between successive pulses or pulse trains from the transducers of the array is generally not shorter than the time of flight of the pulses, including echoes returned from the contralateral wall of the skull. In one embodiment, the pulse strength is such that the returning echo is generally consumed before the next pulse is transmittedAnd (4) scattering. This may correspond to a pulse interval of about 167 microseconds. Thus, the pulse interval is in the range of 150 to 300 microseconds, more preferably 170 to 250 microseconds. In this manner, the pulse spacing is configured to prevent echoes from continually interfering with the outgoing pulses and increasing the local sparse pressure beyond an acceptable limit of about 300 KPa. This configuration synergistically enables low power consumption and allows extended operation when portability is required.

Fig. 11B does not illustrate to scale a pair of pulse bursts 341a, 341B, each pulse burst comprising a plurality of pulses. To illustrate, 100 to 300 pulses may be grouped into a single burst of pulses transmitted from a single transducer. The repeating cycle of consecutively transmitted pulse bursts constitutes a "meta-pulse" 342. In one embodiment, simultaneous transmission of a particular transducer pair or triplet may be used without increasing the amplitude.

The overall pattern or waveform of the US emitted by embodiments of the invention optionally comprises a cyclic pattern of spatially distributed and temporally modulated elementary pulses formed from sub-patterns of the pulse train and constitutes a scheme. Turning to fig. 12A, for example, another operational scenario of an embodiment of the US device is shown, this time defined by a meta-pulse 344 having an MCRF of about, for example, 2 Hz. Along the left edge, the individual tracks are labeled with the designation of the particular transducer for each array, e.g., "RT 1" for the right temporal #1 transducer, "OC 1" for the occipital #1 transducer, and so on. The figure represents a complete transmission sequence of the earpiece, a cyclic "meta-pulse" 344, which is transmitted repeatedly. During a single unit pulse, a burst of pulses is transmitted from each of the sixteen transducers. Thus, the timeline may be viewed as an interleaved chronology in which a first transducer transmits a first burst 343a, a second transducer transmits a second burst, and so on until the last transducer transmits a last burst 343n, ending the burst cycle. Accordingly, by properly defining a sequence according to which transducers from different transducer arrays are actuated, the resulting pulse burst impacts the target anatomy, as in "acoustic nudging," each acoustic perturbation arriving somewhere from a different direction than the meta-pulse cycle. A 6KHz burst of 100 pulses has a duration of about 17 milliseconds and may be referred to as "nudging" to stimulate fluidization. (fluidization or microfluidization is a term used in the art to indicate the effect of ultrasound on the behavior of liquids subjected to sound waves, including the increase in enzymatic fibrinolysis, the increase in plasminogen activator bound to fibrin and entering the thrombus with low intensity ultrasound acoustic fluidization and microfluidization also promotes interstitial and blood flow, as described in U.S. patent 3,961,140.) thus, a cyclically repeating meta-pulse is a "super nudge" consisting of multiple "nudges", each nudge being a pulse burst. Thus, FIG. 12A illustrates a patterned cyclic emission or "meta-pulse" of burst emissions from an array of sixteen crystals, where the emission of each crystal emission is uniquely directed and emitted once per cycle. The mode of action of the acoustic wave can be said to be a cyclically repeating meta-pulse comprising one or more patterns of temporally modulated and spatially distributed pulse bursts, each pulse burst comprising a plurality of ultrasonic pulses. Thus, the insonation may be characterized as a cyclic and stereo space-time modulated insonation. Although not limiting to characterizing the present invention, a headset with 16 transducers transmitting 16 millisecond bursts one at a time will cycle sequentially approximately once every half second. Of course, other permutations and/or sequences of transducer operation employed to construct a particular pattern of temporally modulated and spatially distributed acoustic beams are within the scope of the present invention.

In general, the programmed insonating patterned waveform includes pulse bursts, each of the pulses having a pulse duration of about 0.2 to 10 microseconds (in some embodiments, more preferably about 1 to 8 microseconds, and in related embodiments, most preferably about 6 microseconds), in pulse bursts having 2 to 300 pulses per burst (in some embodiments, more preferably about 100 to about 300 pulses per burst), the pulse bursts having a pulse repetition frequency of about 3KHz to about 10KHz (in related embodiments, more preferably about 4KHz to about 8KHz, and most preferably about 4KHz to about 8KHzAbout 6 KHz) with a magnitude that is taken as the unattenuated peak sparse pressure P of about 0.3 to about 1.0MPa or more_r0And measured at an ultrasonic frequency of 0.5 to 3.5MHz (and, in some embodiments, more preferably about 0.8 or 0.9 to about 3.0MHz, and most preferably about 1MHz, or about 1.2MHz, or about 2.0 MHz). The pulse bursts may also be directed (vector) from multiple independently emitting transducers, thereby resulting in spatial modulation or distribution of the patterned waveform.

An apparatus of the present invention has program instructions (discussed with reference to processor 115 of FIG. 9C) stored on a tangible computer readable non-transitory medium encoded for autonomously driving a plurality of ultrasonic transducers to transmit cyclically repeating meta-pulses comprising wave patterns of spatially and temporally modulated ultrasonic pulse bursts having a dominant frequency f_cAnd P configured to achieve no more than 300KPa_rAZspAnd the pulse burst has a pulse repetition frequency corresponding to a duty cycle of 1-10%, preferably 2-6% and more preferably about 3 to 5%, for each transducer, the meta-pulse having a meta-pulse cycle repetition frequency of 0.25 to 10Hz until a stop command is received; thereby achieving low power consumption for extended portable operation, independent of operator control and without the need for auxiliary cooling devices.

