Hands-free operator-independent transcranial ultrasound apparatus and methods

• US 8,603,014 B2
• Filed: 08/14/2011
• Issued: 12/10/2013
• Est. Priority Date: 10/05/2010
• Status: Active Grant

• Current Assignee: Cerevast Medical, Inc.
• Original Assignee: Cerevast Therapeutics, Inc.
• Inventors: Barnard, William, Radford, Randal Lee, Alleman, Anthony John
• Primary Examiner(s): Chen, Tse
• Assistant Examiner(s): NGUYEN, HIEN NGOC
• Application Number:
  US13/209,408
• Publication Number:
  US 20120083718A1
• Time in Patent Office: 849 Days
• Field of Search: 601/2
• US Class Current: 601/2
• CPC Class Codes: A61B 2017/00734 battery operated
• CPC Class Codes: A61B 8/4427 Device being portable or laptop-like
• CPC Class Codes: A61N 2007/0078 with multiple treatment transducers
• CPC Class Codes: A61N 2007/0095 by modifying an excitation signal
• CPC Class Codes: A61N 7/00 Ultrasound therapy lithotripsy A61B17/22, A61B17/225; massage using supersonic vibration A61H23/00 ; using ultrasound for introducing media into the body A61M37/0092

Abstract

Disclosed is a “hands-free”, autonomously operating, battery-powered apparatus with electronic programmable actuation circuitry for non-invasive ultrasonic treatment of ischemic stroke, microatheromas of the cerebral vasculature, intracranial hypertension, and other cerebrovascular pathologies such as hypoperfusion associated with migraine. The apparatus is provided with registration members to facilitate stereotactic placement of the headset on the skull with respect to target intracranial anatomy. Once fitted in place on the skull and activated, the device does not require clinical intervention during operation; does not need skilled technical adjustment of the waveform patterns; and achieves therapeutic results with power consumption of less than 400 mAmp-hr, thus permitting extended portable operation without external power and eliminating the need for assisted cooling. Using a device of the invention, transcranial ultrasound may be self-administered. The device has application in therapeutic methods, such as methods for treating stroke or migraine, for non-invasively augmenting drug action, and for release or dispersal of endogenous neurovascular mediators.

Claims

1. An apparatus for non-invasive therapeutic application of transcranial ultrasound, which comprises:

a) an adjustably tightenable circumcranial headset assembly configured with registration surfaces for engaging at least three external craniological landmarks of a skull so as to stereotactically position a headset assembly on said skull with respect to an intracranial target or targets;

said headset assembly including anterior and posterior headframe members configured to mate at corresponding ends of said members such as to define, when the headset assembly is positioned on the subject'"'"'s head for transcranial sonothrombolysis, a headset plane that is inclined with respect to a horizontal reference plane and is parallel to a plane of a subject'"'"'s Circle of Willis, so that said headset is raised above the eyes of said skull, has clearance around the ears of said skull, and engages an underside of a occipital protuberance of said skull when stereotactically positioned thereon,

said headset assembly including

a nasion mounting registration bracket having a fixed end affixed to the headset assembly anteriorly at a midpoint at the front and a second end and protruding transversely to the headset plane and along the subject'"'"'s forehead such as to offset said midpoint of the headset by a height h₁ with respect to the nasion, and

a left (Lt) transducer-array registration bracket and a right (Rt) array-registration bracket slidably disposed contralaterally and removably on an internal surface of said headset assembly;

b) a plurality of transducer arrays, each said transducer array comprising a plurality of non-focused ultrasound transducers, wherein said transducers are mounted on said headset so as to be stereotactically directed at said target or targets without need for diagnostic imaging guidance;

said transducer arrays including

left (Lt) and right (Rt) temporal transducer arrays aligned, respectively, by the Lt and Rt transducer-array registration brackets with an otobasion superior and a sphenoid shelf on the opposite sides of the subject'"'"'s head such as to optimize a degree of insonation of a target central cerebral vasculature with an ultrasound (US) beam emitted by said first transducer array, the insonation being directed substantially along the headset plane, and

a posterior occipital transducer array disposed at a back portion of the headset such as to direct corresponding US beams at the basiliar and vertebral artery and a junction of an internal carotids of the Circle of Willis, and

c) operatively attached to said headset, an electronic circuit with microcontroller, clock, memory, instruction set, a portable power and voltage supply, and on/off control for actuating said plurality of transducers in a repeating cycle, each cycle a metapulse comprising a plurality of trains of pulses, each train of pulses emitted intermittently and alternately at low duty cycle from selected transducers in a programmed sequence, whereby said skull is insonated with a stereotemporally modulated pattern of ultrasound without operator intervention and with low power consumption, the low duty cycle eliminating the need for assisted cooling.

