U.S. patent application number 16/158939 was filed with the patent office on 2019-03-28 for systems and methods for non-invasive brain stimulation with ultrasound.
This patent application is currently assigned to The Trustees of Columbia University in the City of New York. The applicant listed for this patent is The Trustees of Columbia University in the City of New York. Invention is credited to Hermes Arytto Salles Kamimura, Elisa E. Konofagou.
Application Number | 20190090738 16/158939 |
Document ID | / |
Family ID | 56693299 |
Filed Date | 2019-03-28 |
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United States Patent
Application |
20190090738 |
Kind Code |
A1 |
Konofagou; Elisa E. ; et
al. |
March 28, 2019 |
SYSTEMS AND METHODS FOR NON-INVASIVE BRAIN STIMULATION WITH
ULTRASOUND
Abstract
Systems and methods for non-invasive brain stimulation using
focused ultrasound are provided. An exemplary method of
non-invasive brain stimulation in the brain of a subject can
include securing the subject in a fixed position relative to an
ultrasound source and providing a focused ultrasound having one or
more ultrasound parameters to a location in the brain of the
subject, the location and the one or more ultrasound parameters
selected to evoke a physical response of the subject, and measuring
the physical response of the subject.
Inventors: |
Konofagou; Elisa E.; (New
York, NY) ; Kamimura; Hermes Arytto Salles; (Rebeirao
Preto, SP, BR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Trustees of Columbia University in the City of New
York |
New York |
NY |
US |
|
|
Assignee: |
The Trustees of Columbia University
in the City of New York
New York
NY
|
Family ID: |
56693299 |
Appl. No.: |
16/158939 |
Filed: |
October 12, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15040926 |
Feb 10, 2016 |
10098539 |
|
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16158939 |
|
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62114321 |
Feb 10, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 3/113 20130101;
A61B 5/0077 20130101; A61B 5/4848 20130101; A61B 5/1128 20130101;
A61B 5/0205 20130101; A61N 2007/0026 20130101; A61B 3/11 20130101;
A61B 5/4821 20130101; A61N 7/02 20130101 |
International
Class: |
A61B 3/113 20060101
A61B003/113; A61B 5/11 20060101 A61B005/11; A61B 5/00 20060101
A61B005/00; A61N 7/02 20060101 A61N007/02; A61B 3/11 20060101
A61B003/11 |
Goverment Interests
STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH
[0002] This invention was made with government support from the
National Institutes of Health under Grant Nos. R01-EB009041 and
R01-AG038961. The government has certain rights in the invention.
Claims
1. A method for non-invasive brain stimulation in a brain of a
subject, comprising: securing an ultrasound source in a fixed
position relative to the subject; targeting the ultrasound source
at a location in the brain of the subject, the location
corresponding to a desired physical response in the subject;
selecting at least one ultrasound parameter of the ultrasound
source to evoke the desired physical response, the at least one
ultrasound parameter comprising one or more of: a frequency
selected from a frequency range to evoke the desired physical
response from the location in the brain of the subject, a target
area selected from a target area range to evoke the desired
physical response from the location in the brain of the subject,
and an acoustic pressure at least equal to the threshold acoustic
pressure for evoking the physical response from the location in the
brain of the subject; and providing an ultrasound wave from the
ultrasound source having the selected at least one ultrasound
parameter to the location in the brain of the subject; and
verifying the desired physical response occurs.
2. The method of claim 1, wherein the location is within at least
one of the primary motor cortex, primary somatosensory cortex,
superior colliculus, locus coeruleus, hippocampus, abducens
nucleus, or medial longitudinal fasciculus.
3. The method of claim 1, wherein the frequency is about 1.9
MHz.
4. The method of claim 1, further comprising determining the
threshold acoustic pressure by providing a focused ultrasound
having an ultrasound parameter to a location in the brain of the
subject, wherein the location corresponds to a physical response,
and verifying whether the physical response occurs.
5. The method of claim 1, wherein the focused ultrasound is
provided as a burst having a pulse repetition frequency and a duty
cycle.
6. The method of claim 5, wherein the pulse repetition frequency is
greater than about 30 kHz.
7. The method of claim 5, wherein the duty cycle is from about 10%
to about 60%.
8. The method of claim 1, wherein the focused ultrasound is
provided as a chirp waveform.
9. The method of claim 1, further comprising anesthetizing the
subject using an amount of sodium barbital.
10. The method of claim 9, wherein the amount of sodium barbital
ranges from about 25 mg/kg to about 100 mg/kg.
11. The method of claim 9, wherein the subject remains under
anesthesia for more than about 90 minutes.
12. The method of claim 1, wherein the measuring further comprises
moving one or more transducers relative to the fixed position to
target the location in the brain of the subject prior to providing
a focused ultrasound.
13. The method of claim 12, wherein the measuring further comprises
moving the one or more transducers within a random grid while
providing the focused ultrasound to generate a random raster
sonication.
14. The method of claim 1, further comprising measuring one or more
vital signs of the subject before, during, and/or after providing
the focused ultrasound.
15. The method of claim 14, wherein the one or more vital signs are
selected from the group consisting of heart rate, respiratory rate,
temperature, body motion, blood pressure, and combinations
thereof.
16. The method of claim 1, wherein the measuring the physical
response comprises recording the physical response.
17. The method of claim 1, further comprising receiving an acoustic
cavitation emission and determining a type of acoustic cavitation
activity based on the acoustic cavitation emission.
18. The method of claim 17, wherein the acoustic cavitation
activity is stable cavitation.
19. The method of claim 17, wherein the acoustic cavitation is
inertial cavitation.
20. The method of claim 17, further comprising modulating the
ultrasound parameter after determining the type of acoustic
cavitation activity.
21. A system for non-invasive brain stimulation in a brain of a
subject, comprising: an ultrasound source for providing a focused
ultrasound having one or more ultrasound parameters to a location
in the brain of the subject, the location and the one or more
ultrasound parameters selected to evoke a physical response of the
subject, and the one or more ultrasound parameters comprising: a
frequency selected from a frequency range to evoke the desired
physical response from the location in the brain of the subject, a
target area selected from a target area range to evoke the desired
physical response from the location in the brain of the subject,
and an acoustic pressure at least equal to the threshold acoustic
pressure for evoking the physical response from the location in the
brain of the subject; and a processor for controlling the
ultrasound source.