In a preferred embodiment, the individual transducers may be about 1cm in diameter or less and spaced apart (unlike conventional phased array transducer assemblies) to allow for heat dissipation between transmissions. The transducer crystals are not transmitted in pairs and the transmitted beams are not converged but are transmitted individually in series under autonomous control of a remote control unit which includes a clock, a pulse generator, logic for transducer activation and optionally the amplitude of the individual transducer outputs can be controlled as compensation for attenuation or variability between transducers. This multiple miniature transducer approach has proven safe, recognized the risk of standing waves and heating, and found surprisingly effective for ultrasonic thrombolysis. While not being bound by theory, it is believed that the device stimulates the dispersion of r-tPA by fluid fluidization caused by acoustic action in response to modulated pulsed ultrasonic patterns directed at the target anatomy from multiple directions, where a first transducer is fired with a burst or "acoustic nudge" and then a second transducer is activated, and, between each pulse of each burst, the intensity of the transmitted ultrasonic wavefront is allowed to decay. Considering a 10-15cm temporo-temporal or occipital-frontal beam path in a typical application, the pulse interval will be about 150 to 300 microseconds, as described in more detail in the previous section.

Other pulse and meta-pulse sequences that define a preprogrammed operating profile for the transducer of an embodiment are also within the scope of the invention. For example, FIG. 12B illustrates a meta-pulse sequence 346 in which two meta-pulses are shown (repeating doublet pattern, left to right). Each elementary pulse comprises a burst of pulses transmitted simultaneously by a respective transducer pair. The doublet pair selected for simultaneous transmission is typically the contralateral pair, thereby minimizing the likelihood of an increase in the magnitude of the peak pressure where the beam encounters. Studies have shown that contralateral beams can be configured to overlap so that a constructive increase in beam intensity is beneficial at a target depth of 4 to 7cm (for each hemisphere) and does not exceed safety limits at any depth. In this case, the opposing doublet pulses are transmitted simultaneously, but the pulse interval between the opposing doublet pairs is about 150 to 300 microseconds. The opposite doublet pulse is particularly useful at higher frequencies, such as at 2MHz, where the pulse decays more rapidly. The example of fig. 12B shows 32 transmitted pulse bursts (345 a-345 n), but in general the number of pulse bursts may vary. Fig. 12C depicts a bin pulse sequence 348 comprising triplets and doublets, in which three bin pulses are shown (repeating pattern, left to right). Each doublet or triplet comprises a burst of pulses transmitted simultaneously by two or three transducers, respectively. Again, these are chosen so as to minimize the additive effect, but are most beneficial in terms of depth. By transmitting three transducers at a time, the amplitude does not rise above a safe level of beam overlap, with the individual transducers of the three transducers being selected from the right temporal, left temporal and occipital arrays. The example of fig. 12C shows a total of 48 pulse bursts transmitted by the transducer.

In a particular embodiment, the apparatus of the present invention is configured to operate by transmitting ultrasound waves in stereo spatiotemporal meta-pulses, each meta-pulse comprising a train of bursts transmitted in, for example, a) a train of bursts transmitted sequentially from a plurality of transducers, wherein, at any given time, only a single transducer is activated according to a programmed sequence; b) transmitting a series of pulse bursts from a transducer pair selected from a plurality of transducers, wherein only one pair of transducers is activated according to a programmed sequence at any given time; c) transmitting a series of pulse bursts from a transducer triplet selected from a plurality of transducers, wherein only one transducer triplet is activated according to a programmed sequence at any given time; d) a series of pulse bursts formed by sequentially activating transducers, the series comprising any combination of single, doublet or triplet transducer activations; or e) a train of bursts transmitted on a carrier wave having a sub-ultrasonic frequency of about 5 to 10KHz, and most preferably about 6 KHz.

Individual arrays or transducers may be activated more frequently than others, at the discretion of the clinician, for example, when it is desired to insonate a particular hemisphere or forehead of the brain preferentially over the occipital aspect of the brain blood vessel. In other cases, a particular transducer is selected to transmit more frequently than other transducers in order to optimize acoustic fluidization in a particular direction, for example by cyclically alternating transmitting the anterior-pointing Lt temporal transducer and the posterior-pointing Rt temporal transducer in the Willis's circle, then reversing the direction, alternating transmitting the posterior-pointing Lt temporal transducer and the anterior-pointing Rt temporal transducer, thereby creating stimulation-directed acoustic fluidization and clockwise and counterclockwise pressure gradients of the flow. Also of interest are reciprocating pressure pulses, such as alternating pulse bursts between matched transducers located on opposite sides of the temporal array, or orthogonally directed pulses alternating from the ipsilateral transducer of the temporal and occipital arrays.

By transmitting only a few transducers at a time, and by transmitting individual transducers at a duty cycle in the range of 1 to 10% (as determined by the pulse repetition frequency), the need for auxiliary cooling is avoided, with a duty cycle more preferably in the range of about 3 to 6%, and in one embodiment with a duty cycle of about 3.6%. TI and heating effects due to the longer duty cycle are limited. This approach allows the use of higher frequencies, which may be advantageous because the Mechanical Index (MI) is more easily limited. Lower power consumption also results; without loss of efficacy. The device is typically passively air cooled, avoiding power consumption by fans, circulating coolant, etc.

The necessary pulse spacing may be achieved with a pulse repetition frequency of about 4 to 10KHz, more preferably about 5 to 8KHz, and most preferably about 6 KHz. Fortunately, this PRF is more physiologically compatible than the lower frequencies, since it has been observed that the user can perceive the action of pulsating sound waves in the 2-4KHz range, in particular as unpleasant sounds; this has a paradoxical perception that, through a biological demodulation, the pulsatile acoustic action is by definition an inaudible ultrasonic pulse. The dominant frequency of 0.5 to 3.5MHz is much higher than the human auditory range, but can be "demodulated" when pulsed at 2-4 KHz.

Figure 13 quantifies the threshold for audible ultrasonic exposure sensing as a function of modulated burst frequency. A larger amplitude is required to cause a sensation beyond the range of 0.2 to 4 KHz. Pulse repetition at a frequency greater than 4KHz is unlikely to be noticeable to the user. Frequencies in the range of 2KHz to 3KHz are most noticeable. It has been empirically determined that the choice of 5KHz or 6KHz PRF is most appropriate for most personal perceptions and, at a duty cycle of about 3 to 6%, does not pose a significant risk of overheating or overexposure, as represented by TI and I_sppa.3As measured. At PRFs greater than 10KHz, spatial overlap of the continuous wave modes may be associated with standing waves, and thus PRFs of about 4KHz to about 10KHz have proven to encompass a narrow comfort range within which the safety of the subject is not compromised.