2. The apparatus of claim 1, wherein said at least three external craniological landmarks are nasion, Rt otobasion superius, and Lt otobasion superius, said craniological landmarks forming an Isosceles triangle which defines a foundational reference plane containing the sphenoid shelf and the Circle of Willis of said skull, said triangle having a base, an apex, and a midline, said triangle for stereotactically positioning said headset and for stereotactically aligning said non-focused ultrasound transducers to insonate the vasculature of said Circle of Willis, the branches and junctions of the internal carotid and basilar arteries conjoined thereto, and the cerebral arteries projecting therefrom, thereby directing said insonation to said vasculature without need for diagnostic imaging guidance;

and further wherein said plurality of transducer arrays comprise arrays selected from i) a right temporal transducer array and a left temporal transducer array or ii) a right temporal transducer array, a left temporal array, and an occipital transducer array, and wherein each transducer of said plurality of transducer arrays is independently operable.

3. The apparatus of claim 2, wherein said headset assembly comprises:

a) an anterior headframe member configured for spanning ear to ear across the brow of said skull;

said anterior headframe member generally “

U-shaped”

in form, with first end and second end contralaterally disposed thereon;

b) a posterior headband member configured for spanning ear to ear under the occipital protuberance of said skull, said posterior headband having two ends, wherein each said end is configured for inserted into one apposing end of said anterior headframe member, said anterior headframe member further comprising a tensioning mechanism for engaging said ends of said posterior headband member and tightening said headset circumcranially around said skull;

wherein the left an right transducer-array registration brackets each has a registration surface configured for engaging one each said Rt otobasion superius craniological landmark and said Lt otobasion superius craniological landmark.

4. The apparatus of claim 3, wherein each said registration surface of the left and right transducer-array registration brackets is an earpiece, and said Rt earpiece is fixedly mounted in relation to said Rt temporal transducer array and said Lt earpiece is fixedly mounted in relation to said Lt temporal transducer array, said earpieces each having dimensions for stereotactically positioning said each temporal transducer array in acoustic contact with a temporal acoustic window when said nasion registration pad is seated on said nasion and said each earpiece is seated on one said otobasion superius.

5. The apparatus of claim 4, wherein said occipital transducer is seated proximate to an occipital acoustic window when said posterior headband is circumcranially tightened around said skull.

6. The apparatus of claim 1, wherein said circuit with portable power and voltage supply are operatively attached to said headset by a detachable electromagnetically shielded umbilicus.

7. The apparatus of claim 1, wherein said circuit with microcontroller and memory comprise digitally encoded instructions in non-volatile memory for autonomously driving at least one therapeutic or prophylactic ultrasonic treatment regimen until a stop instruction is executed;

said ultrasonic treatment regimen comprising metapulses of stereotemporally modulated ultrasound having;

a) a metapulse cycle repetition frequency of 0.25 to 20 Hz, wherein each metapulse comprises a plurality of pulse trains emitted intermittently and asynchronously from said plurality of transducers;

b) wherein each pulse train comprises 2 to 300 pulses of ultrasound per train at a pulse repetition frequency of 4 kHz to 10 kHz;

c) wherein each pulse comprises ultrasound at a primary frequency f_c and has a pulse duration of 0.2 to 10 microseconds; and

,

d) further wherein each transducer of said plurality of arrays has a duty cycle of 0.1 to 10% per metapulse, thereby achieving low power consumption and passive cooling for extended autonomous portable operation.

8. The apparatus of claim 7, wherein said ultrasound pulses are emitted at a primary frequency f_c selected from a group of frequency ranges consisting of frequencies a) from about 0.8 MHz to about 2.2 MHz;

b) from about 0.5 MHz to about 3.5 MHz;

c) from about 1 to about 2 MHz;

d) about 1 MHz;

e) about 2 MHz;

f) about 1.2 MHz, and g) about 0.8 MHz.

9. The apparatus of claim 7, wherein each said pulse at said frequency f_c is driven by a voltage (V.sub.p-p) configured such that a maximum attenuated peak rarefaction pressure P_rA delivered at depth z_sp in a head does not exceed 300 KPa and does not exceed pressure corresponding to a physiologically compatible thermal index.

10. The apparatus of claim 9, wherein said therapeutic or prophylactic insonation regimen is configured for self-administration at the press of a button.

