Hands-Free Operator-Independent Transcranial Ultrasound Apparatus and Methods

• US 20120083718A1
• Filed: 08/14/2011
• Published: 04/05/2012
• Est. Priority Date: 10/05/2010
• Status: Active Grant

• Current Assignee: Cerevast Medical, Inc.
• Original Assignee: Cerevast Therapeutics, Inc.
• Inventors: Alleman, Anthony J., Barnard, William, Radford, Randal Lee
• Granted Patent: US 8,603,014 B2
• Time in Patent Office: Days
• 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 said headset assembly on said skull with respect to an intracranial target or targets;

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; 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;

c) a nasion registration bracket disposed anteriorly at a midpoint on said anterior headframe member and a nasion registration pad pendant therefrom, said nasion registration pad for engaging said nasion craniological landmark and offsetting said midpoint of said anterior headframe member by a height h₁;

d) a pair of otobasion superius registration members slideably disposed contralaterally on said anterior headframe member, each said otobasion superius registration member with registration surface configured for engaging one each said Rt otobasion superius craniological landmark and said Lt otobasion superius craniological landmark;

and further wherein said headset is obliquely inclined relative to said foundational reference plane by said height h₁ anteriorly so that said anterior headframe member is raised above the eyes of said skull, has clearance around the ears of said skull, and wherein said posterior headband member is obliquely inclined below said reference plane by said height h₂, thereby engaging the underside of said occipital protuberance of said skull when stereotactically positioned thereon.

4. The apparatus of claim 3, wherein each said registration surface of said otobasion superius registration member 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) 0.8 to 2.2 MHz;

b) 0.5 to 3.5 MHz;

c) 1 to 2 MHz;

d) 1 MHz;

e) 2 MHz;

f) 1.2 MHz, or

g) 0.8 MHz.

9. The apparatus of claim 7, wherein each said pulse at said frequency f_c is driven by a voltage (V_p-p) configured to deliver a maximum attenuated peak rarefaction pressure P_{r A} at depth z_sp not to exceed 300 KPa and not to exceed 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 is generically a battery or batteries, 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, or any equivalent portable power source.

13. The apparatus of claim 1, said headset 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±

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;

or

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. A method for treating a neurological or a neurovascular condition with transcranial ultrasound, which comprises:

a) adjustably tightening a circumcranial headset assembly of claim 1 around a skull, wherein said circumcranial headset is configured with a plurality of transducer arrays, each said array having a plurality of ultrasound transducers, and with registration surfaces for engaging one or more external craniological landmarks of a skull so as to stereotactically position said headset on said head without need for diagnostic imaging guidance; and

b) causing to be emitted from said plurality of actuated ultrasonic transducer arrays at least one therapeutic or prophylactic insonation regimen comprising a cyclically repeated metapulse of spatially and temporally modulated pulse trains of ultrasound having a primary frequency f_c, said pulse trains having a pulse repetition frequency corresponding to a duty cycle of 1-10%, more preferably 2-6%, and most preferably about 3 to 5% per transducer at a pulse repetition frequency of about 4 kHz to about 10 kHz, more preferably about 4 kHz to about 8 kHz, and most preferably about 6 kHz, said pulse trains having 1 to 300 pulses per train, more preferably of about 100 to about 300 pulses per train, each said pulse having a pulse duration of about 0.2 to 10 microseconds, more preferably about 1 to 8 microseconds, most preferably about 6 microseconds, and said metapulse having a metapulse cycle repetition frequency of 0.25 to 20 Hz, more preferably about 0.5 to 5 Hz;

until a stop instruction is received.

19. The method of claim 18, wherein said spatially and temporally modulated pulse trains comprise pulses, each pulse having a pulse duration of about 0.2 to 10 microseconds, more preferably about 1 to 8 microseconds, most preferably about 6 microseconds, in trains of pulses of 1 to 300 pulses per train, more preferably of about 100 to about 300 pulses per train, said pulses having an amplitude measured as unattenuated peak rarefaction pressure (P_r0) of about 0.3 to about 1.0 MPa, and having a primary frequency f_c of 0.5 to 3.5 MHz, more preferably about 0.8 or 0.9 to about 3.0 MHz, and most preferably about 1 MHz, or about 1.2 MHz, or about 2.0 MHz

20. The method of claim 18, wherein said pattern and amplitude of acoustic pulses or train of pulses is configured for self-administration.

21. The method of claim 18, wherein said apparatus is configured for use by first responders prior to obtaining a differential diagnosis of ischemic or hemorrhagic stroke.

22. The method of claim 19, further comprising a step for measuring skull thickness using a CT scan and for adjusting a voltage (V_p-p) to said transducer to a safe and effective intensity as calculated from an equation or a look-up table relating insonation voltage (V_p-p) to peak rarefaction pressure (P_r) at depth of insonation z_sp and not exceeding a calculated P_rAzsp of 300 KPa.