U.S. patent application number 16/211143 was filed with the patent office on 2019-04-11 for devices and methods for modulating brain activity.
The applicant listed for this patent is Arizona Board of Regents on behalf of Arizona State University. Invention is credited to WIlliam James TYLER.
Application Number | 20190105517 16/211143 |
Document ID | / |
Family ID | 43970342 |
Filed Date | 2019-04-11 |
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United States Patent
Application |
20190105517 |
Kind Code |
A1 |
TYLER; WIlliam James |
April 11, 2019 |
DEVICES AND METHODS FOR MODULATING BRAIN ACTIVITY
Abstract
Devices and methods for brain modulation are provided herein. A
device may comprise a body and components for activating the brain.
Such components include ultrasound transducers. The devices are
used to provide ultrasound waves to brain structures in a subject
wearing a device for methods to treat traumatic brain injury,
affect postural control, affect wakefulness, attention, and
alertness, to provide memory control, to alter cerebrovascular
hemodynamics, to minimize stress, and to reinforce behavioral
actions.
Inventors: |
TYLER; WIlliam James;
(Tempe, AZ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Arizona Board of Regents on behalf of Arizona State
University |
Scottsdale |
AZ |
US |
|
|
Family ID: |
43970342 |
Appl. No.: |
16/211143 |
Filed: |
December 5, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15014805 |
Feb 3, 2016 |
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16211143 |
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13453179 |
Apr 23, 2012 |
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15014805 |
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PCT/US2010/055527 |
Nov 4, 2010 |
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13453179 |
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61257915 |
Nov 4, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 7/00 20130101; A61N
2007/0026 20130101; A61N 2007/0091 20130101; A61N 2007/0078
20130101; A61B 8/0816 20130101; A61B 5/0476 20130101; A61B 5/04008
20130101 |
International
Class: |
A61N 7/00 20060101
A61N007/00; A61B 5/04 20060101 A61B005/04; A61B 5/0476 20060101
A61B005/0476 |
Claims
1. An ultrasonic method for modulating brain activity of a user,
the method comprising: stimulating one or more brain circuits of
the user by delivering, from a wearable interface, transcranial
ultrasound at an intensity of between 0.0001 mW/cm.sup.2 to about
100 W/cm.sup.2 and an ultrasound frequency in a range of about 0.02
MHz to about 10.0 MHz, wherein the wearable interface is worn on
the user's head and includes at least one ultrasonic transducer;
and monitoring the user's brain activity during the stimulation of
the one or more brain circuits.
2. The method of claim 1, further comprising determining, in a
controller coupled to the wearable interface, a waveform emitted by
the at least one ultrasound transducer.
3. The method of claim 1, wherein monitoring comprises any one of
photoacoustic tomography, functional near-infrared spectroscopy
(fNIRS), magnetoencepholography (MEG), and electroencephalography
(EEG).
4. The method of claim 1, wherein monitoring comprises monitoring
the user's brain activity from one or more sensors on the wearable
interface.
5. The method of claim 1, wherein monitoring comprises detecting
specific thalamocortical oscillations.
6. The method of claim 1, further comprising transmitting
information between the wearable interface and one or more remote
processors.
7. The method of claim 1, further comprising transmitting
instructions to the wearable interface to modulate one or more of
an ultrasound waveform and a frequency, intensity or waveform
characteristic to adjust the ultrasound being delivered to the user
based on the user's brain activity.
8. The method of claim 1, wherein the ultrasound intensity at the
one or more brain circuits is in a range of 10 mW/cm.sup.2 to 500
mW/cm.sup.2.
9. The method of claim 1, wherein the ultrasonic transducer is
configured to deliver ultrasound energy with a pulse duration in
the range from 100 to 10000 microseconds.
10. The method of claim 9, wherein the pulse duration is a variable
pulse duration.
11. The method of claim 1 further comprising providing chemical,
pharmaceutical, electrical, magnetic or light therapy before,
during, or after ultrasound is provided.
12. The method of claim 1, wherein ultrasound is delivered to the
brain to attenuate or terminate seizure activity.
13. The method of claim 1 wherein stimulating one or more brain
circuits comprises applying ultrasound to a brain region, wherein
the brain region comprises one of: a hippocampal formation,
hippocampus proper, amygdala, thalamus, cerebellum, striatum,
entorhinal cortex, perirhinal cortex, cerebral cortex, prefrontal
cortex, auditory cortex, visual cortex, somatosensory cortex, motor
cortex, locus coeruleus, a paraventricular nucleus of the
hypothalamus (PVN), adrenal medulla, a pons, basal forebrain, a
hypothalamus, tuberomamillary nuclei, basolateral amygdala, ventral
tegmental area, medial forebrain bundle, a dorsal raphe nucleus, a
mesolimbic pathway, a mesocortical pathway, connections between the
medial forebrain bundle (MFB) and the nucleus accumbens, an
anterior cingulate cortex (ACC), basolateral amygdala (BLA), or a
ventral tegmental area (VTA), a vestibular system, aural region,
visual region, olfactory region, proprioceptive region, afferents
or efferents of the regions, or combinations thereof.
14. The method of claim 1, further comprising identifying the brain
structure to be activated.
15. The method of claim 1, further comprising directing at least
one ultrasound transducer to a brain structure to be activated.
16. The method of claim 1, further comprising providing pulsed
ultrasound waveforms.
17. The method of claim 1, further comprising providing continuous
ultrasound waveforms.
18. An ultrasonic method for modulating brain activity of a user,
the method comprising: stimulating one or more brain circuits of
the user by delivering, from a wearable interface, transcranial
ultrasound at an intensity of between 0.0001 mW/cm.sup.2 to about
100 W/cm.sup.2 and an ultrasound frequency in a range of about 0.02
MHz to about 10.0 MHz, wherein the wearable interface is worn on
the user's head and includes at least one ultrasonic transducer;
and monitoring the user's brain activity during the stimulation of
the one or more brain circuits; and modulating one or more of the
ultrasound frequency, intensity, a waveform characteristic, or a
position of the one or more ultrasonic transducers to adjust the
ultrasound being delivered to the user based on the user's brain
activity.
19. An ultrasonic method for modulating brain activity of a user,
the method comprising: stimulating one or more brain circuits of
the user by delivering, from a wearable interface, transcranial
ultrasound at an intensity of between 0.0001 mW/cm.sup.2 to about
100 W/cm.sup.2 and an ultrasound frequency in a range of about 0.02
MHz to about 10.0 MHz, wherein the wearable interface is worn on
the user's head and includes at least one ultrasonic transducer;
and monitoring the user's brain activity during the stimulation of
the one or more brain circuits with any one of: photoacoustic
tomography, functional near-infrared spectroscopy (fNIRS),
magnetoencepholography (MEG), and electroencephalography (EEG); and
modulating one or more of the ultrasound frequency, intensity, a
waveform characteristic, or a position of the one or more
ultrasonic transducers to adjust the ultrasound being delivered to
the user based on the user's brain activity.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/014,805, filed Feb. 3, 2016, now U.S.
Patent Application Publication No. 2016/0220850, which is a
continuation application of U.S. patent application Ser. No.
13/453,179, filed Apr. 23, 2012, now U.S. Patent Application
Publication No. 2012/0289869, which is a continuation of
PCT/US2010/055527, filed Nov. 4, 2010, which claims the benefit of
U.S. Provisional Patent Application No. 61/257,915, filed Nov. 4,
2009, the contents of which are incorporated herein in their
entirety.
FIELD
[0002] The present invention is directed to devices and methods for
modulating brain activity using ultrasound, particularly devices
and methods that provide ultrasound wavelengths to neural
tissues.
BACKGROUND
[0003] Ultrasound (US) has been used for many medical applications,
and is generally known as cyclic sound pressure with a frequency
greater than the upper limit of human hearing. The production of
ultrasound is used in many different fields, typically to penetrate
a medium and measure the reflection signature or to supply focused
energy. For example, the reflection signature can reveal details
about the inner structure of the medium. A well known application
of this technique is its use in sonography to produce a picture of
a fetus in a womb. There are other applications which may provide
therapeutic effects, such as lithotripsy for ablation of kidney
stones or high-intensity focused ultrasound for thermal ablation of
brain tumors.
[0004] A benefit of ultrasound therapy is its non-invasive nature.
Neuromodulation techniques such as deep brain stimulation (DBS) and
repetitive transcranial magnetic stimulation have gained attention
due to their therapeutic utility in the management of numerous
neurological/psychiatric diseases. These methods for stimulating
neuronal circuits have been demonstrated to hold promise for the
treatment of such diseases and disorders as Parkinson's,
Alzheimer's, coma, epilepsy, stroke, depression, schizophrenia,
addiction, neurogenic pain, cognitive/memory dysfunction, and
others.
[0005] What is needed are devices that can provide effective
ultrasound therapy to neural tissue, such as the brain, for
continuous or short-term applications. Devices that could provide
treatments shortly after injury to neural tissue would also be
desirable.