The amplitude of the acoustic action is directly related to the peak sparse pressure, and the circuitry is configured to operate at a depth z_spNot more than 300KPa is delivered. For a selected transducer pressure (V)_p-p) From 30 to 80V_p-pFig. 14A shows peak sparse pressure as a function of depth. As determined here from a retrospective analysis of data from clinical trials, fig. 14B plots peak sparse pressure (KPa) versus intracranial hemolysis (ICH) shift (%). When correlated with the maximum peak sparse pressure 360, the local acoustic intracranial pressure is believed to be at least partially reliable for the increase in ICH shown in fig. 14B above the untreated baseline (361). The relationship between the acoustic pressure applied at the front of the transducer and the resulting acoustic pressure at a depth in the skull depends on a complex analysis of the attenuation. It can be seen that 300KPa represents a threshold at which an increase in insonation amplitude is associated with an increase in ICH conversion, a previously unrecognized technical problem. Based on this analysis, a particular embodiment of the apparatus is configured to operate, for example, to not exceed P in the target tissue being evaluated_rThe threshold value is less than or equal to 300 KPa. Coincidentally, it is a technical advance in the art that such a configuration operates at lower power for longer periods of time, and that improved treatment results are found herein.

In a first example demonstrating the role of attenuation, fig. 15A is a graph of peak sparse pressure 363 as a function of depth at 1MHz illustrating the effect of thick and thin cranial phenotypes. A curve for unattenuated emission 362 is also shown. FIG. 15B is the attenuation coefficient for the temporal bone (A)_TempBONE) Curve fitting to frequency. The attenuation coefficient alpha is given in units dB/mm-MHz.

For the transducer located in the temporal acoustic window (fig. 16A) and the transducer juxtaposed to the occipital acoustic window (fig. 16B), fig. 16A and 16B give a physical model for analyzing the attenuation profile as a function of depth, with a layer of adipose tissue usually overlying the muscle and the spine overlying the atlas and occipital macropores. An overview of the attenuation calculation is first shown with pictographic symbols. The perspective view represents a physical model of the analysis of the attenuation profile as a function of depth for the transducer located in the temporal acoustic window (fig. 16A) and the transducer juxtaposed to the occipital acoustic window (fig. 16B), with a layer of adipose tissue generally overlying the muscles and the spine overlying the atlas and occipital macropores.

Description of related mathematics

Developing a mathematical description of the temporal interface model (corresponding to fig. 16A) requires information about the speed of sound and attenuation in various tissue types. The tissue-specific attenuation constant can be approximated from literature values that factor the measured thickness, and the combined attenuation profile can then be calculated as a function of depth, where P_rThe attenuation across the temporal acoustic window is given as follows:

wherein P is_r(Z) is the attenuation (P) as a function of the depth (Z) in centimeters_rAz) And unattenuated (P)_rUz) Ratio of ultrasonic pressure. The attenuation parameter may be determined from the following equation:

A_TOTAL＝A_SKIN+A_BONE+A_REFLECTION+A_BRAIN （2）

and also

Generating

Wherein P is_rAzIs the peak sparse pressure decaying at a depth z on the beam path, and P_rUzIs the unattenuated peak sparse pressure at depth z; a. the_SKINIs an acoustic attenuation in the outer skin and tissue; a. the_BONEIs acoustic attenuation through the skull; a. the_REFLECTIONIs equivalent to attenuation of reflection loss at the interface between the skull and the inner surface of the brainNominal 3.02 dB; a. the_BRAINIs the acoustic attenuation in the brain, typically a constant of about 0.06 dB/mm-MHz; z is depth, the distance traveled by the ultrasonic beam wavefront; t is t_SKINIs the thickness of the outer skin and tissue layers; t is t_SKULLIs the thickness of the skull near the transducer; and f_cIs the center frequency (MHz).

Each component is now considered separately. For reference, the following attenuation coefficients taken from the general literature are listed in table 1:

TABLE 1

The attenuation caused by the skin is generally small and negligible, but is given by:

in comparison, bone attenuation is significant and depends on the thickness of the bone in the transducer beam path, the frequency and is best described by the non-linear curve of the physiological data. Attenuation for temporal bone (A)_TempBONE) Is derived by parabolic curve fitting of the available data (fig. 15B) and is mathematically described as:

regression fitting (R) to data obtained using equation (6)²) Is 0.875. Brain attenuation is given by:

A_BRAEM＝α_BRAEM·ε_BRAIM

（7）

the attenuation of reflections at the cranial/brain interface is a function of the relative difference in acoustic impedance between the temporal bone and the underlying brain tissue and is essentially a constant: a. the_REFLECTION=3.02 dB. By knowing the thickness of the bony layer and having a reference value for the constant term, the total attenuation plus reflection (K) in decibels can be easily determined_SKULL). Similar measurements and calculations can be made for the skin. In most cases, the attenuation associated with the outer skin layer is negligible compared to the greater contribution made by the skull, so equation 3 is further simplified:

wherein P is_rAzIs the calculated pressure at depth z after tissue attenuation and P_rUzIs the measured sparse pressure like the depth z measured in the water tank. Equation (8) is easily solved by a computational machine, such as a microcontroller with on-board mathematical functions, when the thickness of the skull is given, and allows the device to predict P based on the measurement of the thickness of the skull layer as a function of depth by, for example, CT scanning_rAZsp(in z)_spPeak sparse pressure).

Turning now to fig. 16B, a physical model for analyzing the attenuation profile as a function of depth is depicted for a transducer located in a sub-occipital acoustic window. Figure 16B depicts the sub-occipital transmit path of ultrasonic energy into the cranial crown between the spine and the foramen magnum. The physiological structure corresponding to the sub-occipital acoustic window is different from that of the temporal acoustic window, which typically lacks the bony layer. Moreover, the attenuation of the US associated with its propagation through the sub-occipital acoustic window is substantially less than the attenuation corresponding to the temporal acoustic window. The fundamental mode of wave transmission is assumed to be transverse, i.e., the wavefront associated with the transmitted wave is substantially parallel to the transmit face of the corresponding transducer. The overall model for attenuation along the sub-occipital path as the ultrasonic pressure wave propagates from the transducer to the point of maximum exposure of the skull can be approximated by evaluating the transmission characteristics across four major layers, each of which has a tissue attenuation coefficient (skin, fat, muscle and brain tissue as shown in fig. 16B).