22. The system of claim 21, wherein the ultrasound source comprises
a function generator, an amplifier, and one or more
transducers.
23. The system of claim 22, further comprising a frame for securing
the subject in a fixed position relative to the ultrasound
source.
24. The system of claim 23, further comprising a 3D positioning
system for moving the one or more transducers relative to the fixed
position to target the location in the brain of the subject.
25. The system of claim 21, further comprising a vital sign monitor
for measuring at least one of a heart rate, a respiratory rate, a
temperature, a body motion, and a blood pressure of the
subject.
26. The method of claim 1, wherein the location and the one or more
ultrasound parameters are selected to treat a condition of the
subject, the condition comprising at least one of chronic pain,
Parkinson's disease, depression, obsessive-compulsive disorder
(OCD), obesity, epilepsy, schizophrenia, brain tumor, and essential
tremor.
27. The method of claim 26, wherein the location is within a region
in the brain that corresponds to the condition.
28. The method of claim 26, wherein the subject is experiencing one
or more symptoms associated with the condition.
29. The method of claim 28, further comprising increasing the
acoustic pressure to relieve the one or more symptoms.
30. The method of claim 28, wherein the focused ultrasound is
provided as a burst having a pulse repetition frequency and a duty
cycle, and the duty cycle is selected based on the one or more
symptoms.
31. The system of claim 21, further comprising at least one camera
for measuring the physical response of the subject.
32. The system of claim 31, wherein the at least one camera
comprises a monochrome camera for recording at least one of an eye
movement and pupil dilation.
33. The system of claim 31, wherein the at least one camera
comprises a digital camera for recording a body movement.
34. The system of claim 21, wherein the ultrasound source is
configured as a wearable device.
35. The system of claim 34, wherein the wearable device includes
one or more securing features for aligning the ultrasound source
with respect to the location in the brain of the subject.
36. The system of claim 35, wherein the one or more securing
features are configured to secure the ultrasound source with
respect to the location in the brain of the subject while the
subject moves around.
37. The system of claim 34, wherein the wearable device is adapted
for use to treat a condition of the subject, the condition
comprising at least one of Parkinson's disease, essential tremor,
chronic pain, and brain tumor.
38. The system of claim 37, wherein the ultrasound source is
configured to permit a user to adjust at least one of the one or
more ultrasound parameters.
39. The system of claim 38, wherein the user can adjust at least
one of the one or more ultrasound parameters to correspond to one
or more symptoms of the condition.
40. The system of claim 39, wherein the ultrasound source is
configured to provide the focused ultrasound as a burst having a
pulse repetition frequency and a duty cycle, and the user can
adjust the duty cycle to correspond to the one or more
symptoms.
41. The system of claim 40, wherein the user can adjust one or more
of a function generator and an amplifier.
42. The system of claim 37, wherein the location is within a region
in the brain that corresponds to the condition.
43. The method of claim 1, wherein the frequency is from about 0.1
MHz to about 5 MHz.
44. The method of claim 1, wherein the target area is from about
0.5 mm to about 5 mm in the lateral direction and from about 2 mm
to about 20 mm in the axial direction.
45. The method of claim 1, wherein the verifying comprises
measuring or recording the desired response.
46. The system of claim 21, wherein the frequency is from about 0.1
MHz to about 5 MHz.
47. The system of claim 21, wherein the target area is from about
0.5 mm to about 5 mm in the lateral direction and from about 2 mm
to about 20 mm in the axial direction.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and is a continuation of
U.S. patent application Ser. No. 15/040,926, filed on Feb. 10,
2016, which claims priority to U.S. Provisional Application No.
62/114,321, filed on Feb. 10, 2015, each of which is hereby
incorporated by reference in its entirety.
BACKGROUND
[0003] Brain stimulation can involve evoking a neural response by
touching or otherwise activating the brain, either directly or
indirectly. For example, brain stimulation can be used to evoke
neuromodulation, which can be used in treating various neurological
disorders, as well as other conditions involving the brain, such as
psychiatric disorders. Brain stimulation can thus be used to treat
neuropathic pain, Parkinson's disease, depression,
obsessive-compulsive disorder, essential tremor, and brain tumors,
among other disorders. Additionally, systems and techniques for
brain stimulation can be used to analyze various conditions,
including epilepsy, Alzheimer's disease, multiple sclerosis,
hydrocephalus, stroke, trigeminal neuralgia, and traumatic brain
injury. Furthermore, neuromodulation can be used in brain mapping
techniques.
[0004] Deep brain stimulation (DBS) is a brain stimulation
technique using electrodes implanted in the brain to transmit
electrical impulses to specific parts of the brain. However, DBS
can have adverse neuropsychiatric side-effects due at least in part
to its invasive nature. Another brain stimulation technique is
optogenetics, which involves using light to stimulate genetically
modified neurons. However, such gene modification can be
challenging and undesirable.
[0005] Non-invasive brain stimulation techniques can include
transcranial magnetic stimulation (TMS), which can be used to
stimulate small regions of the brain using a magnetic field.
However, TMS can have poor spatial resolution, and can have
inadequate depth penetration. Furthermore, the effects of TMS can
be relatively short lasting (e.g., in the millisecond range).
[0006] Thus, there remains an opportunity for improved techniques
for non-invasive brain stimulation.
SUMMARY
[0007] The presently disclosed subject matter provides techniques
for non-invasive brain stimulation using focused ultrasound. An
exemplary method of non-invasive brain stimulation in the brain of
a subject can include securing the subject in a fixed position
relative to an ultrasound source and providing a focused ultrasound
having one or more ultrasound parameters to a location in the brain
of the subject, the location and the one or more ultrasound
parameters selected to evoke a physical response of the subject,
and measuring the physical response of the subject.
[0008] For example, and as embodied herein, the physical response
can be one or more of a body movement, an eye movement, and pupil
dilation. The location can be within the primary motor cortex,
primary somatosensory cortex, superior colliculus, locus coeruleus,
hippocampus, abducens nucleus, and/or medial longitudinal
fasciculus.