SUMMARY OF THE DISCLOSURE
[0006] The present invention comprises methods and devices for
modulating the activity or activities of the brain in humans and
other organisms. Methods of the present invention comprise
application of ultrasound (US) to the brain to affect the brain and
modulate the brain's activities. Devices of the present invention
comprise an ultrasound device operably attached to or associated
with a head containing a brain, the ultrasound device may comprise
one or more components for generating ultrasound waves, such as
ultrasonic emitters, transducers, piezoelectric transducers,
piezopolymer transducers, composite transducers, gas matrix
piezoelectric transducers, CMUTs (capacitive micromachined
ultrasound transducers), and may be provided as single or multiple
transducers or in array configurations. Ultrasound transducer
elements may also comprise focusing lenses such as acoustic
hyperlenses or metamaterials when providing ultrasound waves to
affect brain regions. The lenses or metamaterials are useful for
brain regions with a size below wavelength diffraction limits of
some ultrasound used to treat the brain targets. Optionally, the
ultrasound device may comprise power sources, components for
transmitting or receiving data, components for remote activation of
the ultrasound transducers or other components, global positioning
components or other location or tracking components. The ultrasound
waves provided may be of any shape, and may be focused or
unfocused, depending on the application desired. The ultrasound may
be at an intensity in a range of about 0.0001 mW/cm.sup.2 to about
100 W/cm.sup.2 and an ultrasound frequency in a range of about 0.02
to about 10.0 MHz at the site of the tissue to be modulated.
[0007] Methods of the present invention comprise modulating brain
activity by providing ultrasound waves to the brain, or particular
brain regions, or brain efferents or brain afferents of one or more
regions, or combinations thereof, at an effective intensity and for
an effective time range so that the brain activity is altered. It
is contemplated that an ultrasound device that is operably attached
to the subject, such as an ultrasound device comprising a helmet
comprising at least ultrasound generating components, is used to
provide the ultrasound treatments described herein. Such ultrasound
methods and treatments described herein may also be provided to a
subject using ultrasound components that are not incorporated into
a wearable device, but are attached directly to the subject or are
at some physical distance from the subject.
[0008] Methods comprise modulating brain activity in a subject by
providing an effective amount of at least ultrasound waves to one
or more brain structures, for example, by using an ultrasound
device, a BRI (Brain Regulation Interface), disclosed herein. A
method comprises treating or ameliorating the effects of trauma to
the brain by providing an effective amount of ultrasound to a brain
region that has received trauma or to a surrounding or remote brain
area that may be affected by the trauma. Such a method can reduce
the secondary effects of traumatic brain injury. A method comprises
impeding or inhibiting memory formation in a subject. A method
comprises facilitating the formation of memories. A method of the
present invention comprises altering a stress response in a
subject. A method comprises activating arousal brain areas to
increase alertness, awareness, attention or long-term wakefulness
in a subject. A method comprises activation of reward pathways in a
subject. Methods of the present invention comprise activation of
reward pathways, activating sensory or motor brain regions, and
methods for treating humans and animals. Methods of the present
invention may comprise combinations of the methods taught herein,
and wherein ultrasound is provided by an ultrasound device
disclosed herein. Methods disclosed herein may be accomplished by
ultrasound devices known to those skilled in the art.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] The accompanying drawings, which are incorporated in and
constitute a part of this specification, illustrate several
embodiments and together with the description illustrate the
disclosed compositions and methods.
[0010] FIG. 1A-E are diagrams that illustrate exemplary systems and
devices for modulating brain activity. 1A shows device comprising
ultrasound transducers, 1B shows a cross-section of the body
portion and the transducers of 1A. FIG. 1C shows a chassis-type
body for attachment of transducers, FIG. 1D shows the chassis
attached within a helmet, and FIG. 1E shows the chassis positioned
on a subject.
[0011] FIG. 2 shows an exemplary embodiment of an ultrasound device
of the present invention comprising components that provide both
ultrasound and electromagnetic energy to the brain.
[0012] FIG. 3 illustrates an exemplary embodiment of a pulsing
strategy used to generate ultrasound stimulus waveforms that
provide ultrasound energy to the brain or neural tissue for
modulation of activity.
[0013] FIG. 4 is a flow chart showing a brain regulation interface
(BRI) device of the present invention and exemplary components that
the device may comprise.
[0014] FIG. 5 illustrates an exemplary ultrasound device comprising
a plurality of components for modulation of brain activity, for
monitoring brain activity and for transmitting and receiving
information about the subject's physical location and/or vital
statistics such as blood pressure, heart rate, respiration rate,
and/or blood oxygenation levels. The illustration also illustrates
components that may be used with a brain regulation interface (BRI)
device including ultrasound transducers, magnetic transducers,
light emitting devices, and communication devices.
[0015] FIG. 6 illustrates an exemplary ultrasound device (BRI)
comprising locational or global positioning components.
[0016] FIG. 7 illustrates an exemplary ultrasound device having
movable or rotatable components, such as a movable or rotatable
ultrasound transducer.
[0017] FIG. 8A-F illustrates exemplary arrangements of phased array
transducers.
[0018] FIG. 9A-B are graphs showing the energy produced in the
conversion of mechanical energy to electrical energy using
piezopolymers.
[0019] FIG. 10A-B illustrate exemplary examples of an acoustic
hyperlens (A) and such an acoustic hyperlens or metamaterials
attached to ultrasound transducers and an ultrasound device (B) for
achieving subdiffraction spatial resolutions in treating very small
brain regions with ultrasound.
[0020] FIG. 11A-C shows ultrasound stimulus waveforms for the
transcranial stimulation of intact brain circuits (A) Illustration
of the method used to construct and transmit pulsed US waveforms
into the intact mouse brain. Two function generators were connected
in series and used to construct stimulus waveforms. An RF amplifier
was then used to provide final voltages to US transducers. (B) An
example low-intensity US stimulus waveform is illustrated to
highlight the parameters used in their construction. The acoustic
intensities generated by the illustrated stimulus waveform are
shown in the yellow box. (C) Projected from a transducer surface to
the face of a calibrated hydrophone, the acoustic pressure
generated by a 100 cycle pulse of 0.5 MHz ultrasound is shown
(left). The pressure generated by the same US pulse when
transmitted from the face of the transducer through a fresh ex vivo
mouse head to regions corresponding to motor cortex (0.8 mm deep)
is shown (right).
[0021] FIG. 12A-D shows low-intensity pulsed US stimulates neuronal
activity in the intact mouse motor cortex (A) The coronal brain
section shows an electrolytic lesion illustrating a recording site
from which US-evoked neuronal activity was acquired in M1. (B)
(Top) Raw (black) and average (gray; 25 trials) US-evoked MUA
recorded from M1 cortex in response to the delivery of pulsed US
waveforms. (Middle) Addition of TTX to the cortex reduced synaptic
noise and attenuated US-evoked MUA. (Bottom) Raw control (black),
average control (green), and average TTX (red) LFP recorded from M1
cortex in response to 25 US stimulus waveforms delivered every 10
s. (C) The spike raster plot illustrates the increase of cortical
spiking as a function of time in response to 25 consecutive US
stimulation trials. (D) A poststimulus time histogram illustrates
the average MUA spike count recorded 500 ms prior to and 500 ms
following the delivery of US stimulus waveforms to motor cortex.
Data shown are mean.+-.SEM.
[0022] FIG. 13A-E shows transcranial stimulation of motor cortex
with pulsed US functionally activates descending corticospinal
motor circuits in intact mice. (A) Raw (left) and full-wave
rectified (FWR; right) EMG traces obtained for a spontaneous muscle
twitch (top) and average (ten trials) increase in muscle activity
produced by transcranial US stimulation of motor cortex
(bottom).The duration of the US stimulus wave-form (black), average
US-evoked EMG trace (gray), and EMG integral (gray dashed line) are
shown superimposed at lower right. (B) EMG response latencies (top)
and amplitudes (bottom) recorded from the left triceps brachii in
response to right motor cortex stimulation are plotted as a
function of trial number repeated at 0.1 Hz. Individual US-evoked
raw EMG traces are shown for different trials (right). (C) EMG
failure probability histograms are shown for four progressively
increasing stimulus repetition frequencies (left;). Raw US-evoked
EMG traces are shown for two different stimulus repetition
frequencies (right). Data shown are mean.+-.SEM. (D) Raw EMG traces
illustrating application of TTX to the motor cortex blocks
US-evoked descending corticospinal circuit activity. (E) Raw
(black) and averaged (gray; ten trials) temperature recordings
obtained from motor cortex in response to transmission of US
waveforms with short pulse durations (PD) used in stimulus
waveforms (top). Similarly, temperature recordings of cortex in
response to waveforms having a PD .about.100 times longer than
those used in stimulus waveforms (middle and bottom).