The attenuation parameter can be solved from:

accordingly, the number of the first and second electrodes,

wherein P is_rAzIs the peak sparse pressure attenuated at depth z on the beam path; p_rUzIs the unattenuated peak sparse pressure at depth z; a. the_SKINIs the acoustic attenuation in the outer skin; a. the_FATIs acoustic attenuation through bone; a. the_MUSCLEIs attenuation through the fat layer; a. the_BRAINIs the acoustic attenuation in the brain, typically a constant of about 0.06 dB/mm-MHz; z is depth, the distance traveled by the ultrasonic beam wavefront; t is t_SKINIs the thickness of the outer skin layer; t is t_FATIs the thickness of the fat layer; t is t_MUSCLEIs the thickness of the muscle layer; and f_cIs the center frequency (MHz).

Each component is now considered separately. The attenuation coefficient (α) has been summarized above in table 1. Skin attenuation is generally small, but is given by:

wherein the thickness is about 1 mm. Fat attenuation is given by:

based on empirical observations of a TCD ultrasound examination, the total tissue thickness behind the neck will vary between about 2cm and about 5cm, with about 1cm being muscle. Thus, the fat layer may vary between about 1cm and about 4 cm.

The muscle tissue attenuation is given by:

for most applications, the nominal muscle thickness is taken to be 10 mm.

Brain attenuation is given by:

A_BRAIN＝α_BRAIN·ε_BRAIN （14）

because of the great variability of the fat layer and the maximum pressure point (z) selected depending on the transducer_sp) It is possible that the actual point of maximum peak negative pressure may be in a layer adjacent to the brain rather than in the brain itself.

If the fat layer associated with the subject's skull is 1cm thick, then the point of maximum peak negative pressure will of course be within the brain. Mathematically speaking, if z_sp=3cm and the overlying tissue layer is 2.1cm thick (= 0.1cm +1cm +1 cm) (skin + fat + muscle), then P_rAmax0.9cm into the brain tissue. P_rAmaxIs the point of maximum acoustic amplitude in the tissue. Unless P_rAmaxIn the connective tissue layers, otherwise the calculation of the attenuation is direct.

However, if z is_spWithin the fat or muscle layer, the change is then estimated. In this case, it is necessary to take into account the total attenuation across the skin, fat and muscle, and then estimate the peak negative pressure at the muscle-brain tissue interface. This will be the estimated maximum peak negative pressure (P) in the brain tissue_rAmax）。

For most ultrasound systems, it is conservatively assumed that peak negative pressure is reduced by about 0.5% per centimeter. Thus, the maximum peak negative pressure in the brain tissue (taking into account it) can be estimated fromBefore his attenuation value) (for z_sp≤t_SKIN+t_FAT+t_MUSCLE）：

P_r(Amax)＝PrI(UsIsp)·(-0.05(t_SRLN+t_FAT+t_MUSCLR)+(0.05z_sp)+1) （15）

And for z_sp>t_SKIN+t_FAT+t_MUSCLE

P_r(Amsx)＝P_rI(UsIsp)

（16）

These considerations and calculations are useful in selecting operating conditions for the headset of the present invention.

Additional arrangements

FIG. 17 is a flow chart or logic diagram for the automated operation of the device 390 in which the coupling of the transducers is tested and verified before or during operation of the device. After attaching the headset to the skull bone at step 391, typically using a gel attachment on the transducer, the device is powered up and a start-up self-diagnosis is performed at step 392. Then, at step 393, the processor of the device determines for each transducer whether the physical coupling to the head is sufficient for effective sound transmission. If all systems are operational (GO) and acoustic coupling is verified, the device begins an insonating element pulse cycle at 394 and continues this cycle until power is removed at 395 or for a programmed duration. This cycle can be repeated, as can be seen at 396, if desired.

Fig. 18A and 18B depict the use of phase angle θ to verify acoustic coupling. FIG. 18B depicts voltage output corresponding to the phase angle for the coupling verification circuit of FIG. 19. In such applications, ultrasonic pulses may be used to effect acoustic coupling between the transducer interface and underlying tissue targets. If the transducer is not acoustically coupled to the underlying skull, typically with a couplant gel, the ultrasound waves jump out of the air layer in the middle and fail to penetrate the skull. To verify coupling, in one embodiment, a voltage comparator circuit is used to measure the phase angle of the voltage pulse that activates the transducer. A high phase angle indicates poor coupling, typically indicating the presence of air between the transducer and the target tissue. A low phase angle indicates good coupling. These circuits are all viable solutions to the problem of ensuring good acoustic coupling before initiating an autonomous ultrasound pulse therapy regime. The microcontroller will verify that the phase angle does not exceed a preset threshold before initiating insonation.

As shown in fig. 18A, the impedance matching system may be designed to match the power source to the load impedance when the headset is properly placed and acoustically coupled to the skull. The signal source in this application is an amplified clock frequency of the pulse emission and the load is a piezoelectric transducer.

When considering an ultrasonic transducer with a capacitive reactance, the total power load impedance is the sum of the real resistance "R" and the imaginary resistance "-jX". The phase of the current is offset from the voltage by an angle theta. Total impedance Z_magThe following calculations were made:

Z_LOAD＝R-I/ωC （17）

where R is the resistance in ohms, ω is the frequency expressed in radians, ω =2 π f, where f is the frequency in Hz, and C is the capacitance expressed in farads, can also be written as:

wherein X_CIs a capacitive reactance (ohm)Mu) are used.