[0009] The one or more ultrasound parameters can include a
frequency, a target area, and/or an acoustic pressure. The
frequency can be from about 0.1 MHz to about 5 MHz. For example,
and as embodied herein, the frequency can be about 1.9 MHz. The
target area can be from about 0.5 mm to about 5 mm in the lateral
direction and from about 2 mm to about 20 mm in the axial
direction. The acoustic pressure can be at least equal to a
threshold acoustic pressure for evoking the physical response. The
method can include determining the threshold acoustic pressure by
providing a focused ultrasound having an ultrasound parameter to a
location in the brain of the subject corresponding to a physical
response, and verifying whether the physical response occurs. The
focused ultrasound can be provided as a burst. The burst can have a
pulse repetition frequency of greater than about 30 kHz. The burst
can have a duty cycle from about 10% to about 60%. Alternatively,
the focused ultrasound can be provided as a chirp.
[0010] The method can include anesthetizing the subject using
sodium barbital. The dosage of sodium barbital can range from about
25 mg/kg to about 100 mg/kg. The subject can remain under
anesthesia for more than about 90 minutes.
[0011] The method can further include moving transducers relative
to the fixed position of the subject in order to target a location
in the brain prior to providing the focused ultrasound.
Alternatively or additionally, the method can include moving the
transducers within a random grid while providing the focused
ultrasound to the brain of the subject in order to generate a
random raster sonication.
[0012] The method can further include measuring one or more vital
signs of the subject before, during, and/or after providing the
focused ultrasound. The vital signs can include heart rate,
respiratory rate, temperature, blood pressure, body motion, and
combinations thereof. Measuring the physical response can include
recording the physical response.
[0013] The method can include receiving an acoustic cavitation
emission and determining a type of acoustic cavitation activity
based on the acoustic cavitation emission. The acoustic cavitation
activity can be stable cavitation and/or inertial cavitation. The
method can further include modulating the ultrasound parameter
after determining the type of acoustic cavitation activity.
[0014] The presently disclosed subject matter also provides systems
for non-invasive brain stimulation in the brain of a subject. An
exemplary system can include an ultrasound source for providing a
focused ultrasound having one or more ultrasound parameters to a
location in the brain of the subject, where the location and the
ultrasound parameters are selected to evoke a physical response of
the subject, at least one camera for measuring the physical
response of the subject, and a processor for controlling the
ultrasound source and/or the camera.
[0015] The ultrasound source can include a function generator, an
amplifier, and/or one or more transducers. The system can further
include a frame for securing the subject in a fixed position
relative to the ultrasound source. The system can further include a
3D positioning system for moving the transducers relative to the
fixed position in order to target the location in the brain of the
subject.
[0016] The camera can be a monochrome camera for recording an eye
movement and/or pupil dilation. Alternatively or additionally, the
camera can be a digital camera for recording a body movement. The
system can further include a vital signs monitor, which can measure
the heart rate, respiratory rate, temperature, body motion, and/or
blood pressure of the subject.
BRIEF DESCRIPTION OF THE FIGURES
[0017] FIG. 1 is a diagram illustrating an exemplary embodiment of
a system for non-invasive brain stimulation using focused
ultrasound according to the disclosed subject matter.
[0018] FIG. 2 is a diagram illustrating another embodiment of a
system for non-invasive brain stimulation using focused ultrasound
according to the disclosed subject matter.
[0019] FIG. 3 is a diagram illustrating an exemplary method for
non-invasive brain stimulation using focused ultrasound according
to the disclosed subject matter.
[0020] FIG. 4A is a diagram illustrating multiple electromyography
(EMG) graphs indicating contralateral responses in mice during
brain stimulation at various acoustic pressures.
[0021] FIG. 4B is a diagram illustrating the success rate of
evoking a physical response with focused ultrasound at acoustic
pressures ranging from 1.1 MPa to 1.8 MPa.
[0022] FIG. 4C depicts two series of images illustrating
contralateral paw movement in response to focused ultrasound.
[0023] FIGS. 5A-5B are diagrams illustrating the location of two
sonications, and indicating where contralateral and ipsilateral paw
movements were observed.
[0024] FIG. 6A depicts two series of images illustrating pupil
dilation and eye movement in response to focused ultrasound.
[0025] FIG. 6B is a diagram illustrating pupil dilation at various
acoustic pressures for focused ultrasound at two different regions
in the brain.
[0026] FIG. 7A is a diagram illustrating locations where focused
ultrasound evoked pupil dilation and/or eyeball movement, and the
corresponding threshold acoustic pressures.
[0027] FIG. 7B includes diagrams illustrating the maximum pupil
dilation observed at various acoustic pressures for focused
ultrasound at two different regions in the brain.
[0028] FIG. 8A is a diagram illustrating acoustic pressure fields
within mouse brains that were subjected to six different forms of
focused ultrasound.
[0029] FIG. 8B is a diagram illustrating the acoustic pressure
along the axial path of the focused ultrasound, when the focused
ultrasound was provided as a continuous wave, a high
pulse-repetition frequency burst, and a quadratic chirp.
DETAILED DESCRIPTION
[0030] The presently disclosed subject matter provides techniques
for non-invasive brain stimulation using focused ultrasound.
According to one aspect of the disclosed subject matter, methods
and systems for applying focused ultrasound to the brain of a
subject to stimulate a response are provided.
[0031] FIG. 1 is a diagram illustrating an exemplary system for
non-invasive brain stimulation according to the disclosed subject
matter. FIG. 2 is an illustration of an exemplary embodiment of the
system of FIG. 1. For purposes of illustration and not limitation,
the system of FIG. 1 includes certain additional features that are
not illustrated in the embodiment of FIG. 2. Systems according to
the disclosed subject matter can include various combinations of
some or all of the components of FIG. 1 or 2 according to the
desired application(s) and are not limited to the particular
combinations of components described herein. With reference to
FIGS. 1 and 2, system 100 can include a transducer 110 for
providing focused ultrasound to a subject 101.
[0032] The disclosed methods and systems can be applied to a
variety of living subjects, including humans and animals. For
example, and as embodied herein, the subject can be anesthetized.
Additionally or alternatively, and as embodied herein, the subject
can be secured, for example, to stabilize the target area of the
focused ultrasound. System 100 can include various components for
securing the subject. For example and without limitation, the
system can include one or more restraints 121, such as frames,
straps, holders, bars, and/or other features for securing the
subject.