[0023] FIG. 14A-C shows interactions of the acoustic frequency and
acoustic intensity of stimulus waveforms on descending
corticospinal circuit activation. (A) Maximum-peak normalized
(Norm) US-evoked EMG amplitude histograms are plotted for the four
US frequencies used in the construction of stimulus waveforms. Data
shown are mean.+-.SEM. (B) Mean maximum-peak normalized US-evoked
EMG amplitudes are plotted as a function of US intensities
(/.sub.SPTA) produced by 20 distinct stimulus wave-forms (see Table
S1). (C) The interaction between US intensity (/.sub.SPTA) and US
frequency is plotted as a function of maximum-peak normalized EMG
amplitudes (pseudocolor LUT).
[0024] FIG. 15A-E shows spatial distribution of neuronal activation
triggered by transcranial pulsed US. (A) Diagrams showing the
anatomical locations where transcranial pulsed US was delivered
through an acoustic collimator (green; d=2 mm) and the brain volume
subsequently reconstructed (blue) to develop functional activity
maps using antibodies against c-fos. (B) Light micrographs showing
c-fos activity in a coronal brain section at different locations
inside (i) and outside (ii and iii) the US transmission path. (C) A
psuedocolored map of c-fos+ cell densities in 250.times.250 .mu.m
regions is shown for a reconstructed coronal section obtained from
within the stimulus zone. Small regions inside (i) and outside (ii
and iii) the US brain transmission path are highlighted and contain
c-fos density data obtained from the corresponding images shown in
(B). (D) Similar psuedocolored c-fos activity maps are shown for
coronal brain sections rostral (left) and caudal (right) to the
stimulated brain regions. (E) The line plots illustrate the mean
c-fos+ cell densities observed along the rostral-caudal axis of
reconstructed brain volumes for stimulated (black) and
contralateral control hemispheres (gray). Regions of cortex within
the stimulation zone are indicated in red. Data shown are
mean.+-.SEM.
[0025] FIG. 16A-D shows FIG. 7. transcranial stimulation of the
intact mouse hippocampus with pulsed ultrasound (A) Shown is an
illustration of the geometrical configuration used for targeting
the dorsolateral hippocampus with transcranial pulsed US while
recording evoked electro-physiological responses in the dorsal
hippocampus (left). A lesion illustrates the site of an
electrophysiological recording location in the hippocampal CA1 s.p.
region (right). (B) Raw (black) and average (cyan) hippocampal CA1
LFP recorded in response to 50 consecutive US stimulation trials
(left). A pseudocolored spike-density plot illustrates the increase
in CA1 s.p. spiking as a function of time in response to 50
consecutive pulsed US stimuli delivered at 0.1 Hz (right). (C) An
individual recording trace of CA1 s.p. extracellular activity in
response to a pulsed US waveform is shown in its wideband (top),
gamma (middle), and SWP (bottom) frequency bands. An expanded 250
ms region of the SWP trace (red) illustrates SWP "ripples". (D)
Confocal images illustrating BDNF (green) expression in the CA1
s.p. (top) and CA3 s.p. (bottom) regions of hippocampus from
contralateral control (left) and stimulated hemispheres (right).
Histograms (far right) illustrate the significant increase in the
density of BDNF+ puncta triggered by transcranial US stimulation
for the CA1 s.p. (top) and CA3 s.p. (bottom) regions of
hippocampus. Data shown are mean.+-.SEM.
[0026] FIG. 17A-B shows the results of using ultrasound to modify
cognitive performance. (A) Shows the stimulus strategy used
stimulating the hippocampi of mice with transcranial pulsed
ultrasound prior to their training (four trials per day for three
consecutive days) on a spatial learning task the Morris Water Maze.
(B) Task learning acquisition curves show a decreasing mean
platform escape latency across days for both the sham treated and
US stimulated mice (left). As can be seen by the line plot (left),
mice stimulated with US (red) just prior to training learned the
task slower compared to sham treated controls (black) as indicated
by their slower acquisition rates or slower decreasing escape
latency times. The data showing mean escape latencies for the
treatment groups (US stimulated and sham control) are shown for the
four individual trials across the three training days. The line
plot (middle) shows an increase in the escape latency observed from
trial 4 on day 1 to trial 1 on day 2 for US stimulated mice (red)
compared to sham controls (black). These data illustrate that mice
stimulated with US have more pronounced "forgetting" or disrupted
memory consolidation processes compared to sham treated controls,
which retain escape latencies across the .about.22 hour delay
between the end of trial 4 on day 1 and the beginning of trial 1 on
day 2. On the day following three days of Morris Water Maze
training, mice underwent a test in which the escape platform was
removed from the maze. The time spent searching in the water maze
quadrant where the escape platform had been located on training
days was quantified and is shown in the histogram (right). The
shorter times spent in the correct quadrant for US stimulated mice
compared to sham controls indicates that US stimulation occurring
at times near the acquisition of information (learning; prior to
Morris Water Maze training in this case) can disrupt the memory or
consolidation of that information.
[0027] FIG. 18A-18B shows the results of using ultrasound to
enhance cognitive processes. (A) A strategy is illustrated by which
naive mice had their hippocampi stimulated with transcranial pulsed
US for 5 minutes per day for 7 consecutive days prior to beginning
training on a spatial cognition task the Morris Water Maze. As
illustrated, mice were then trained on a Morris Water Maze task
without receiving further US stimulation before being tested on the
Morris Water Maze task. (B) The line plot (left) shows that chronic
brain stimulation (7 days in this case) with transcranial pulsed US
can enhance learning as indicated by the faster task acquisition
rates or faster decreasing escape latency times on the Morris Water
Maze for US stimulated mice (red) compared to sham treated controls
(black). On the day following three days of Morris Water Maze
training, mice underwent a test in which the escape platform was
removed from the maze. The time spent searching in the water maze
quadrant where the escape platform had been located on training
days was quantified and is shown in the histogram (right). The
longer times spent in the correct quadrant for US stimulated mice
compared to sham controls indicates that chronic US stimulation not
occurring at times near the acquisition of information (learning;
prior to Morris Water Maze training in this case) can enhance the
memory or consolidation of that information. Thus, depending on the
stimulation paradigm transcranial pulsed ultrasound delivered
through brain regulation devices can be used to either enhance or
impair cognitive processes such as learning and memory.
[0028] FIG. 19A-C illustrates that transcranial pulsed ultrasound
can be used to modulate brain activity to study and or treat
neurological diseases. (A) Shows EMG recordings in response to
transcranial ultrasound stimuli delivered to the brain of normal
mice in a continuous wave mode for 5 seconds. The brain activity
pattern stimulated by continuous wave transcranial ultrasound is
indicative of that observed during epileptic seizure activity. Such
seizure activity patterns are known to occur for ten seconds or
longer following the onset of a brain stimulus as shown by the EMG
traces in response to transcranial stimulation of brain tissues
with continuous wave ultrasound. Evoking such seizure activity
patterns can be helpful in studying epilepsy by mapping diseased or
prone circuits, as well as by using US to modulate brain activity
patterns to screen for pharmacological compounds or genes useful
for treating abnormal brain activity. When compared to the activity
patterns illustrated in FIGS. 12-16 produced with pulsed
ultrasound, the data in panel (A) triggered with continuous wave
ultrasound show that transcranial ultrasound can influence brain
activity in radically different manners depending on the ultrasound
stimulus waveform used and depending on the desired outcome. (B) A
mouse is shown at left immediately after being injected with kainic
acid to produce a standard model of epilepsy. EMG activity before
(top right) and after (bottom right) the onset of epileptic seizure
activity is illustrated. The EMG traces on the bottom right show
the presence of seizure activity as indicated by the increased
persistent EMG activity compared to the pre-seizure trace on the
top right. (C) EMG traces showing that brain stimulation achieved
with transcranial ultrasound can be used to terminate seizure
activity in a mouse model of epilepsy. Four different examples
illustrate the delivery of transcranial ultrasound is capable of
quickly attenuating pronounced seizure activity as indicated by the
decreasing EMG amplitude soon after the delivery of a transcranial
ultrasound stimulus waveform. Such an effect of ultrasound on
diseased brain activity can be administered manually in response to
seizures detected visually or by way of EEG or EMG activity. In
another embodiment of the present invention, the delivery of
ultrasound to the brain can be controlled automatically in response
to seizure activity detected by EEG, EMG, MEG, MRI, or other
readout of brain activity.
[0029] FIG. 20A-B show A-an exemplary embodiment for treating
peripheral nerves. The dark circles represent ultrasound
transducers for stimulating peripheral nerve structures to evoke
mechanical, thermal, or painful sensations, which are processed by
the brain and result in a change in brain activity to process the
stimulus. B-Different skin receptors making up the nervous system
are shown. These nerve structure receptors can be differentially
modulated by ultrasound to evoke different types of somatosensory
feedback cues, which are interpreted by the brain. Such sensations
can be pain, heat, cold, light touch, deep pressure, or other
mechanical sensation.
DETAILED DESCRIPTION
[0030] The present invention comprises methods and devices for
modulating the activity of the brain of humans or animals. The
methods and devices comprise use of ultrasound waves directed to
the brain in living subjects. Methods of the present invention
comprise providing an effective amount of ultrasound waves, such as
low intensity, low frequency ultrasound, low intensity ultrasound,
or other intensity or frequency ultrasound to the brain to affect
the brain and modulate the brain's activities, and to alter or
control physiological or behavioral responses by the body of the
subject.