An impedance vector Z using an RC network and assigning the real part of the impedance to the real axis and the imaginary part to the imaginary axis_magWill look like 18A. The Pythagorean relationship for right-angle triangular geometries allows the solution of the impedance Z from the resistance and capacitive reactance XC_magThe triangle is associated with a vertical coordinate R and a horizontal coordinate X_CAnd a hypotenuse Z. However, all that is required to determine whether the surface of the transducer is acoustically coupled to an external load is the phase angle θ. Phase angle (θ) when the transducer is acoustically mismatched to air_OPEN) Will be large (i.e., the capacitive reactance will be large) and will be significantly reduced (θ) when the transducer is acoustically matched to the tissue of the skull_COUPLED). This observation is illustrated in fig. 18A. When coupling is established, detection of the level of operation of the acoustic coupling between the crystal and the subject's head wearing the headset does not require complex impedance (for Z)₁、Z₂Z in vector representation_magAngle θ) change. A quick check of the phase angle can be made by transmitting an acoustic pulse and evaluating the phase angle of the pulse in the transducer. The circuitry used to digitally report the phase angle to the microcontroller is sufficient to assess acoustic coupling, and the microcontroller can be programmed to perform such tests on each transducer individually, without operator intervention. If the transducer is not coupled, the operator will have to readjust the fit of the headset on the wearer, or eliminate any air between the transducer and the skin, for example by adding a gel couplant.

An example of one implementation of circuitry 400 driven by an oscillator 402 for phase measurement of a transducer load 403 is shown in fig. 19. Here, this implementation is performed using an integrated circuit with a phase comparator, for example HCT2046A (Philips semiconductors, data sheet 1997), which contains an edge-triggered RS-type triggered phase comparator (PC 3). The average output from phase comparator 401 (405, V) fed through a low pass filter to a voltage comparator and seen at the demodulator output at pin 10_PHASE) Is SIG_INAnd COMP_INThe result of the phase difference of (a) is generally linear between 0 and 360 degrees theta as shown in fig. 18B. From R_SENSEMay be offset to produce the desired V at zero degrees_PHASEAnd =0. More details of the device are provided in a 74HC/HCT4046A phase locked loop with VCO IC data sheets from Philips.

These considerations are realized by a phase detection circuit with a linear output voltage that can be digitally encoded to mark the uncoupled transducer in the headset array for corrective action, as required by a relatively unskilled technician or self-use of the device. For example, a simple LED may be used to indicate an uncoupled transducer.

In autonomous operation of the apparatus for detecting acoustic coupling under each transducer prior to being configured to initiate insonation, the apparatus will malfunction if the coupling needs to be adjusted.

Various watchdog circuits may be employed to verify proper function prior to initiating sonication. Status lights or other indicators, such as sounds, buzzers, LEDs, or even liquid crystal displays, may be used to communicate the readability of the device to begin ultrasound emission. For example, the LCD may scroll through messages indicating that a transducer is not properly positioned on the head. The status display may also include a battery status indicator, a temperature sensor and indicator, and the like. Circuit fault detectors may also be incorporated within those who practice the electronic technology.

In general, the frequency is also known or easily measured, allowing Z_magThe use of the angle θ information in other calculations, such as time of flight, which can be used in preliminary imaging of the midline offset condition and quantification of the total dose (from measurements of transducer-to-transducer pulse reception).

Early reports indicated partial success with highly focused ultrasound, where individual thrombi were visualized with TCCD, then at approximately 400mW/cm²Receiving sound waves at 2MHz (Cintas et al, 2002, High Rate o)f Recardisation of middle cellular arm oxygen precipitation During2-MHz Transcritical Color-codec linkage Monitoring Without Thrombolytic Drug, Stroke33; 626-. This study requires precise ultrasonic positioning of the transducer and focused acoustic action at the precise location of the thrombus.

Surprisingly, however, the use of temporally and spatially modulated unfocused transcranial ultrasound as described in the present application is useful in the absence of exogenous management of r-tPA. In a series of patterned bursts, the modulated ultrasound waves as a whole are directed toward the cerebral vasculature from multiple directions (i.e., spatially distributed modulation), which is essentially a pattern within a pattern in which pulsed bursts are transmitted from a single unfocused transducer and multiple arrays of multiple transducers are transmitted in a patterned sequential order (i.e., as meta-pulses, which are spatially and temporally patterned bursts of pulses). Ultrasound waves can be provided in this manner without requiring specific information about the presence or location of a thrombus and, if desired, can be performed prophylactically without diagnosis.

Figures 20A and 20B depict a model of vasodilation for the release of endogenous nitric oxide, in which blood shear (figure 20A) is replaced by ultrasound (figure 20B). This model predicts that the ultrasound apparatus of the present invention will have positive effects as a stand-alone device for non-invasive treatment of a variety of conditions, including migraine headaches, intracranial hypertension, hydrocephalus, etc., and can increase blood flow to the brain, thereby improving the delivery of a variety of injectable and orally prescribed drugs.

The structural components of the headset of the device are preferably constructed entirely of plastic, and the elements of the electronics are isolated from the headset so that the headset is remotely operated, thereby allowing the headset to be inserted into a CT or MRI machine for CT/MRI scanning.

Examples of Industrial Applicability and practical use

In one example, fifteen healthy volunteers were equipped with the device of the present invention. The modulated ultrasound insonation is initiated and sustained while monitoring the vascular and neurological status according to autonomous instructions embedded in the EEPROM memory of the device. Specific parameters for the ultrasonic wave mode have been generally disclosed above. The sonication lasted for two hours with no adverse effects. No adverse effects were reported in any of the tests.