[0033] According to another embodiment of the disclosed subject
matter, a wearable device for providing focused ultrasound to the
brain of the subject is provided. The wearable device can include
any or all of the features of a system for providing focused
ultrasound to the brain as described herein. For example, and as
embodied herein, such wearable device can include one or more
transducers for providing focused ultrasound, and one or more
processors for controlling and targeting the focused ultrasound. A
wearable device can further include a vital signs monitor for
observing the bodily functions of the subject. Additionally, and as
embodied herein, the wearable device can include one or more
securing features to secure the wearable device in alignment to
provide focused ultrasound to a desired region of the brain. For
example and without limitation, the one or more securing features
can include straps, buckles, elastic bands, tape, velcro, or any
other suitable securing features. In this manner, the securing
features can be configured to maintain the desired alignment of the
focused ultrasound transducer with respect to the cranial geometry
while the subject moves around, and/or can be configured to be
applied and removed by the subject without assistance from a
clinician.
[0034] The disclosed techniques can be used in a wide variety of
clinical applications. For example, focused ultrasound can be used
to treat varied conditions, including chronic pain, Parkinson's
disease, depression, obsessive-compulsive disorder (OCD), obesity,
epilepsy, schizophrenia, and essential tremor. In this manner, the
configuration of the system and delivery of focused ultrasound can
be modified based on the particular condition to be treated.
Moreover, either the stationary device or the wearable device
described herein, or both such devices, can be used to treat these
conditions using the techniques described herein.
[0035] For purpose of illustration and not limitation, it can be
more convenient for the subject to have a wearable device that can
be used without assistance from a clinician. For example, and as
embodied herein, certain conditions can be treated using frequent
or regular treatments, and thus it can be desirable to allow the
treatment to be performed outside a clinical setting, such as and
without limitation, in the subject's home. Such conditions can
include Parkinson's disease, essential tremor, chronic pain, and
brain tumors. For example, a subject diagnosed with a condition can
be provided with a wearable device that can be used to perform
treatments outside a clinical setting. Focused ultrasound can be
provided by the wearable device when symptoms occur and/or pursuant
to a predetermined schedule. The wearable device can be
pre-programmed with particular ultrasound parameters to treat the
subject's condition. Additionally or alternatively, the wearable
device can include an interface to permit the ultrasound parameters
to be adjusted, for example and without limitation, by the subject
or by a clinician. For purpose of illustration and not limitation,
for certain conditions, for example and without limitation,
essential tremor, the focused ultrasound parameters can be adjusted
according to the symptoms experienced by the subject. For example,
and as embodied herein, the ultrasound parameters of the wearable
device that can be pre-programmed and/or adjusted can include,
without limitation, an ultrasound frequency, a duty cycle and/or
pulse repetition frequency. In this manner, the wearable device can
be configured to provide ultrasound to the subject at the desired
ultrasound parameters, for example and without limitation, by
modulating a function generator and/or amplifier.
[0036] For the treatment of certain conditions, it can be desirable
for the subject to receive focused ultrasound within a clinic. For
example, certain conditions can be treated with a single treatment
or infrequent, periodic treatments that can be performed by a
clinician. For purpose of illustration and not limitation, as
embodied herein, a stationary device can be used to provide the
focused ultrasound to treat various conditions, such as and without
limitation, certain psychiatric disorders, including depression,
obsessive-compulsive disorder (OCD), and schizophrenia. The
stationary device can be used as an alternative to, or in
combination with, a wearable device, for example and without
limitation, in the treatment of brain tumors.
[0037] Referring again to FIGS. 1 and 2, for purpose of
illustration and not limitation, system 100 can include a
transducer 110 for providing focused ultrasound to a subject 101.
The transducer 110 can be a single-element focused ultrasound
transducer for providing focused ultrasound. As embodied herein,
the transducer 110 can have a focal length of 60 mm and a radius of
30 mm. The transducer can be driven by any suitable equipment, such
as a function generator 111. For example, and as embodied herein,
function generator 111 can be a 33220A Function/Arbitrary Waveform
Generator (Agilent Technologies, Palo Alta, Calif., USA). As
embodied herein, function generator 111 can be joined to an
amplifier 112, which can increase the power from the generator,
e.g., by about 20 dB to about 100 dB, or, as embodied herein, by
about 50 dB. In this manner, a signal from the function generator
111 can be amplified by the amplifier, and the transducer can
convert the amplified signal into focused ultrasound.
[0038] Ultrasound can refer to a sound wave having a frequency
above that of human hearing, e.g., greater than 16 kHz. As such,
the focused ultrasound for use in the presently disclosed subject
matter can have a frequency greater than about 16 kHz, and as
embodied herein, can be within a range from about 50 kHz to about
20 MHz. For purpose of illustration and not limitation, the focused
ultrasound can have a frequency from about 0.1 MHz to about 5 MHz,
or from about 0.5 MHz to about 3 MHz, or from about 1 MHz to about
2 MHz, and as embodied herein, the focused ultrasound can have a
frequency of about 1.9 MHz.
[0039] As used herein, the term "about" or "approximately" means
within an acceptable error range for the particular value as
determined by one of ordinary skill in the art, which will depend
in part on how the value is measured or determined, i.e., the
limitations of the measurement system. For example, "about" can
mean a range of up to 20%, up to 10%, up to 5%, and or up to 1% of
a given value.
[0040] The focused ultrasound can be delivered in multiple
different forms. For example, and not limitation, the focused
ultrasound can be a continuous ultrasound wave. Alternatively, the
focused ultrasound can be a chirp, i.e., a swept frequency cosine
signal. The swept frequency cosine signal can be linear, quadratic,
or logarithmic. Providing the focused ultrasound as a chirp can
improve the focus of the ultrasound on a particular location in the
brain. Additionally, providing the focused ultrasound as a chirp
can inhibit or prevent the formation of standing waves within the
brain, which can improve the safety of the focused ultrasound.
[0041] As a further example, the focused ultrasound can include one
or more pulses, i.e., isolated ultrasound waves. As embodied
herein, the focused ultrasound can be a burst, i.e., a sequence of
pulses. For example, a burst can have high pulse repetition
frequency, e.g., greater than about 30 kHz, greater than about 40
kHz, or greater than about 50 kHz. The burst can have a duty cycle
from about 10% to about 60%, or from about 15% to about 40%, and,
as embodied herein, the burst can have a duty cycle of about 20%.