[0031] Devices of the present invention comprise a device operably
connected to the subject comprising one or more components for
generating ultrasound waves, herein referred to as transducers, and
including but not limited to, ultrasonic emitters, transducers or
piezoelectric transducers, piezocomposite transducers,
piezopolymers, CMUTs (capacitive micromachined ultrasound
transducers), and which may be provided as single or multiple
transducers or in array configurations. The ultrasound waves
provided may be of any shape or amplitude, and may be focused or
unfocused, depending on the application desired. The ultrasound may
be at an intensity in a range of about 0.0001 mW/cm.sup.2 to about
100 W/cm.sup.2 and an ultrasound frequency in a range of about 0.02
MHz to about 10.0 MHz at the site of the cells or tissue to be
modulated.
[0032] One or more cooling components may be incorporated into the
body of the device, or may be placed on the scalp before, during or
after providing ultrasound waves to the head. A cooling component
may be ultrasound transparent, so that the waveforms, intensity
and/or frequency are not altered by the cooling component. A
cooling component may be an ice bag; a freezable container that is
chilled by placing in a cold location, such as a freezer; a
container of chemicals such that a chemical reaction can be
initiated that is endothermic and cools the container; a
mechanically chilled material or container which is cooled by
mechanical means; or any other material or container known in the
art that may provide a cool or cold surface that may be applied to
the head of a subject.
[0033] As disclosed herein, aspects of the invention are described
in the context of providing ultrasound to mammalian brain tissue,
which includes specific regions of the brain, or brain afferents or
brain efferents, or providing ultrasound to one or more brain
regions, combinations of these, or to cause alterations in
synthesis, release or uptake of neurotransmitters. For example, the
brain may comprise tissue with neurons within it located in the
head region, neural precursor cells, such as neural stem cells,
neurons, axons, neural cell bodies, ganglia, dendrites, synaptic
regions, neuronal tissue, or other cells positioned in the brain of
a living organism among neurons, such as glial cells,
oligodendrites, or astrocytes. Treatments of neural cells is
disclosed in PCT/US2009/050560, which is incorporated herein in its
entirety.
[0034] Ultrasound has been shown to influence neuronal activity by
suppressing the amplitudes and/or conduction velocity of evoked
action potentials. The use of moderate and high intensity,
high-frequency ultrasound and long exposure times to control
neuronal activity minimizes ultrasound's practicality for
modulating neuronal activity in living organisms. The present
invention comprises methods for low-intensity (<500
mW/cm.sup.2), low-frequency ultrasound (<0.9 MHz) and effects on
cellular modulation, such as methods for influencing neuronal
activity. For example, low intensity may comprise about 450
mW/cm.sup.2, 400 mW/cm.sup.2, 350 mW/cm.sup.2, 300 mW/cm.sup.2, 250
mW/cm.sup.2, 200 mW/cm.sup.2, 150 mW/cm.sup.2, 100 mW/cm.sup.2, 50
mW/cm.sup.2, 25 mW/cm.sup.2, 10 mW/cm.sup.2, and levels of
ultrasound intensity within these stated amounts, including from
about 450 m W/cm.sup.2 to about 1 mW/cm.sup.2. Other intensities
that are contemplated by the present invention comprise from about
1 W/cm2 to about 100 W/cm.sup.2. For example, an acoustic intensity
of the present invention may comprise about 1 W/cm.sup.2, about 2
W/cm.sup.2, about 3 W/cm.sup.2, about 4 W/cm.sup.2, about 5
W/cm.sup.2, about 10 W/cm.sup.2, about 15 W/cm.sup.2, about 20
W/cm.sup.2, about 25 W/cm.sup.2, about 30 W/cm.sup.2, about 40
W/cm.sup.2, about 50 W/cm.sup.2, about 60 W/cm.sup.2, about 70
W/cm.sup.2, about 75 W/cm.sup.2, about 80 W/cm.sup.2, about 90
W/cm.sup.2, about 100 W/cm.sup.2, or in a range of about 10
mW/cm.sup.2 to about 500 mW/cm.sup.2. Low frequency ultrasound may
comprise ranges from about 0.88 MHz to about 0.01 MHz, from about
0.80 MHz to about 0.01 MHz, 0.80 MHz to about 0.1 MHz, from about
0.70 MHz to about 0.1 MHz, from about 0.60 MHz to about 0.1 MHz,
from about 0.50 MHz to about 0.1 MHz, from about 0.40 MHz to about
0.1 MHz, from about 0.30 MHz to about 0.1 MHz, from about 0.20 MHz
to about 0.1 MHz, from about 0.10 MHz to about 1.0 MHz, and
ultrasound frequencies within these ranges. Other frequencies
contemplated by the present invention comprise ranges from about
0.1 MHz to about 1.5 MHz, from about 0.1 to about 1.3 MHz, from
about 0.1 to about 1.0 MHz, from about 0.1 to about 0.9 MHz, from
about 0.1 to about 0.8 MHz, from about 0.1 to about 0.5 MHz, from
about 0.1 to about 0.4 MHz, from about 0.5 to about 1.5 MHz, from
about 0.7 to about 1.5 MHz, from about 1.0 to about 1.5 MHz, from
about 0.02 MHz to about 10 MHz, and ultrasound frequencies within
these ranges.
[0035] As used herein, the cited intensities and frequencies are
the intensity and frequency levels at the target tissue site, not
the actual output number of the transducer. For example, the
pressure waveform experienced at the site of the target tissue
would have a frequency below about 0.9MHz and an intensity below
about 900 mW/cm.sup.2. The output of a transducer may have to be
much larger than the resulting effective amount at the target
tissue site. For example, a transducer may output 0.9 MHz
ultrasound at about 90 W for transmission through an intact scalp
and skull for the effective amount at the brain tissues being
treated to be about 0.9 MHz and below about 900 mW/cm.sup.2, as the
skull absorbs a significant portion of ultrasound waves. Thus, the
frequencies and intensities stated and claimed herein are the
frequencies and intensities experienced at the target tissue site,
not the output of the ultrasound transducers.
[0036] As used herein, providing ultrasound waves to a target site
to modulate brain activity comprises providing an ultrasound
stimulus waveform to a subject. The ultrasound stimulus waveform
may also alternatively be referred to herein as a waveform, and the
two terms are used interchangeably as can be understood by those
skilled in the art. As used herein, modulating brain activity means
altering the brain activity in one or more sites of the brain. The
brain activity may be increased or decreased by the action of at
least the ultrasound waves, which may include increasing or
decreasing neuron firing, receptivity, release or uptake of
neurohormones, neurotransmitters or neuromodulators, increase or
decrease gene transcription, protein translation or protein
phosphorylation or cell trafficking of proteins or mRNA, or affect
the activity of other brain cell or structure activity.
[0037] A stimulus waveform may be provided to a subject, human,
animal or other subjects, once or multiple times in a single
treatment, or in a continuous treatment regimen that continues for
a day, days, weeks, months, years, or for the life of the subject.
Determining the length of treatment needed is within the skills of
medical and/or research professionals. It is contemplated by the
present invention that a stimulus waveform may be pulsed or
continuous, have one or multiple frequencies, and other
characteristics as described herein. For example, in particular
methods, a pulsed ultrasound stimulus waveform may be transmitted
for about 10 microseconds, for about 25 microseconds, for about 50
microseconds, for about 100 microseconds, for about 250
microseconds, for about 500 microseconds, for about 1000
microseconds, for about 2000 microseconds, for about 3000
microseconds, for about 4000 microseconds, for about 5000
microseconds, for about 1 second, for about 2 seconds, for about 3
seconds, for about 4 seconds, for about 5 seconds, for about 6
seconds, for about 7 seconds, for about 8 seconds, for about 9
seconds, for about 10 seconds, and then this treatment may be
repeated for the same or a different length of time, one or more
times. For example, a stimulus waveform may be provided every 11
seconds for a duration of about 250 microseconds for years, or for
the life of the subject.
[0038] FIG. 3 illustrates ultrasound waves in a graph that
illustrates an example ultrasound waveform 200 for modulating
neural activity, according to an embodiment. The horizontal axis
202 indicates time, and the vertical axis 204 indicates pressure,
both in arbitrary units. The modulating waveform 200 contains one
or more pulses, such as pulse 220a and pulse 220b and pulse 220c.
Each pulse includes one or more cycles at an ultrasound frequency.
For example, pulse 220a includes five cycles of an ultrasound
frequency with a period (.tau.) 210 in seconds equal to the
reciprocal of the frequency (f) in Hertz (i.e., .tau.=1/j). The
number of cycles in a pulse is designated cycles per pulse (c/p).
The pulse length 222 is designated PL and is given in seconds by
the product of the period t and number of cycles per pulse c/p,
i.e., PL=.tau.*c/p.