According to an embodiment of the invention, the earpiece 101 of the US device (see e.g. fig. 1) is configured to allow the clinician to target critical blood vessels without the need for collateral or advanced imaging studies, i.e. the earpiece is simply worn on the skull bone according to the skull landmarks defining the reference plane and the location of the main artery. Accordingly, empirical studies were conducted to determine how much cerebrovascular targeting could be achieved with embodiments of the present invention. In this study, the transducer array of the headset of the present invention was modified to allow transcranial doppler monitoring, in which the "on-target" aim of the insonation was scored by the detection of doppler signals from the target blood vessels. In one study, review of case reports revealed that 86% of patients had detectable doppler waveforms in the MCA and associated cerebral vessels. On average 4.1 transducers received a return signal indicating that multiple transducers were on the target. In another study, MCA localized doppler was detected in all 100% of subjects; on average, 5.8 of the 12 time-deployed transducers received doppler return signals from the target MCA region, and 2.7 of the 4 transducers in the sub-occipital array received doppler return signals from the target basilar artery. Combining these studies, 91% of the subjects showed evidence that the headset transducer array was correctly aimed at the cerebrovascular ring of interest. The ability of the headset to achieve rapid, unassisted, "passive" stereotactic targeting of the ultrasound transducer at critical vascular targets is one factor in this success.

The 90-day outcome improvement is achieved by periodic follow-up therapy with ultrasound (without r-tPA) for a period of days or weeks following the onset of transient cerebral ischemia, and, in fact, the headset can be used prophylactically on its own if desired, due to its ability to non-invasively initiate the endogenous mediators of thrombolysis.

The ultrasonic cerebral infarction treatment device of the present invention is a device showing the dissolution of a clot causing cerebral infarction by cyclically irradiating the affected tissue with a repetitive ultrasonic pattern. The device is useful for non-surgical applications in ischemic stroke and, with surface modification, can also be used in the case of occlusion or embolization of other vascular structures. In one embodiment, the device functions autonomously without intervention, essentially as a pre-programmed automatic device for delivering transcranial ultrasound, but optionally with sensors for collecting data and for adjusting operating parameters accordingly. In a first sensor mode, a transcranial ultrasound device is configured with phase detection circuitry for verifying acoustic coupling prior to initiation of ultrasound transmission. In another mode, the transcranial ultrasound device is configured to adjust VBANG using data regarding transducer voltage response. With multiplexed drive signal or signals, ultrasound waves are transmitted by multiple transducers of an array while varying the voltage to each individual transducer in real time, thereby increasing the reproducibility and consistency of the insonation, which can be irregular due to variations in transducer fabrication.

Each of the references cited (including patent documents and non-patent documents) is incorporated by reference herein in its entirety.

Embodiments of the invention are described as including a processor controlled by instructions stored in a memory. The memory may be Random Access Memory (RAM), Read Only Memory (ROM), flash memory, or any other memory or combination thereof suitable for storing control software or other instructions and data. Those skilled in the art will also readily appreciate that the instructions or programs defining the functions of the present invention can be delivered to a processor in a variety of forms, including, but not limited to, information permanently stored on non-writable storage media (e.g., read-only memory devices within a computer such as ROM or by computer I/O attached readable devices such as CD-ROM or DVD disks), information alterably stored on writable storage media (e.g., floppy disks, removable flash memory and hard drives), or information conveyed to a computer by a communications medium, including a wired or wireless computer network. Further, while the present invention may be embodied in software, the functionality required to implement the invention may alternatively, or in addition, be embodied in part or in whole using firmware and/or hardware components, such as combinational logic, an Application Specific Integrated Circuit (ASIC), a Field Programmable Gate Array (FPGA), or other hardware or some combination of hardware, software, and/or firmware components.

While the present invention has been described by way of examples of the embodiments described above, it will be appreciated by those of ordinary skill in the art that modifications and variations may be made to the illustrated embodiments without departing from the inventive concepts disclosed herein. For example, the processor of one embodiment may optionally be preprogrammed to determine whether the degree of acoustic coupling of a given transducer of the headset to the subject's head is satisfactory, and to alert a clinician or other user if the quality of the coupling should be improved. Although not limited thereto, the craniological marks used to position the headset may be selected from the group consisting of nasion, left otobasion superior (Lt OBS), right otobasion superior (Rt OBS), tragus point, mandible condyle, zygomatic arch, alveolar midpoint, or occipital protuberance. At least three are selected to define the triangle and/or the reference plane. To facilitate field use by unskilled operators, the nasion/LtOBS/Rt OBS triad has proven to be well suited. The mounting assembly on the headset is configured with a surface for engaging a head landmark and orienting the transducer array stereoscopically with respect to temporal and occipital acoustic windows into the skull, so that the device can be used without requiring further adjustment of the imaging modality, such as transcranial doppler, which is not readily available, for example, to the first responder. Further, although some embodiments are described with reference to a remote control unit, it should be appreciated that in related embodiments, at least some of the control unit components (e.g., such as the microprocessor, electronic circuitry, and/or storage medium) may alternatively be incorporated into or built-in or affixed to a headset assembly, such as the headset assembly 101 of fig. 1. In particular, it is within the scope of the present invention to employ at least one headgear member 101a, 101b in mechanical cooperation with and in contact with components of the control unit.

Although aspects of the present invention have been described with reference to flow diagrams, those skilled in the art will readily appreciate that the functions, acts, decisions, etc. of all or a portion of each block of the flow diagrams, or combinations of blocks, may be combined, divided into separate operations, or performed in other orders. Moreover, although the described embodiments have been described in connection with various illustrative data structures, those skilled in the art will recognize that the system may be embodied using a variety of data structures. In addition, the disclosed methods and structures may be used with appropriate substitute materials. Further, the disclosed aspects or portions of these aspects may be combined in ways not listed above. Accordingly, the invention should not be construed as being limited to the disclosed embodiments.

Claims (47)

1. An apparatus for transcranial sonothrombolysis of a subject's head, the apparatus comprising:

a first temporal transducer array cooperating with the first transducer array registration member;

a headset defining a headset plane and having a front face corresponding to a forehead of a subject's head, a headset face and a nasion registration member fixed to the headset at the front face and protruding transverse to the headset plane, the headset adapted to support the first transducer array on the headset face;

the nasion registration member and the first transducer array registration member are configured such that, when the headset is placed on the subject's head for transcranial sonothrombolysis,

the nasion registration member rests on the nasion of the subject to ensure that the headphone plane is tilted with respect to a reference plane defined by a left otobasion superior (OBS), a right OBS, and the nasion of the subject's head, and the headphone plane passes through the left and right OBSs, an

The first transducer array registration member aligns the first temporal transducer array with an otobasion point of a subject's head and a sphenoid sinus support to optimize an extent of insonation of a target cardiovascular vessel with an Ultrasound (US) beam emitted by the first transducer array, the insonation directed substantially along the headset plane.