As embodied herein, the burst can be repeated for at least about 5
cycles, at least about 6 cycles, or at least about 7 cycles.
[0042] As embodied herein, and with reference to FIG. 2, system 100
can include one or more chambers 115, 116 containing a couplant,
such as oil or water, for transmitting the ultrasound. Additionally
or alternatively, a conductive material 117 can be placed on the
subject 101. For example, such conductive material includes
ultrasound gel and/or water, which is preferably degassed.
[0043] The focused ultrasound can impart a certain acoustic
pressure onto the brain of the subject. An increased acoustic
pressure can increase the ability of the focused ultrasound to
elicit a physical response in a subject. However, the acoustic
pressure can influence the type and magnitude of acoustic
cavitation activity, which can cause neurovascular and neuronal
damage in the subject. For these reasons, the acoustic pressure
should be calibrated to achieve the desired response without
compromising safety. As embodied herein, the acoustic pressure can
range from about 0.5 MPa to about 2.5 MPa, from about 0.7 MPa to
about 2.25 MPa, or from about 0.75 MPa to about 1.6 MPa. The
resulting acoustic cavitation activity can be monitored by
receiving cavitation emissions. With reference to FIG. 2, system
100 can include a pulse echo transducer 114 and/or a hydrophone,
which can be configured to receive cavitation emissions in active
or passive mode.
[0044] With continued reference to FIGS. 1 and 2, the transducer
110 can be secured within a 3D positioning system 113, which can be
used to align the focused ultrasound from the transducer with a
target area on the subject 101. The 3D positioning system can move
the transducer in the x-, y-, and z-directions. For example, the 3D
positioning system can include a motor and a controller. For
purpose of illustration and not limitation, and as embodied herein,
the controller can include a VXM.TM. Controller (Velmex Inc., New
York, N.Y., USA).
[0045] As embodied herein, the 3D positioning system 113 can move
the transducer 110, for example and without limitation, within a
predefined grid. The size and resolution of the predefined grid can
be selected by the user. For example, and as embodied herein, the
grid can be 8 mm by 8 mm and can have a resolution of 1 mm. The
grid can be centered of a specific region of the brain, for
example, as defined relative to the bregma and/or the lambda. A
person having ordinary skill in the art will appreciate that the
center of the grid can correspond to the region of the brain
targeted for the focused ultrasound, and thus the center of the
grid will depend on the study or neurostimulation being performed.
The 3D positioning system 113 can move the transducer 110 within
the grid to produce a random raster sonication on the subject 101
using the focused ultrasound.
[0046] Referring still to FIG. 1, system 100 can include a vital
signs monitor 120 for monitoring one or more vital signs of the
subject 101. By way of example, and not limitation, the vital signs
monitor can measure the state of one or more bodily functions,
e.g., heart rate, respiratory rate, body temperature, body motion,
and/or blood pressure. Additionally or alternatively, the vital
signs monitor can include one or more components for measuring
bodily functions, e.g., thermometers, gauges, sensors,
transmitters, and receivers. The components of the vital signs
monitor and/or the bodily functions measured can be configured for
different applications, for example based on the size, age, and
species of the subject.
[0047] With continued reference to FIG. 1, system 100 can include
one or more cameras 130. Camera(s) 130 can be used to record any
physical responses in the subject 101 during brain stimulation.
Additionally or alternatively, the one or more cameras can also be
used to record the resting state of the subject. The one or more
cameras can be capable of capturing video and/or still images. The
cameras can be capable of capturing digital images. For example,
and as embodied herein, system 100 can include at least one
monochrome camera. A monochrome camera can be used, for example, to
record pupil dilation and eye movement in the subject. For example
and as embodied herein, camera 130 can include Model DMK 23U618
(The Imaging Source GmbH, Bremen, Germany), or any suitable camera.
Additionally or alternatively, the system can include at least one
digital camera. The digital camera can be used, for example, to
record body movements in the subject, e.g., movements of limbs,
paws, hands, tails or other extremities. Exemplary digital cameras
can include Model EOS Rebel T3i (Canon, Melville, N.Y., USA),
and/or web cameras, such as Model C920 (Logitech, CA, USA), or any
other suitable digital camera.
[0048] Referring still to FIG. 1, system 100 can include a
processor 140. The processor can be configured to carry out the
instructions specified by software stored in a hard drive, a
removable storage medium, or any other storage media. The software
can include computer codes, which can be written in a variety of
languages, e.g., Matlab and/or Microsoft Visual C++. Additionally
or alternately, the processor can include hardware logic, such as
logic implemented in an application-specific integrated circuit
(ASIC). The processor 140 can be configured to control one or more
of the system components described above. For example, and as
embodied herein, the processor 140 can be configured to control the
output of the function generator 111 and/or the transducer 110 to
provide the focused ultrasound to the subject 101. Additionally or
alternatively, the processor 140 can instruct a controller within
the 3D positioning system 113. The processor 140 can also be
configured to control the one or more cameras 130.
[0049] With continued reference to FIG. 1, the processor 140 can be
configured to receive information from one or more system
components. For example, the processor 140 can receive one or more
images from the one or more cameras 130. The processor 140 can also
receive one or more measurements from the vital signs monitor 120.
Additionally or alternatively, the processor 140 can be configured
to transmit such information to an acquisition board 150 for
storage. Non-limiting examples of suitable acquisition boards
include Gage (DynamicSignals LLC, Lockport, Ill., USA) and MP150
(Biopac Systems Inc., Santa Barbara, Calif., USA).
[0050] System 100 can be used to target a desired area of the brain
for stimulation, which can be any area of the brain. For purpose of
illustration and not limitation, as embodied herein, system 100 can
be used to target cortical and subcortical regions of the brain,
e.g., the primary motor cortex, primary somatosensory cortex,
superior colliculus, locus coeruleus, hippocampus, abducens
nucleus, medial longitudinal fasciculus.
[0051] As embodied herein, system 100 can have high target
specificity, and can achieve a resolution in the millimeter range.