[0039] Pulses are separated by quiescent periods that are related
to the time between pulse starts, shown in FIG. 3 as pulse repeat
time 230. The reciprocal of the pulse repeat time 230 in seconds is
the pulse repeat rate in Hertz, designated herein the pulse repeat
frequency PRF, to distinguish it from the ultrasound frequency f.
In some embodiments, the pulse repeat frequency PRF is a constant
for a waveform 200. In some embodiments, the pulse repeat frequency
PRF increases from a minimum (PRFmin) to a maximum (PRFmax) over a
time interval called a ramp time. For example, in some embodiments,
PRF increases from PRFmin=0 to PRFmax=3000 Hz over ramp time=5
seconds. In other embodiments the PRF is not swept and may range
from 0.001 kHz to 900 KHz. The waveform continues for a waveform
duration 234 that ends with the last pulse in the waveform. The
number of pulses in the waveform is designated Np.
[0040] The pressure amplitude of the ultrasound wave is
proportional to a voltage range used to drive a piezoelectric
transducer(s), for example a lead zirconate titanate (PZT)
transducer or other piezoelectric element. For example, a voltage
range may be selected between 100 milliVolts (mV, 1 mV=10.sup.-3
Volts) and 50 V, which correspond to intensity levels less than 500
mW/cm.sup.2 depending on the sensitivity and output characteristics
of the transducer(s) used Although pulses may be sine waves having
a single ultrasound frequency herein, other oscillating shapes may
be used, such as square waves, or spikes, or ramps, or a pulse
includes multiple ultrasound frequencies composed of beat
frequencies, harmonics, or a combination of frequencies generated
by constructive or deconstructive interference techniques, or some
or all of the aforementioned.
[0041] The present invention comprises devices, methods using such
devices, and systems for modulation of brain structures, which
results in modulation of the activities of such structures. Such
devices, systems and methods comprise providing ultrasound waves to
brain structures, cells or other tissues. Exemplary embodiments of
devices and methods of the present invention are provided herein.
Methods comprise providing ultrasound to a subject, for example, by
the use of one or more low intensity, low frequency ultrasound
and/or low intensity ultrasound, or one or more other ultrasound
intensity or frequency transducers. For example, an ultrasound (US)
transducer can be acoustically coupled to an external surface of a
subject, or alternatively, the US transducer can be in an
acoustically effective range of the target tissue. The ultrasound
transducer is then be driven to form stimulus waveforms in the
tissue, cell, or organ, for example with an intensity below about
100 Watts per square centimeter (mW/cm.sup.2), below about 1
W/cm.sup.2, or below about 500 mW/cm.sup.2. The ultrasound
waveforms may comprise one or multiple frequencies.
[0042] In an embodiment, driving the ultrasound transducer
comprises driving the ultrasound transducer to form a pressure
fluctuation waveform or a stimulus waveform including a plurality
of pulses, each pulse of duration less than about 10000
microseconds (.sub.0). Pulse duration may be variable depending on
a particular method or device, and may have a duration of about 10
seconds or less, such as about 100 to 10000 microseconds. Driving
the ultrasound transducer may comprise driving the ultrasound
transducers to form a pressure fluctuation waveform or a stimulus
waveform with a plurality of pulses within a waveform duration that
is less than about ten second(s). This comprises only one stimulus
waveform and this waveform may be repeated a nearly infinite number
of times. As used herein, pressure fluctuation waveform and
stimulus waveform are used interchangeably.
[0043] Driving the ultrasound transducer may comprise driving the
ultrasound transducers to form a stimulus waveform at a frequency
above about 0.20 MHz. The waveform may be one or more of known
waveforms arbitrary or not, including but not limited to, sine,
square, sawtooth, triangle, ramps and spikes. The ultrasound waves
may be focused to provide action at a particular site in or on the
subject, or focused at more than one site, or the waves may be
unfocused and provide action at multiple sites. The waves may be
continuous or pulsed, depending on the desired application. The
frequency or intensity may be uniform throughout a treatment
period, or may alternate or sweep from one number to another, and
back to the original number. Those skilled in the art are able to
determine such parameters for the desired application. Examples are
disclosed herein.
[0044] The acoustic frequency and intensity characteristics of an
UNMOD stimulus underlie its core effect on brain activity. A broad
range of acoustic frequencies, intensities, and transmission modes
have been used to produce variable excitation and inhibition of
neuronal activity. The acoustic frequencies used to manipulate
neuronal activity range from 0.25 MHz (Tufail et al., 2010) to 7.0
MHz (Mihran et al., 1990b). While lower frequencies of US have
longer wavelengths and lower spatial resolutions than higher
frequencies, acoustic frequencies <1 MHz for stimulating intact
brain circuits using US are a useful range. US <0.7 MHz
represents the frequency range where optimal gains between
transcranial transmission and brain absorption of US have been
observed (Hayner and Hynynen, 2001; White et al., 2006a, b). In
mice, optimal waveforms for evoking intact brain circuit activity
are composed of acoustic frequencies ranging between 0.25 and 0.50
MHz (Tufail et al., 2010). For these ranges, implementing broadband
transducers, which have a center frequency between 0.2 and 0.7 MHz
for UNMOD is useful. Use of immersion-type (water-matched)
transducers coupled to the skin with US gel to minimize acoustic
impedance mismatches when transmitting acoustic energy from a
transducer into the brain is also contemplated by the present
invention.
[0045] Other waveform variables, in addition to acoustic frequency
and transducer characteristics, such as mode of transmission
(continuous wave versus pulsed wave) and pulse profile (cycles per
pulse, cp; pulse repetition frequency, PRF; and number of pulses,
np) may affect the intensity characteristics of any given US
stimulus waveform. Those skilled in the art can determine an
intensity profile for a stimulus waveform. In in vitro studies
(Tyler et al., 2008), stimulus waveforms composed of US pulses
having a high pulse intensity integral (P//; .apprxeq.4.0
J/cm.sup.2) were used, which were repeated at slow PRFs (.apprxeq.,
50 Hz) for long durations (.apprxeq., 5 sec). Stimulation of brain
activity in vivo may use other US waveforms. For example, stimulus
waveforms constructed of US pulses having a low P// (<0.1
mJ/cm.sup.2), which were repeated at high PRFs (1.0-3.0 kHz) for
short durations (<0.4 sec) were effective for stimulating normal
brain circuit activity in vivo (Tufail et al., 2010). These two
different US pulsing strategies (high P// with a low PRF for in
vitro stimulation versus a low P// with a high PRF for in vivo),
indicated optimal US waveforms for triggering brain activity and
have low temporal average intensity values in a range between 30
and 300 mW/cm.sup.2.
[0046] In addition to the general pulsing strategies described
herein, US transmitted in a continuous wave (CW) mode is capable of
influencing brain activity, and may show different effects and time
courses compared to pulsed US. Short bursts of pulsed US can
stimulate brief (tens of milliseconds) periods of neuronal activity
and US stimuli delivered in CW-mode for 5 seconds can induce
seizure activity lasting >20 seconds in normal mice, and can
disrupt kainic acid-induced electrographic seizure activity in
epileptic mice. Repeated short bursts of pulsed US can attenuate
seizure activity in epileptic mice indicating UNMOD may be a
general interference source for disrupting aberrant activity. The
influence of US stimuli on brain activity patterns may depend on
stimulus amplitude, duration, and temporal frequency, as well as
the initial state of the brain when stimulation ensues. The
implementation of any particular UNMOD stimulus waveform or
transmission approach may depend on the outcome sought.
[0047] Disclosed herein are several methods for delivering US
across the skin and skull in order to achieve brain stimulation.
For example, an aspect of the present invention comprises use of
unfocused US for stimulating broad, nonspecific brain regions. A
nonspecific brain stimulation method with single element planar US
transducers can be useful depending on the desired outcome. For
example, unfocused US transmitted from planar transducers may
rapidly terminate seizure activity in mice suffering from epilepsy
or for treating a variety of other brain diseases including severe
or mild traumatic brain injuries.
[0048] Transmission of US from the transducer into the brain may
occur at points where acoustic gel is coupling the transducer to
the head. One may cover the entire face of the transducer with
acoustic gel to prevent transducer face heating and damage.
Alternatively, coupling the transducer to the head through small
gel contact points may be a physical method for transmitting US
into restricted brain regions. The spatial envelope of US
transmitted into the brain may be laterally restricted by using
acoustic collimators. The use of acoustic collimators allows one to
stimulate restricted brain regions in a targeted manner. Single
element focused transducers may be used for delivering spatially
restricted acoustic pressure fields to brains. Such single element
focused transducers can be manufactured having various focal
lengths depending on the size and center frequency of the
transducer. An aspect of the invention comprises using air-coupled
transducers to deliver transcranial pulsed ultrasound into the
brain from single-element transducers or from phased arrays as
described below. In aspects, gel-filled pads or other fluid filled
bladders may be used for acoustically coupling transducers to the
skin and or the skull in brain regulation interface designs.