11. The apparatus of claim 9, where said therapeutic or prophylactic insonation regimen is configured for:

a) non-invasively dispersing or generating an endogenous mediator of a physiological state;

b) non-invasively accelerating activity of a drug having an effect on a neurological or vascular condition;

c) non-invasively controlling or preventing ischemic stroke of a cerebral vasculature;

d) non-invasively controlling or preventing atheroma or microatheroma of a cerebral vasculature;

e) non-invasively controlling or preventing headache, migraine, or hydrocephaly;

f) non-invasively applying transcranial ultrasound following administration of a recombinant tPA or other plasminogen activator in treatment of ischemic stroke;

g) non-invasively applying transcranial ultrasound outside a 3 hour window post onset of stroke, said 3 hour window being a generally recognized window for efficacious administration of r-tPA;

h) non-invasively applying transcranial ultrasound for treatment or control of stroke without co-therapy;

i) non-invasively applying transcranial ultrasound for treatment or control of stroke in combination with administration of a microbubble suspension or microbubble suspension precursor;

j) non-invasively applying transcranial ultrasound for treatment of cerebrovascular ischemia, where said ischemia is caused by ischemic stroke or by hemorrhagic stroke; and

/or, k) non-invasively applying transcranial ultrasound following administration of an exogenous plasminogen activator, a plasminogen activator prodrug, a urokinase, a pro-urokinase, a mutant pro-urokinase a streptokinase, a staphylokinase, an anisolated plasminogen-streptokinase activator complex (APSAC), a single-chain urokinase-type PA, a monteplase, an Alteplase, a Reteplase, a Tenecteplase, and a desmoteplase, a Factor IX inhibitor, a Factor X inhibitor, an anticoagulant, a prostaglandin synthase inhibitor, a GP IIb-IIIa antagonist, a nitrone, an Edaravone, a heparin, a warfarin, a coumadin, a nitroglycerin or related NO precursors, a microbubble suspension or precursor, and the like;

l. non-invasively applying transcranial ultrasound before obtaining a diagnosis of ischemic versus hemorrhagic stroke;

m. non-invasive application of transcranial ultrasound by a first responder, an emergency technician, or a patient prior to a confirmation of a diagnosis of stroke by imaging means.

12. The apparatus of claim 1, wherein said portable power and voltage supply is battery pack, said battery pack having weight of less than 250 grams, and said battery pack includes at least one of a rechargeable battery, an insertable battery, a lithium ion battery, a lithium ion polymer battery, a lithium iron 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 9 V battery, a cell phone battery, or at least one AA or AAA battery, and a portable power source.

13. The apparatus of claim 1, said headset assembly and operating circuit having a power consumption of less than about 400 mAmp-hr, more preferably less than about 300 mAmp-hr, and thereby having an operating life on battery power without recharging of more than 2 hours but not limited to up to about 12 hours at an operating voltage of about 3 to about 9 VDC, more preferably about 3.5.+−

0.1 VDC, thereby permitting transport, ambulation, or carrying without interruption of a programmable continuous or intermittent therapeutic or prophylactic insonation regimen.

14. The apparatus of claim 1, wherein said headset assembly weighs less than 500 grams, or wherein said apparatus with headset, microcontroller and power supply weighs less than 1 kilogram.

15. The apparatus of claim 1, wherein said apparatus is configured an autonomon for operator-independent use, said operator interface comprising only an on-off/pause control surface and at least one status indicator selected from green LED, red LED, LCD display, touch screen, buzzer, vibrator, or speaker.

16. The apparatus claim 1, further comprising a subcircuit selected from:

a) a watchdog subcircuit for safe operation;

b) an acoustic coupling subcircuit for verifying acoustic coupling;

c) a voltage regulation subcircuit with digital resistor feedback means and non-volatile data storage means for adjusting transducer boost voltage according to calibration data stored therein, thereby compensating for transducer-to-transducer variability; and

d) a fuel gauge subcircuit for optimizing battery life.

17. The apparatus of claim 1, wherein a peak amplitude P_r0 of said pulse or train of pulses emitted from said each ultrasonic transducer is adjusted in amplitude on the fly to reduce intertransducer manufacturing variability, thereby improving insonation consistency.

18. An apparatus for transcranial sonothrombolysis of a targeted cerebral vasculature of a subject'"'"'s head, the apparatus comprising:

a set of transducer arrays; and

a headset supporting said set of transducer arrays and mountable on the subject'"'"'s head, said headset including anterior and posterior headframe members configured to mate at corresponding ends of said members such as to define, when the headset is positioned on the subject'"'"'s head for transcranial sonothrombolysis, (i) a headset plane that is inclined with respect to a horizontal reference plane and is parallel to a plane of the subject'"'"'s Circle of Willis, and (ii) a circumcranial loop of said headset, wherein mutual positioning of the anterior and posterior headframe members is tensionally adjustable,

said headset and including one or more mounting registration brackets adapted

to stereotactically cooperate with the subject'"'"'s head such as to align transducer arrays from said set of transducer arrays with corresponding transcranial acoustic windows of the subject'"'"'s head when the headset is positioned on the subject'"'"'s head for transcranial sonothrombolysis, and