For example, and as embodied herein, system 100 can provide focused
ultrasound to a target area that is from about 0.5 mm to about 5
mm, or from about 0.75 mm to about 2 mm, or about 1 mm in the
lateral direction (i.e., in diameter) and from about 2 mm to about
20 mm, or from about 5 mm to about 15 mm, or about 10 mm in the
axial direction. This high target specificity can enable the
focused ultrasound to target a specific region of the brain
corresponding to a particular physical response.
[0052] According to another aspect of the disclosed subject matter,
methods for non-invasive brain stimulation are provided. FIG. 3
illustrates an exemplary method according to the disclosed subject
matter. The method 300 can include securing a subject 301 and
providing focused ultrasound to the brain of the subject 303.
[0053] The subject can be secured such that the target area of the
focused ultrasound, i.e., the brain, remains still. For example,
and as embodied herein, the subject can be secured using the
restraints described above. Additionally or alternatively, the
method 300 can include anesthetizing the subject 302. When the
method includes both securing and anesthetizing the subject, the
steps can be performed in either order. For example, the subject
can be secured prior to being anesthetized, or alternatively, the
subject can be secured after being anesthetized.
[0054] For purpose of illustration and not limitation, the
performance of brain stimulation using focused ultrasound can be
affected at least in part by the type of anesthesia used. For
example, selecting an anesthetic that reduces or limits suppression
of evoked responses can be desirable when targeting certain areas
of the brain. For example, sodium pentobarbital can be a suitable
anesthetic to target the cortex. For purpose of illustration and
comparison, and not limitation, sodium pentobarbital can suppress
cortical evoked responses less than certain other anesthetics,
e.g., isoflurane. Additionally, for purpose of illustration and
comparison, and not limitation, sodium pentobarbital can last
longer than certain other anesthetics, e.g., ketamine. Furthermore,
using light amounts of certain anesthetics such as isoflurane or
ketamine can result in spontaneous movements, which can be confused
with the evoked responses, and thus can affect the performance of
brain stimulation described herein.
[0055] For example, and as embodied herein, the subject can be
anesthetized using sodium pentobarbital. The sodium pentobarbital
can be provided in a certain dosage relative to the body weight of
the subject. For example, and as embodied herein, the dosage can be
from about 25 mg/kg to about 100 mg/kg, or from about 50 mg/kg to
about 75 mg/kg, or about 65 mg/kg. The method can include waiting a
certain resting period for the anesthesia to take effect. By way of
example, the resting period can be from about 20 minutes to about
30 minutes. The sodium pentobarbital can remain in effect for a
certain period, e.g., up to 60 minutes, up to 90 minutes, up to 2
hours, or up to 2.5 hours.
[0056] With continued reference to FIG. 3, the method 300 can
further include providing focused ultrasound to the brain of the
subject 303. The focused ultrasound have various ultrasound
parameters. For example, and as embodied herein, ultrasound
parameter can include at least one of the frequency, the target
area, the acoustic pressure, and/or the duty cycle of the focused
ultrasound. The focused ultrasound can have a frequency from about
1 MHz to about 5 MHz, or from about 1 MHz to about 3 MHz, or from
about 1 MHz to about 2 MHz, or as embodied herein, of about 1.9
MHz. Additionally, and as embodied herein, the focused ultrasound
can have a target area that is from about 0.5 mm to about 5 mm in
the lateral direction and from about 2 mm to about 20 mm in the
axial direction.
[0057] The focused ultrasound can be targeted at a location within
the brain of the subject. Particular regions of the brain can
correspond to certain physical responses, and thus the focused
ultrasound can be targeted at a particular location to evoke a
particular physical response. For example, the focused ultrasound
can be targeted at locations within the cortical and subcortical
regions of the brain, e.g., the primary motor cortex, primary
somatosensory cortex, superior colliculus, locus coeruleus,
hippocampus, abducens nucleus, medial longitudinal fasciculus.
Additionally, the focused ultrasound can be provided at a certain
acoustic pressure in order to evoke the response, which can depend
at least in part, e.g., on the type of physical response and the
location within the brain. The acoustic pressure to evoke a
physical response can be referred to as the "threshold acoustic
pressure." The threshold acoustic pressure can be determined using
the techniques described herein.
[0058] As embodied herein, the method can include providing a
focused ultrasound having a certain acoustic pressure to a location
within the brain of the subject to evoke a physical response
corresponding to that location. The acoustic pressure can be
greater than or equal to the threshold acoustic pressure to evoke
the physical response at that location.
[0059] With further reference to FIG. 3, the method 300 can include
measuring one or more vital signs of the subject 304. For example,
the heart rate, respiratory rate, body temperature, body motion,
and/or blood pressure of the subject can be measured, e.g., using a
vital signs monitor as described above. Measuring the vital signs
of the subject can occur before, during, and/or after providing
focused ultrasound to the brain of the subject 303.
[0060] For example, and as embodied herein, the measured vital
sign(s) of the subject can be used to detect whether the subject
has been fully anesthetized. As such, the focused ultrasound can be
provided after the subject has been fully anesthetized. By way of
example, and not limitation, the subject can be considered fully
anesthetized when its heart rate and/or respiratory rate are below
a threshold, and as embodied herein, the threshold can depend on
the characteristics of the subject, e.g., the age, species, or any
other suitable characteristics of the subject. For example, and as
embodied herein, a mouse subject can be considered fully
anesthetized when its heart rate is below 200 beats per minute
(bpm) and/or its respiratory rate is below 70 breaths per minute
(brpm).
[0061] Additionally or alternatively, the measured vital sign(s) of
the subject can be used to monitor the bodily function of the
subject while providing focused ultrasound. In this manner, the
method can detect any changes in the bodily function of the subject
during brain stimulation. The measured vital sign(s) can be used to
detect any irregularities in the subject that may have been caused
by the brain stimulation.
[0062] In addition, or as a further alternative, the measured vital
sign(s) of the subject can be used to determine the status of the
subject after providing the focused ultrasound. For example,
measuring the vital signs can be used to determine whether the
brain stimulation has resulted in any long-term changes in bodily
function.
[0063] With further reference to FIG. 3, the method 300 can include
measuring a physical response of the subject 305. For example, and
as embodied herein, a physical response can include a body and/or
eye movement and/or pupil dilation. By way of example, and not
limitation, a body movement can include front or hind limb, paw,
hand, or leg movement and/or tail movement or rotation. The
physical response can be measured directly and/or with the aid of a
camera.