2. The apparatus of claim 1, wherein the headset plane is tilted about 10 to about 15 degrees with respect to the reference plane.

3. The apparatus of claim 1, wherein the headset plane is tilted about 12 degrees with respect to the reference plane.

4. The device of claim 1, wherein the target central cerebral blood vessel comprises at least one of Anterior Cerebral Artery (ACA), Middle Cerebral Artery (MCA), Posterior Cerebral Artery (PCA), Internal Carotid Artery (ICA), Basilar Artery (BAS), and vertebral artery (VER), and the circle of Willis.

5. The apparatus of claim 1, further comprising an occipital transducer array fixed on the headset surface opposite the nasion registration member and configured to emit an Ultrasound (US) beam substantially along a headset plane.

6. The apparatus of claim 5, further comprising a hand-held portable remote control unit configured to control operation of at least one of the occipital transducer array and the first temporal transducer array, and an umbilical cord operatively connecting the remote control unit with the headset.

7. An apparatus as in claim 1, further comprising a second temporal transducer array cooperating with a second transducer array registration member, the first and second transducer arrays being fixed to the headset relative to one another such that, when the headset is placed on a subject's head for transcranial sonothrombolysis, the second transducer array registration member aligns the second temporal transducer array with an supraauricular cardinal point and a sphenoid sinus support of the subject's head in order to optimize the degree of insonation of a target central cerebral vasculature with a US beam emitted by the second transducer array, the insonation being directed substantially along the headset plane.

8. The apparatus of claim 1, wherein the earphone plane is a surface facing the subject's head when the earphone is placed on the subject's head for transcranial sonothrombolysis.

9. An apparatus according to claim 1, wherein the headphones comprise anterior and posterior headgear members configured to mate at corresponding ends of the members so as to define the headphone plane and a circumcranial loop of the headphones.

10. An apparatus according to claim 9, wherein the mutual positioning of the anterior and posterior headgear members is stretch adjustable.

11. An apparatus for transcranial sonothrombolysis of a target cerebral vessel of a subject's head, the apparatus comprising:

a set of transducer arrays; and

a headset supporting the set of transducer arrays and mountable on a subject's head, the headset defining a headset plane and including one or more mounting registration brackets adapted to stereoscopically cooperate with the subject's head to align transducer arrays of the set of transducer arrays with corresponding transcranial acoustic windows of the subject's head when the headset is placed on the subject's head for transcranial sonothrombolysis, and to optimize insonation of target cerebral vasculature through the transcranial acoustic windows by Ultrasound (US) beams emitted by the transducer arrays at such stereoscopically cooperating locations.

12. An apparatus according to claim 11, wherein one or more mounting registration brackets are adapted to align the transducer arrays so as to emit respective corresponding US beams substantially along a headset plane that is tilted with respect to a reference plane defined by selected external cranial landmarks of the subject's head.

13. An apparatus according to claim 12, wherein the selected external cranial marker comprises a left otobasion superior (OBS), a right OBS, and a nasion of the subject's head.

14. An apparatus according to claim 13, wherein the one or more mounting registration brackets include a nasion registration bracket projecting from a front of the earpiece across a plane of the earpiece and a temporal transducer array registration bracket slidably mounted on an inner surface of the earpiece, the nasion registration bracket and the temporal transducer array registration bracket respectively configured to be positioned over a nasion of the subject and to engage the OBS when the earpiece is placed on the subject's head for transcranial sonothrombolysis.

15. The apparatus of claim 12, wherein an earphone plane passes through the left and right OBS when the earphone is placed on the subject's head for transcranial sonothrombolysis.

16. An apparatus according to claim 11, wherein the one or more mounting registration brackets include a registration bracket configured to contact one of a nasion, a left otobasion superior (OBS), a right OBS, an tragus point, a mandible condyle, a zygomatic arch, a midpoint of a socket, and an occipital protuberance when the headset is placed on the subject's head for transcranial sonothrombolysis.

17. The apparatus of claim 11, wherein said earpiece includes anterior and posterior headframe members configured to mate at corresponding ends of said members to define a circumcranial loop of said earpiece.

18. An apparatus according to claim 17, wherein the mutual positioning of the anterior and posterior headgear members is stretch adjustable.

19. The apparatus of claim 11, further comprising a hand-held portable remote control unit configured to power at least one of the transducer arrays in the set of transducer arrays and an umbilical cord operatively connecting the remote control unit to the headset.

20. The apparatus of claim 11, wherein the set of transducer arrays includes a temporal transducer array and an occipital transducer array.

21. A method of transcranial sonothrombolysis of a subject's head using an Ultrasound (US) device having a headset defining a headset plane and containing a transducer array and mounting registration elements including a nasion registration member and at least one temporal registration member, the method comprising:

positioning the headset on the subject's head such that the nasion registration member rests on the nasion of the subject and the headset plane is inclined with respect to a reference plane defined by a left Otobasion (OBS), a right OBS and the nasion, the headset plane intersecting the reference plane substantially at the left and right OBS; and

the target cerebral blood vessel defined by the thus tilted earphone plane is insonated.

22. A method according to claim 21, wherein said positioning further comprises positioning the headset on the subject's head such that at least one temporal registration member is in contact with an OBS.

23. The method of claim 21, wherein the positioning further comprises positioning the headset on the subject's head such that the headset plane is tilted about 10 degrees to about 15 degrees with respect to the reference plane.

24. The method of claim 21, wherein the insonating comprises insonating at least one of Anterior Cerebral Artery (ACA), Middle Cerebral Artery (MCA), Posterior Cerebral Artery (PCA), Internal Carotid Artery (ICA), Basilar Artery (BAS), and vertebral artery (VER), and Willis's loop with an US beam emitted by a transducer array.