to optimize an insonation of a targeted cerebral vasculature through said transcranial acoustic windows with ultrasound (US) beams emitted by said transducer arrays in such stereotactically cooperated position,

wherein a nasion mounting registration bracket, from one or more mounting registration brackets, has a fixed end affixed to the headset at the front and a second end and protrudes transversely to the headset plane and along the subject'"'"'s forehead,

wherein a first transducer-array registration bracket and a second array-registration bracket align, respectively, first and second temporal transducer arrays, from the set of transducer arrays, with an otobasion superior and a sphenoid shelf on the opposite sides of the subject'"'"'s head such as to optimize a degree of insonation of a target central cerebral vasculature with an ultrasound (US) beam emitted by said first transducer array, the insonation being directed substantially along the headset plane,

wherein a posterior occipital transducer array, from the set of transducer arrays, is disposed at a back portion of the headset such as to direct corresponding US beams at the basiliar and vertebral artery and a junction of an internal carotids of the Circle of Willis, and

wherein said nasion and first transducer-array registration brackets are configured such that, when the headset is positioned on the subject'"'"'s head for transcranial sonothrombolysis, said first transducer-array registration bracket aligns said first temporal transducer array with an otobasion superior and a sphenoid shelf without a need for measuring or locating of said otobasion superior and sphenoid shelf prior to positioning of the headset on the subject'"'"'s head.

19. An apparatus according to claim 18, wherein said chosen external craniological marks include a left otobasion superior (OBS), a right OBS, and a nasion of the subject'"'"'s head.

20. An apparatus according to claim 19, wherein said temporal transducer array registration bracket is slidably and removably mounted on an internal surface of said headset.

21. An apparatus according to claim 18, wherein the headset plane passes through said left and right OBS when the headset is positioned on the subject'"'"'s head for transcranial sonothrombolysis.

22. An apparatus according to claim 18, wherein said one or more mounting registration brackets includes a registration bracket configured to contact one of a nasion, left otobasion superior (OBS), right OBS, tragion, mandibular condyle, zygomatic arch, prosthion, and occipital prominence when the headset is positioned on the subject'"'"'s head for transcranial sonothrombolysis.

23. An apparatus according to claim 18, wherein said headset includes anterior and posterior headframe members configured to mate at corresponding ends of said members such as to define a circumcranial loop of said headset.

24. An apparatus according to claim 23, wherein mutual positioning of the anterior and posterior headframe members is tensionably adjustable.

25. A headset apparatus for providing transcranial sonothrombolysis of a target cerebral vasculature of a subject'"'"'s head, comprising

(i) a processor;

(ii) a non-transitory tangible computer-readable medium;

(iii) computer-readable program code encoded in said computer-readable medium;

(iv) an ultrasound (US) device that has a headset plane and includes mounting registration brackets, defined with respect to corresponding external craniological marks of the subject'"'"'s head, and a set of transducer arrays, said ultrasound device being positionable onto the subject'"'"'s head such that the mounting registration brackets are brought into contact with respectively corresponding external craniological marks and the headset plane is placed at an angle with respect to a horizontal reference plane that is defined by said external craniological marks and parallel to a plane of the subject'"'"'s Circle of Willis,

wherein

a nasion mounting registration bracket has a fixed end affixed to the headset at the front and a second end and protrudes transversely to the headset plane and along the subject'"'"'s forehead,

a first transducer-array registration bracket and a second array-registration bracket align, respectively, first and second temporal transducer arrays, from the set of transducer arrays, with an otobasion superior and a sphenoid shelf on the opposite sides of the subject'"'"'s head such as to optimize a degree of insonation of a target central cerebral vasculature with an ultrasound (US) beam emitted by said first transducer array, the insonation being directed substantially along the headset plane,

and

a posterior occipital transducer array, from the set of transducer arrays, is disposed at a back portion of the headset such as to direct corresponding US beams at the basiliar and vertebral artery and a junction of an internal carotids of the Circle of Willis,

wherein said nasion and first transducer-array registration brackets are configured such that, when the headset is positioned on the subject'"'"'s head for transcranial sonothrombolysis, said first transducer-array registration bracket aligns said first temporal transducer array with the otobasion superior and the sphenoid shelf without a need for measuring or locating of said otobasion superior and sphenoid shelf prior to positioning of the headset on the subject'"'"'s head;

wherein the computer readable program code comprises a series of computer readable program steps to effect;

insonating, in the headset plane, the target cerebral vasculature; and

defining a regime of operation of the at least one of said transducer arrays.

26. An apparatus according to claim 25, wherein said insonating includes insonating with at least one of a temporal transducer array and an occipital transducer array.

27. An apparatus according to claim 25, wherein said defining includes defining at least one of temporal and amplitude sequence of pulses of US beams.