[0064] For example, and as embodied herein, measuring the physical
response can include recording the physical response using a
camera. For example, and not limitation, and as described above,
eye movement and/or pupil dilations can be recorded using a
monochrome camera and body movements, e.g., limb movement, paw
movement, or tail movement, can be recorded using a digital
camera.
[0065] As discussed above, focused ultrasound imparts a certain
acoustic pressure onto the brain of the subject, which can
influence acoustic cavitation activity. Thus, in certain aspects,
the method can include monitoring acoustic cavitation activity in
the brain of the subject. Monitoring acoustic cavitation activity
within the brain of the subject can permit acoustic pressure of the
focused ultrasound to be properly calibrated to avoid adverse
effects. Exemplary techniques and systems for monitoring acoustic
cavitation activity are disclosed at International Patent
Application Publication Nos. WO2011035312A1 and WO2010030819A1 and
U.S. Patent Application Publication Nos. 2015/0065871, 2015/0045724
and 2014/0114216, each of which incorporated by reference herein in
its entirety.
[0066] As embodied herein, monitoring acoustic cavitation activity
can include detecting cavitation emissions to determine the
presence and/or location of acoustic cavitation. By way of example,
and not limitation, a transducer can passively receive such
cavitation emissions. Certain cavitation emissions can indicate the
presence of cavitation. For example, broadband emissions can
indicate the presence of inertial cavitation, whereas harmonic,
subharmonic, or ultraharmonic emissions can indicate the presence
of stable cavitation. Methods can further include modulating an
ultrasound parameter, e.g., the frequency, target area, acoustic
pressure, and/or duty cycle, of the focused ultrasound after
determining the type or presence of acoustic cavitation
activity.
[0067] The systems and techniques of the disclosed subject matter
provide advantages over certain existing technologies. For purpose
of illustration and not limitation, advantages of the systems and
techniques described herein include high target specificity,
non-invasive procedures, and improved methods of anesthetizing a
subject. Additionally, the systems and techniques described herein
provide non-invasive techniques for brain stimulation having
applications in neuroscience, including brain mapping, medical
treatment, and therapy. For example and without limitation, the
systems and techniques disclosed herein can be used in the
treatment of chronic pain, Parkinson's disease, depression,
obesity, epilepsy, obsessive-compulsive disorder (OCD),
schizophrenia, and essential tremor. Additionally, the systems and
techniques disclosed herein can be used during high-intensity
focused ultrasound (HIFU) treatment to provide increased target
specificity while avoiding sensory effects, e.g., paresthesia of
the lips and/or fingers.
Examples
[0068] For purpose of illustration and confirmation of the
disclosed subject matter, and without limitation, exemplary
techniques for non-invasive brain stimulation are further
illustrated with reference to the examples below. Although the
exemplary techniques are described with respect to a mouse subject,
the techniques described herein can be applied to perform brain
stimulation in any subject, including mammals, such as humans.
Example 1
[0069] This exemplary technique was performed on C57BL-6 mice. The
mice were anesthetized with an intraperitoneal injection of sodium
pentobarbital (65 mg/kg). The animals remained in the cage for a
period of 20 to 30 minutes to allow the anesthesia to take effect.
The effect of the anesthesia was assessed by pedal reflex and vital
signs recordings. The animals were shaved (on the scalp and on the
throat) and positioned in a 3-axes stereotaxic frame (e.g., David
Kopf Instruments, Tujunga, Calif., USA) using ear bars and a teeth
holder. Oxygen was delivered continuously via a mask.
[0070] A vital signs monitor (e.g., MouseOx Plus, Starr Life
Sciences Corp., Torrington, Conn., USA) was placed on the throat of
the animals to assess their heart rates and respiratory rates
before and during sonication. Focused ultrasound was applied when
the heart rate and respiratory rate were less than 200 bpm and 70
brpm. During sonication, the heart rate and respiratory rate were
respectively less than 400 bpm and 120 brpm.
[0071] A single-element focused ultrasound transducer was driven by
a function generator (e.g., 33220A, Agilent Technologies, Palo
Alto, Calif., USA), through a 50 dB power amplifier (e.g., ENI
Inc., Rochester, N.Y., USA). The sonications were carried out at
1.9 MHz with a 50% duty cycle, a pulse repetition frequency of 1
kHz, a sonication duration of 1 second and interstimulus interval
of 1 second, and was repeated 10 times for each sonication spot.
The transducer was fixed in a 3D positioning system (e.g., VXM,
Velmex Inc, New York, N.Y., USA) and moved randomly within a grid
of 8 mm by 8 mm with a resolution of 1 mm. The center of the grid
was placed at anteroposterior (AP)=-2 mm and mediolateral (ML)=0 mm
from lambda.
[0072] The vital signs were recorded during the sonication using an
acquisition board (e.g., MP150, Biopac Systems Inc., Santa Barbara,
Calif., USA), which was triggered by the same function generator
used to drive the ultrasound transducer. Some paw movements were
observed in the animals. Videos of the evoked paw movements were
recorded by cameras positioned on the backs of the animals (e.g.,
model C920, Logitech, CA, USA and model EOS Rebel T3i, Canon,
Melville, N.Y., USA). Additionally, pupil dilation were observed,
and recorded using a second camera (e.g., Model DMK 23U618, The
Imaging Source GmbH, Bremen, Germany), which was positioned beside
the mice and trained on the right eye. Muscle activity was measured
using an electromyography (EMG) system (e.g., BN-EMG2, Biopac
Systems Inc., Santa Barbara, Calif., USA) with 26-gauge electrodes
placed 5 mm apart at the biceps femoris of both hind limbs and the
ground electrode on the tail.
[0073] The animals remained under anesthesia for about 90 minutes,
and were not responsive to pinches at any time. At approximately 30
minutes after the anesthesia took effect (e.g., between 30 minutes
and 60 minutes after injection), no motor response was observed in
certain animals. Thereafter, the first signs of evoked motor
responses and pupil dilations were observed. The working time
lasted about 60 minutes after this first stage of anesthesia.