[0049] A focusing method may involve the use of multiple
transducers operating in phased arrays to focus US through the
skull to specific brain regions. US can be focused through human
skulls using phased transducer arrays. Although the spatial
resolution for focusing US is currently limited by the acoustics or
wavelength employed, recent advances in focusing US with adaptive
optics (Zhang et al., 2009) allows US to gain spatial resolutions
below the diffraction limits, similar to that recently achieved in
optical microscopy (Abbott, 2009). US may confer spatial
resolutions similar those achieved by DBS electrodes. Aspects of
methods described herein contemplate use of subdiffraction methods
using hyperlenses, metamaterials, and acoustic bullets with
nonlinear lenses.
[0050] One or more US transducer may function individually or in
multiples, such as in one or more arrays. FIG. 8A-F illustrate
exemplary arrangements of phased array transducers. FIG. 8A, shows
a specific arrangement of a phased array transducer, for example,
made from a piezoelectric material such as polyvinylidene fluoride
(PVDF). The darker areas represent the active region of the phased
array. FIG. 8B shows a different phased array arrangement
containing 24 elements. Different phased array arrangements may
contain differing numbers of elements, any of which can be used in
an ultrasound device of the present invention. For example,
depending on the intended use and the intended brain structure to
be targeted, an ultrasound device of the present invention may have
circular arrays like those of 8A or B, or may have arrays arranged
in rectangular patterns like those of 8C or E, or both, as in 8D.
Piezoelectric materials can be flat or curved in convex or concave
orientations.
[0051] An ultrasound device of the present invention may use any
combination of curved, concave, convex, or flat phased arrays in
any desired geometrical shape or arrangement necessary to produce a
focused or unfocused ultrasound field in one or more brain regions
or structures. Phased arrays may be mounted statically on or in the
body of an ultrasound device of the present invention, or may have
piezoactuators or other motion control devices to change the shape
and/or position of one or more transducers or one or more arrays.
Such movement control allows for adjustments or changes to focus
the ultrasound fields. Such adjustments or changes may be made in
response to feedback information received from the subject wearer
or made by other controllers, such as a remote control site. FIG.
8F illustrates an ultrasound device of the present invention
comprising multiple phased arrays, wherein two arrays are in a
circular arrangement and two arrays are in a rectangular
arrangement.
[0052] In other aspects of the device or methods, acoustic
hyperlenses or metamaterials may be used to achieve focusing and
spatial resolutions of the ultrasound waves below the diffraction
limits. See FIG. 10 which shows an illustration of an ultrasound
device of the present invention comprising an acoustic hyperlens.
Systems, methods and devices for providing ultrasound for the
present invention may comprise materials that bend light or sound
and can focus the waves. Such materials have been used to make
hyperlenses, also referred to as superlenses or metamaterials. Such
materials, superlenses and other similar components may be used to
focus the ultrasound waves in the methods and devices of the
present invention. For example, transducers, of any type, in
conjunction with a focusing element such as a hyperlens or
metamaterial are used for focusing the ultrasound waves used to
modulate brain activity. Such materials can refract light backward,
or have a negative index of refraction. Acoustic metamaterials can
manipulate sound waves in many ways, including but not limited to,
collimation, focusing, cloaking, sonic screening and extraordinary
transmission. An example of a hyperlens comprises a non-resonant
radially symmetric layered structure as taught in Li, et al.,
Nature Materials, DOI:10:1038, NMAT2561, p. 1-4, 25 October 2009,
herein incorporated in its entirety.
[0053] As used herein, a device of the present invention capable of
delivering ultrasound to a human or animal subject may be referred
to as an ultrasound device or as a Brain Regulation Interface
(BRI), and such terms are used interchangeably. In general, an
ultrasound device may be worn on the head of a subject and the
device comprises at least one ultrasound transducer for providing
ultrasound waves to a portion of the brain of the subject. The
methods of providing ultrasound herein may be used on exposed brain
tissue, with allowance for the effect removal of the skull would
have on the ultrasound amount provided.
[0054] A device of the present invention comprises a structure that
is acoustically connected with a subject's body, such as a head,
that may be removably attached or adjacent to the body part. In
some embodiments, transducer can be coupled to the skin of
appendages such as the hands or feet using air- or water-matched
transducers to stimulate various somatosensory experiences
processed by the nervous system including the brain. The structure
may comprise elements for providing ultrasound, an ultrasound
transducer, including but not limited to, ultrasonic emitters,
transducers or piezoelectric transducers, piezocomposite
transducers, piezopolymers, and CMUTs.
[0055] A device of the present invention comprises at least a body
and one or a plurality of components for generating ultrasound
waves. The body of a device may be a chassis that is insertable
into other head gear, or a body may be head gear such as a cap, a
headband, a helmet, a protective head covering, a hood, a
stretchable material, a flexible material similar to a scarf that
can be tied on the head, or other head gear that may be adapted to
hold components for generating sound waves and/or other components.
For simplicity, the body of a device is referred to herein as a
chassis or as a helmet, but that reference is not meant to be a
limitation of the invention. A chassis generally refers to a body
of a device that can be physically combined with other head gear.
Methods of the present invention may comprise use of ultrasound
transducers or other components that are affixed to the head of the
subject, such as bolted to the skull bone and under the skin of the
scalp, to provide ultrasound waveforms to the brain. One or more,
or all, of the components of a device may be held within the body
of the device, affixed to the skull or scalp of the subject, or
provided in a separate element. The separate element may be
provided between the body and the head of the subject or may be
exterior to the body of the device.
[0056] A device of the present invention comprises a device that is
wearable by a subject and used for providing at least ultrasound
waves to the brain of the subject, comprising a body which covers
at least a portion of a subject's head and/or scalp, when worn by
the subject, and a plurality of components, wherein at least one
component is an ultrasound component. Head as used herein comprises
the region from the top of the shoulder blades, including the neck
region and at least the last two vertebrae of the top of the spine,
the skull and jaw bones, the ears, and the tissues residing on and
within, particularly the brain. The scalp is included within this
region and refers to the area of the head where hair grows or where
hair can be found in persons who are not bald, not including facial
hair. When scalp is referred to, it refers to the region of the
head from the forehead, behind the ears, and to the hairline dorsal
to the face.
[0057] FIG. 1A is a diagram that illustrates an exemplary system
for modulating brain activity, according to an embodiment wherein
the device comprises a helmet or head covering to be worn on the
head of a subject. It is contemplated that the helmet portion is
attached to the head by attachment components such as a chin strap
or other components used to hold a helmet or hat on a head. It is
contemplated that the device is not connected by wires to an
external source, though such embodiments may be employed if
necessary, for example, for downloading information, or charging a
mobile energy source, or providing energy to a device.
[0058] To illustrate the operation of a system and device of the
present invention, a head is depicted wearing an ultrasound device
of the present invention. However, the system or device does not
include the head or its external surface. A system or device
comprises components for generating ultrasound waves such as
ultrasound transducers, of which several are shown, and controller,
not shown. The controller may be within the helmet portion, or
located at a separate site on the subject's body, or may be located
at a separate site on or within the subject's body, such surgically
implanted controllers, or carried in a pack or pocket, or may be
remote and not attached, to the subject's body. A controller may be
built into a transducer. A controller may provide drive voltages
and pulse patterns to one or more transducers, or may receive
information from a remote or local component and using that
information, drive one or more transducers. In some aspects, the
transducer may be an emitting transducer, a receiving and
transmitting transducer, or a receiving transducer. The ultrasound
transducers are connected to a controller for receiving waveform
and power, and the transducers are driven by the controller. The
transducers are acoustically coupled to the brain in order to
introduce acoustic energy into the brain. For example, acoustic
coupling may be accomplished using air, water, gel or other
acoustic transmitting substrates. Such substrates may be
incorporated into ultrasound transducers, or may be provided in
separate containers provided between a transducer and the scalp of
a subject, or may be applied directed to the scalp of the subject,
such as by applying a gel directly to the scalp of a subject.
Transducers may be coupled to body parts other than the head in
order to provide stimulation of somatosensory experiences, which
are processed by the nervous system including the brain. Although
applied peripherally, ultrasound transducers coupled to the body
for providing somatosensory experiences such as pain, mechanical
sensation, and thermal sensations will modify the activity of the
brain in certain circuits. Such embodiments and devices are
therefore collectively referred to as brain regulation interfaces
although coupling of transducers may occur on peripheral tissues.
The transducers use the received waveform and power to emit
ultrasound frequency acoustic beams or waves, such as those shown
as wavy lines entering the brain of the subject in the figures. The
controller may comprise a process for waveform formation, which
determines the waveform to be emitted by transducers into the
brain. For example, a controller may comprise an electrical circuit
for providing drive voltages to a piezoelectric transducer so the
transducer can deliver ultrasound waveforms to the brain. In some
aspects, the transducers are battery powered and receive only
waveform information from the controller.
[0059] Although a particular number of transducers and controllers
are depicted in FIG. 1 for purposes of illustration, in other
aspects, more or fewer or the same number of transducers is
included, and a controller may be replaced by one or more devices
that each perform a different or redundant function of a
controller, including the waveform formation process. Controllers
and transducers may operate independently of one another or may
operate in conjunction with each other such as in a phased array
design. Connections between transducers and a controller to send
power and waveforms to transducers may be wired, or in other
embodiments, one or more connections may be wireless, or carry
power or waveforms for multiple transducers.