25. The method of claim 21, wherein the headset comprises a temporal transducer array, an occipital transducer array, and a hand-held portable remote control unit having a processor preprogrammed to define an operational profile for at least one of the temporal and occipital transducer arrays.

26. A method for transcranial sonothrombolysis of a target cerebral vessel of a subject's head using an Ultrasound (US) device having a headset, wherein the headset defines a headset plane and includes a set of mounted registration elements and a transducer array, the method comprising:

selecting an external cranial marker associated with a subject's head, the external cranial marker defining a location of the target cerebral vessel;

defining on the headset mounting registration elements corresponding respectively to the external skull markings; and

the headset is positioned on the subject's head so as to establish contact between the mounting registration elements and the respective corresponding external skull markers.

27. The method of claim 26, further comprising activating a transducer array to insonate the target cerebral vasculature substantially along an earpiece plane.

28. The method of claim 27, wherein said activating a transducer array comprises activating a transducer array with a hand-held portable remote control unit.

29. The method of claim 27, wherein the activating comprises controlling operation of a transducer array with a processor located in a hand-held portable remote control unit connected to the headset through an umbilical cord.

30. The method of claim 26, wherein the selecting an external skull marker comprises selecting an external skull marker that defines a reference plane across the subject's head.

31. A method according to claim 26, wherein selecting external cranial markers comprises selecting at least three of a nasion, a left otobasion superior (OBS), a right OBS, an ototragus point, a mandible condyle, a zygomatic arch, a midpoint of an alveolar, and an occipital protuberance.

32. A method according to claim 26, wherein the transducer array comprises a temporal transducer array, and wherein said defining mounting registration elements comprises defining a nasion registration support projecting transverse to a plane of the headset and configured to be located at a nasion of the subject when the headset is placed on the head of the subject for transcranial sonothrombolysis, and defining a registration member associated with the temporal transducer array and configured to be in contact with an supraaural base point when the headset is placed on the head of the subject for transcranial sonothrombolysis.

33. A computer program product for providing transcranial sonothrombolysis of a target cerebral blood vessel of a subject's head using an Ultrasound (US) device having a headset, wherein the headset defines a headset plane and includes a set of mounted registration elements and a transducer array, wherein the set of mounted registration elements are defined with respect to corresponding external cranial markers of the subject's head, the headset being positionable on the subject's head such that the mounted registration elements are in contact with the respective corresponding external cranial markers to place the headset plane at an angle with respect to a reference plane defined by the external cranial markers, the computer program product comprising a tangible computer usable medium having computer readable program code thereon, the computer readable program comprising:

program code for activating at least one of the transducer arrays to optimize insonation of a target cerebral blood vessel substantially in the plane of the earpiece; and

program code for defining an operational scenario for at least one of the transducer arrays.

34. A computer program product as claimed in claim 33 wherein said program code for defining an operational scenario includes program code for such insonation of a target cerebral vessel such that peak sparse pressure does not exceed 300kPa and thermal index does not exceed physiologically compatible thermal index at a predetermined depth within a subject's head.

35. The computer program product of claim 33, wherein the program code for defining an operational scenario includes program code to cause, by at least one of the transducer arrays, US pulses to be transmitted at pulse intervals determined to prevent echo constructive interference between the US pulses and outgoing pulses.

36. The computer program product of claim 34, wherein the pulse interval is between 150 milliseconds and 300 milliseconds.

37. An apparatus for transcranial sonothrombolysis of a target cerebral vessel of a subject's head, the apparatus comprising:

one or more transducer arrays;

a headset defining a headset plane and supporting the one or more transducer arrays;

one or more legs extending outwardly from the earpiece;

wherein different holders are used to position the headset with respect to different external cranial markers of the subject's head.

38. An apparatus as recited in claim 37, wherein the one or more brackets are adapted to cooperate stereoscopically with the cranial markers to position the one or more transducer arrays to optimize insonation of the target cerebral vasculature with Ultrasound (US) beams emitted by the one or more transducer arrays.

39. The apparatus of claim 38, wherein the one or more stents are adapted to stereotactically align the one or more transducer arrays for transcranial sonothrombolysis and optimize insonation of a target cerebral vasculature through one or more transcranial acoustic windows with the US beam.

40. An apparatus according to claim 37, wherein the external cranial marker comprises a left otobasion superior (OBS), a right OBS, and a nasion of the subject's head.

41. An apparatus as recited in claim 37, wherein the one or more brackets include a nasion registration bracket protruding from a front face of a headset and a transducer array registration bracket slidably mounted on an inner surface of the headset.

42. The apparatus of claim 37, wherein an earphone plane passes through the left and right OBS when the earphone is placed on the subject's head for transcranial sonothrombolysis.

43. An apparatus according to claim 37, wherein the one or more stents include a registration stent configured to contact one of a nasion, a left otobasion superior (OBS), a right OBS, an tragus site, a mandible condyle, a zygomatic arch, a midpoint of a socket, and an occipital protuberance when the headset is placed on the subject's head for transcranial sonothrombolysis.

44. An apparatus according to claim 37, wherein said headphones comprise anterior and posterior head frame members configured to mate at corresponding ends of said members so as to define a circumcranial loop of said headphones.

45. An earphone device for providing transcranial sonothrombolysis of a target cerebral blood vessel of a subject's head, comprising:

a processor;

a non-transitory computer readable medium;

computer readable program code encoded in the computer readable medium;

an Ultrasound (US) device having a headset plane and including a transducer array and a mounting registration bracket defined with respect to a corresponding external skull marker of a subject's head, the ultrasound device being positionable onto the subject's head such that the mounting registration bracket is in contact with the respective corresponding external skull marker and the headset plane is placed at an angle with respect to a reference plane defined by the external skull marker,

the computer readable program code includes a series of computer readable program steps to implement:

performing acoustic wave action on the target cerebral vessels in the plane of the earphone; and

an operational scheme of at least one of the transducer arrays is defined.

46. The apparatus of claim 45, wherein said insonating comprises insonating with at least one of a temporal transducer array and an occipital transducer array.

47. The apparatus of claim 45, wherein the defining comprises defining at least one of a time and amplitude sequence of pulses of a US beam.