[0074] Contralateral muscle activity recorded on EMG signals was
observed when ultrasound neurostimulation was carried out at +2 mm
of lambda and .+-.2 mm lateral of the midline. The minimum pressure
to elicit movements was 1.45 MPa, which was calibrated using an
excised skull. Increasing the pressure increased the success rate
from 20% (at 1.45 MPa) to 70% (at 1.79 MPa). The estimated latency
was 266.+-.37 milliseconds. FIG. 4A is a diagram illustrating the
EMG of the right hind limb, showing contralateral responses at
different acoustic pressures. FIG. 4B illustrates the trend line of
the success rate across several acoustic pressures ranging from 1.1
MPa to 1.8 MPa. FIG. 4C depicts two series of video frames showing
contralateral paw movement. The left-most series shows left paw
movement when sonicating at anterior/posterior (AP)=+2 mm from
lambda and medial/lateral (ML)=+2 mm. The right-most series shows
right paw movement when sonicating at AP=+2 mm from lambda and
ML=-2 mm.
[0075] Additional paw movements were observed and recorded on
video. The transducer being was successfully used to sonicate first
the left side of the brain and, immediately after, the opposite
side, both of which elicited contralateral paw movements. Further,
ipsilateral hind limb movements were elicited when sonications were
carried out at 0 mm from lambda and .+-.3 mm lateral of the
midline. Additionally, tail movements were observed. The diagram of
FIG. 5A depicts a grid, showing responses with sonications at
AP=+/-2 mm from lambda and ML=+/-2 mm. The diagram of FIG. 5B
depicts a grid, showing responses with sonications at AP=+/-1 mm
from lambda and ML=+/-3 mm. The black squares in the center
represent the lambda and the bregna. Darker squares indicate
ipsilateral movement, while lighter squares indicate contralateral
movement. The circles indicate the areas of the brain where
neuromodulation was recorded.
[0076] Using the second camera, pupil dilations and eye movements
were observed and recorded on video. For example, FIG. 6A depicts
still images from the video recording. The top two images of FIG.
6A show pupil dilation of up to 20% and the bottom two images show
eye movement. These pupil dilation and eye movements were observed
when sonications were carried out at AP=0 mm from lambda and ML=+2
mm. Additionally, the acoustic pressure thresholds varied depending
on the placement of the sonications. For example, FIG. 6B
represents pupil dilation at different acoustic pressures for
sonications carried out at AP=0 mm from lambda and ML=.+-.2 mm, as
well as sonications carried out at AP=-1 mm from lambda and
ML=.+-.0.8 mm. As shown, for example, in FIG. 6B, the sonications
performed at AP=0 mm from lambda and ML=.+-.2 mm evoked pupil
dilation at a lower acoustic pressure compared to the sonications
performed at AP=-1 mm from lambda and ML=.+-.0.8 mm.
[0077] FIG. 7A is a diagram illustrating the sonication locations
where pupil dilation and/or eyeball movement were observed, and the
corresponding threshold acoustic pressure. Various eye
motor-related and anxiety-related regions of the brain (e.g., the
superior colliculus, the hippocampus, the superior colliculus, the
locus coeruleus, the abducens nucleus, and the medial longitudinal
fasciculus) were swept by focused ultrasound having a target area
of 8.73 mm long with a 1.02 mm diameter. FIG. 7B is a series of
diagrams illustrating the maximum pupil dilation at various
acoustic pressures for sonications at AP=0 mm from lambda and
ML=.+-.2 mm, i.e., the superior colliculus (top series of images),
as well as sonications at AP=-1 mm from lambda and ML=.+-.0.8 mm,
e.g., the locus coeruleus (bottom series of images). The superior
colliculus elicited pupil dilation at a lower threshold (e.g., 1.20
MPa). Other regions, e.g., those that have been linked to anxiety
such as the hippocampus and locus coeruleus, elicited pupil
dilations at higher acoustic pressure thresholds (e.g., greater
than 1.8 MPa).
[0078] Whole brain histological examinations using hematoxylin and
eosin (H&E) staining for general histology showed no brain
damage in five mice that were sonicated at 1.93 MPa at AP=+2 mm
from lambda and ML=+2 mm and again with 3.0 MPa at AP=+2 mm from
lambda and ML=-2 mm, indicating that the techniques described
herein do not cause neurovascular or neuronal damage.
Example 2
[0079] This exemplary technique uses various forms of focused
ultrasound while monitoring the acoustic pressure in the brain of
the subject. Six C57BL-6 mice were prepared for sonication as
described herein in Example 1.
[0080] Various forms of focused ultrasound were delivered to the
mice. For the first mouse, focused ultrasound was delivered as a
continuous wave. A burst of 7 cycles was delivered to the second
mouse. The third mouse received a high pulse-repetition frequency
burst, i.e., having a pulse-repetition frequency of 50 kHz and a
duty cycle of 20% for five cycles. The remaining mice received a
focused ultrasound chirp, which was a linearly, quadratically, or
logarithmically swept-frequency cosine signal.
[0081] FIG. 8A depicts the acoustic pressure fields within the
brain of each mouse after each form of focused ultrasound. The
ultrasound was focused at AP=+6 mm, ML=2.2 mm, and a 3 mm depth.
FIG. 8B depicts the acoustic pressure along the axial path of the
focused ultrasound for the continuous wave, the high
pulse-repetition frequency burst, and the quadratic chirp. The
lower plot in FIG. 8B shows the acoustic impedance to indicate the
location of the skull. Such techniques can be used to monitor the
acoustic pressure with the brain of the subject, and to determine
the appropriate form of ultrasound for the desired application.
[0082] In addition to the various embodiments depicted and claimed,
the disclosed subject matter is also directed to other embodiments
having other combinations of the features disclosed and claimed
herein. As such, the particular features presented herein can be
combined with each other in other manners within the scope of the
disclosed subject matter such that the disclosed subject matter
includes any suitable combination of the features disclosed herein.
The foregoing description of specific embodiments of the disclosed
subject matter has been presented for purposes of illustration and
description. It is not intended to be exhaustive or to limit the
disclosed subject matter to those embodiments disclosed.
[0083] It will be apparent to those skilled in the art that various
modifications and variations can be made in the methods and systems
of the disclosed subject matter without departing from the spirit
or scope of the disclosed subject matter. Thus, it is intended that
the disclosed subject matter include modifications and variations
that are within the scope of the appended claims and their
equivalents.
* * * * *