[0060] Transducers may each transmit an acoustic beam into the
brain, and some of the beams may intersect. In some aspects, the
waveform transmitted in a beam is effective in modulating brain
activity everywhere the beam intersects the neural tissue. In some
aspects, the waveform transmitted in a beam is only effective, or
is more effective, in an intersection region with another beam. In
some aspects, the transmitted waveforms are effective in only a
portion of the intersection region, dependent upon interference
patterns of constructive and destructive interference among the
waveforms in the intersecting beams. In some aspects two or more
ultrasound beams may intersect with one another or with other
materials such as metamaterials outside of the brain to create
structured ultrasound patterns, which are then transmitted into the
brain to activate or inhibit one or more regions of the brain.
[0061] The intensity of the acoustic beam is given by the amount of
energy that impinges on a plane perpendicular to the beam per unit
time divided by the area of the beam on the plane, and is given in
energy per unit time per unit area, i.e., the power density per
unit area, e.g., Watts per square centimeter (W/cm.sup.2). This is
the spatial-peak temporal-average intensity (Ispta); and is used
routinely for intensity herein. In aspects, the Ispta at the site
of the brain tissue is less than 500 mW/cm.sup.2. In aspects of the
invention, the Ispta at the site of brain tissue is less than 100
W/cm.sup.2. Another definition of intensity widely used in the art
is spatial-peak pulse-average intensity (Isppa); for multiple cycle
pulses, the Isppa may be less than 10 W/cm.sup.2.
[0062] Any ultrasound transducer known in the art may be
incorporated into the helmet component of the device or bolted to
the skull of a subject and used to transmit an acoustic beam into a
brain. For example, Olympus NDT/Panametrics 0.5 MHz center
frequency transducers, as well as Ultran 0.5 and 0.35 MHz center
frequency transducers may be used in devices of the present
invention. An ultrasound transducer may be composed of any single
or combination of piezoelectric materials known to those skilled in
the art, which include piezeopolymers, piezoceramics,
piezocomposites, or any other piezoelectric material which responds
to a voltage. In some aspects, capacitive micro-machined ultrasonic
transducer (CMUT) technology may be used. For example, CMUTs may be
arranged in flexible array designs that comfortably permit adaptive
beam forming and focusing. For example, the CMUTs may be mounted on
the inner surface of the helmet region to transmit ultrasound to
the brain. CMUTs may be mounted within the helmet material or on
the exterior of the helmet to transmit ultrasound to various brain
regions. In an aspect, CMUTs may be mounted directly to the skull
of the subject through the skin surface or underneath the skin
surface to transmit ultrasound waveforms to the brain. In an aspect
other piezoelectric materials could be used in place of CMUTs in a
similar manner. For example, PVDF or piezocomposites or other
piezopolymers could be mounted directly to the skull of a subject
through the skin or underneath the skin surface to transmit
ultrasound waveforms to the brain. In some aspects, PVDF,
piezocomposites or piezopolymers may be arranged in flexible array
designs that comfortably permit adaptive beam forming and focusing.
An aspect of the invention comprises use of ultrasound transducers
or other components in a device of the present invention used in
combination with ultrasound transducers or other components that
are physically attached to a subject, wherein both the device
components and the physically attached components are used to
provide methods for brain activity modulation.
[0063] Any devices known in the art may be used as a controller or
microcontroller. For example, waveforms may be generated using an
Agilent 33220A function generator (Agilent Technologies, Inc.,
Santa Clara, Calif., USA) and amplified using an ENI 240L RF
amplifier. Pulses in some waveforms may be triggered using a second
Agilent 33220A function generator. Data controlling the above
devices may be generated by waveform formation processes using a
general purpose computer with software instructions. Although a
system or device is depicted with several transducers and
corresponding beams, more or fewer transducers or beams or both may
be included in a system or device to produce the desired
effect.
[0064] FIG. 1B-E illustrate arrangements of transducers in
exemplary embodiments of the present invention. FIG. 1B shows a
cross-section of an ultrasound device of the present invention with
the transducers placed throughout the helmet component. FIG. 1C
shows a chassis-type embodiment which may be removably mounted
within head gear such as a protective helmet. Examples of helmet
components include military antiballistic helmets, fireman helmets,
astronaut helmets, bicycle helmets, sports protective helmets, and
fighter pilot helmets. The chassis comprises transducers affixed to
the chassis body and may further comprise components for attaching
the chassis to a helmet, such as mounting straps, and a suspension
system. The chassis can then be inserted into a helmet and worn by
a subject so that ultrasound can be applied to the brain of the
subject. The chassis can then be removed from the helmet and placed
in the same or a different helmet. FIGS. 1D and E show the
insertion of the chassis in a helmet and the helmet with the
chassis on a subject, respectively.
[0065] Systems and devices of the present invention may comprise
components other than those for providing ultrasound, and which may
be referred to herein collectively as other components. For
example, light waves or electromagnetic energy may be provided to a
brain using devices of the present invention. FIG. 2 shows an
exemplary embodiment of an ultrasound device of the present
invention comprising other components, such as components that
provide electromagnetic energy, to the brain.
[0066] Such a device may be used for stimulating or inhibiting the
activity of the brain using magnetic radiation or for making
ultrasound waves more or less effective at changing brain activity
by delivering magnetic energy prior to ultrasound waves, or after
ultrasound waves, or simultaneously during the delivery of
ultrasound waves.
[0067] FIG. 4 illustrates various other components that a device
may comprise. Information may be sent to or from an ultrasound
device of the present invention and processors or microprocessors
and microcontrollers, computer interfacing components, computers
and software may be implemented in the transfer of such
information. A device of the present invention may comprise
components for measuring or detecting physiological status
indicators such as heart rate, blood pressure, blood oxygenation
levels such as the oxygen content of hemoglobin, hormone levels, or
brain activity by detection methods, including but not limited to,
EEG, MEG, IR lasers and PAT, or fNIRS. A device of the present
invention may comprise components for geographical or global
location, such as GPS, or other navigational detection of the
location of the device, and its wearer. Information and commands
may be transmitted to and from a remote command center, such as a
centralized computing cluster, wherein the remote command center
can control one or more of the other components comprised by the
device. Information and commands may be transmitted to and from a
portable remote command center that comprises a screen or other
informational device, such as a PDA or a cell phone, that the
subject can access and thus control the components of the device.
Communication may be made with devices and controllers onboard or
remotely located using methods known in the art, including but not
limited to, RF, WIFI, WiMax, Bluetooth, UHF/VHF, GSM, CDMA, LAN,
WAN, or TCP/IP. FIG. 5 illustrates a device comprising components
including ultrasound transducers, microprocessors/microcontroller,
a COM device for transmitting information and control to and from a
remote command center, all of which are contained by the helmet
portion, the body, of the device.
[0068] FIG. 6 illustrates an exemplary ultrasound device comprising
locational or global positioning components. For example, the
microprocessor receives information from a GPS unit. The GPS data
may be processed by a microprocessor integrated in an ultrasound
device. This information is used to activate the ultrasound
transducer to generate ultrasound to stimulate a brain structure,
for example, one or more sections of the vestibular system and/or
to modify the vestibular ocular reflex. This aids in the navigation
of the user, for example by causing a change in the subject
wearer's body orientation or position. The GPS component of the
ultrasound device can be used for locating, tracking and providing
navigational support to the subject wearing the device and to
remote command centers. The GPS component may be used to locate or
track a subject wearing the device.
[0069] FIG. 7 illustrates an exemplary device having movable or
rotatable components, such as a movable or rotatable ultrasound
transducer. The ultrasound fields may be adjusted manually or
automatically, either locally or remotely controlled, by using
transducers mounted on a 1-, 2-, 3-spatial axis motion controller.
The direction of the ultrasound transmitted into the brain may be
modified, focused or provide a sweeping action of ultrasound waves
to the brain. A signal may be sent to a motion controller to change
the position of the mounted transducer one or more times, or may
provide a constant movement (sweeping) for the transducer. FIG. 7
also illustrates other components such as a sensor for brain
activity.
[0070] The present invention comprises systems for modulating
activity in a brain structure. For example, a system for modulating
activity in a brain structure may comprise a support for at least
one ultrasound transducer, at least one ultrasound transducer; and
an instruction for at least one ultrasound component. For example,
a support may be a body or an element that contains components such
as an ultrasound transducer. An instruction may comprise commands
from a microprocessor or microcontroller driving the ultrasound
transducer to provide ultrasound waves at a desired frequency,
intensity or waveform.
[0071] Systems and devices for providing ultrasound for the present
invention may comprise helmets having materials that bend light or
sound and can focus the waves. Such materials, including but not
limited to, super-lenses, hyperlenses or metamaterials, and other
similar components may be used to focus the ultrasound waves in the
methods and devices of the present invention. For example,
transducers, of any type, in conjunction with a focusing element,
such as a acoustic hyperlens, super-lens or metamaterial, are used
for focusing the ultrasound waves below the diffraction limits and
are provided to one or more sites in the brain to modulate brain
activity. Such materials can refract light or sound backward, or
have a negative index of refraction and have been referred to as a
"metamaterial". A focusing element, such as a metamaterial, may be
used in conjunction with one or more transducers, and/or with
phased arrays of transducers in order to focus or direct ultrasound
waves to one or more brain regions.
[0072] Ultrasound devices of the present invention may be
constructed of different materials depending on the intended
application. For example, in some aspects where the ultrasound
device comprises a personal protection helmet, the materials used
in the construction of such helmets may include molded
polycarbonate plastics (i.e. GE Lexan), carbon fiber composites,
and/or ABS plastics. In other aspects, the ultrasound devices may
comprise anti-ballistic helmets for combat, tactical, military,
and/or national security personnel. Materials used in the
construction of such helmets may include thermocomposite plastics
(hybrid thermoplastics) reinforced with carbon fibers, DuPont
Kevlar, DuPont Mark III, Honeywell Spectra, DSM Dyneema,
aramid/polyvinyl butyral phenolic combinations, thermoplastic
polyurethane, polyphenylene sulfide, polypropylene, and/or
polyethylene. In aspects where ultrasound devices are used for
medical intervention or treatment, the head gear portion may be
constructed of any plastic or composite materials, and may be made
of or include metals such as aluminum, titanium, steel, and
ceramic-metal composites. Aspects of ultrasound devices, for
example, one used in methods comprising video-gaming/entertainment,
aircraft/space helmets, and/or communication applications, may be
constructed using any suitable material. Devices may comprise other
materials such as natural and/or synthetic raw materials such as,
but not limited to nylon, vinyl, leather, platinum, copper, silver,
gold, zinc, nickel, and polymer-based plastics such as Delrin.
Ultrasound devices of the present invention may also comprise
light-emitting diodes (LEDs), organic light-emitting diodes
(OLEDs), laser-diodes, magnetic coils, and/or epoxies depending on
the embodiment and intended use of an ultrasound device. Materials
and methods of constructing head gear such as helmets are known to
those skilled in the art.
[0073] The present invention comprises devices and methods for
treating or alleviating traumatic brain injury (TBI), which may be
referred to herein as brain trauma. TBI may result from one or
several activities that can cause TBI such as combat injury, trauma
to the brain from sports or trauma resulting from accidents such as
car crashes or falls. While some brain injuries have immediate and
obvious physical effects, some TBI events associated with mild
concussions stemming from combat or blast injury or sport-related
injuries may be mild at first, but develop over time. Following the
initial brain insult, secondary damage may spread throughout the
brain and can lead to severe mental, cognitive, sensory, emotional
and physical impairments arising from cell death, excitotoxicity,
and other events occurring from the secondary injury. The secondary
injury may last from hours to days to months following the primary
insult.
[0074] Methods and devices of the present invention reduce the
deleterious consequences of secondary injury following a TBI
provide enhanced recovery and minimize damage caused during delayed
injuries. Methods and devices of the present invention reduce,
minimize, and/or eliminate primary and secondary injuries stemming
from TBI or other brain injury resulting from ballistic or blast
injuries in military or combat personnel or related civilian
casualties. Devices of the present invention which provide
ultrasound waves may be used to treat, ameliorate, reduce,
minimize, and/or eliminate primary and secondary injuries stemming
from TBI or other brain injury resulting from an accidental head
trauma such as an automobile, bicycle or skateboard accidents,
sport-related concussive injury, such as those commonly found in
American Football, lacrosse, soccer, rugby or hockey. Devices may
comprise personal protective headgear such as a helmet which is
commonly worn by military personnel or sports participants, or may
be provided as a medical device to be administered by emergency
personnel such as a physician and/or EMT. Methods of the present
invention comprise treating or ameliorating the effects of trauma
to the brain by providing an effective amount of ultrasound to a
brain region that has received trauma or a surrounding or remote
brain region that has or could have secondary injuries from the
trauma, said ultrasound may be provided by an ultrasound device of
the present invention.
[0075] Devices of the present invention that are useful in treating
TBI may provide focused and/or unfocused ultrasound having a
frequency ranging from 25 kHz to 50 MHz and an intensity ranging
from 0.025 to 250 W/cm.sup.2 which may modulate brain function and
provide neuroprotection by regulating cerebrovascular dynamics
(vasodilation/vasoconstriction), direct modification (inhibition)
of neuronal circuit (bioelectric) activity, direct excitation of
neuronal circuit activity, modulating the buffering of
intracellular calcium concentrations, and/or increasing the
synthesis and/or release of neurotrophic factors such as
brain-derived neurotrophic factor. A device may be provided to the
head of a subject, such as a human or animal, during the engagement
of risk-related activity, or provided to the subject as long as
needed, for example, from 500 msec to years following the initial
injury. An aspect of the invention comprises using an ultrasound
device of the present invention in rapid response situations, such
as responding to a car accident, or during evaluation of the
subject after an incident of force to the head to reduce secondary
injury to the brain. In use, a device may be automatically
activated in response to an external event, such as a concussive
blow detected by a pressure/force sensor or may be activated by the
subject wearing the device or by other appropriate personnel,
either in direct contact with the subject or by remote activation.
A device may comprise a pressure/force transducer or sensor to
detect a force event impacting the head of a device wearer. The
pressure/force transducer or sensor may communicate with a
controller or microprocessor, either contained within the device or
at a remote site, to initiate the sequence of steps needed to
activate at least one ultrasound transducer to provide ultrasound
to the device wearer to minimize subsequent secondary injury to the
brain. A device may comprise global positioning capabilities, such
as a GPS transceiver for communicating the global position of an
injured subject with a device attached, which would aid in medical
personnel locating the injured subject.
[0076] The present invention comprises methods for stimulating
normal brain wave activity patterns in deep or superficial brain
circuits using transcranial pulsed ultrasound. The present
invention comprises modifying cognitive processes such as learning
and memory using transcranial pulsed ultrasound, for example, by
stimulating sharp wave ripple oscillations, or activity in any
other frequency band including gamma, beta, theta, or alpha. Though
not wishing to be bound by any particular theory, it is believed
that sharp wave ripple oscillations underlie memory consolidation.
Pulsed transcranial ultrasound methods may be used to modulate BDNF
signaling and for example, other cellular cascades mediating
processes underlying synaptic plasticity and learning. Such methods
may comprise application of ultrasound to one or more brain regions
for one or more times. Methods comprise administration of
ultrasound waves to the brain continuously, or on regular
intervals, as necessary to affect the brain area and reach the
desired outcome. Such methods are disclosed herein.
[0077] The present invention comprises methods of using
transcranial pulsed US to stimulate one or more intact brain
circuits wherein such methods do not require exogenous factors or
surgery. Due to temperature increases <0.01.degree. C. in
response to US stimulus waveforms (FIG. 5D), an aspect of the
invention comprises predominantly nonthermal (mechanical)
mechanism(s) of action. Though not wishing to be bound by any
particular theory, it is thought that the nonthermal actions of US
are understood in terms of cavitation--for example, radiation
force, acoustic streaming, shock waves, and strain neuromodulation,
where US produces fluid-mechanical effects on the cellular
environments of neurons to modulate their resting membrane
potentials. The direct activation of ion channels by US may also
represent a mechanism of action, since many of the voltage-gated
sodium, potassium, and calcium channels influencing neuronal
excitability possess mechanically sensitive gating kinetics (Morris
and Juranka, 2007). Pulsed US could also produce ephaptic effects
or generate spatially inhomogeneous electric fields, proposed to
underlie aspects of synchronous activity (Anastassiou et al., 2010;
Jefferys and Haas, 1982). underlying the ability of US to stimulate
intact brain circuits.
[0078] Methods, systems and devices of the present invention
comprise using pulsed US to probe intrinsic characteristics of
brain circuits. For example, US stimulation of motor cortex
produced short bursts of activity (<100 ms) and peripheral
muscle contractions, whereas stimulation of the hippocampus with
similar waveforms triggered characteristic rhythmic bursting
(recurrent activity), which lasted 2-3 s. Stimulation of a given
brain region with US can mediate broader circuit activation based
on functional connectivity. Such abilities have been shown and
discussed for other transcranial brain-stimulation approaches like
TMS (Huerta and Volpe, 2009). For example, the effects of US on
activity in corticothalamic, corticocortical, and thalamocortical
pathways are contemplated by the present invention. Brain
activation with transcranial pulsed US may be dependent on the
plane of anesthesia. For example, when mice were in moderate to
light anesthesia planes (mild responsiveness to tail pinch),
US-evoked activity was highly consistent across multiple repeated
trials.
[0079] Using a method of transcranial US brain stimulation with an
acoustic collimating tube (d=2 mm), an estimate of the volume of
cortical activation may be .apprxeq.3 mm.sup.3 as indicated by
c-fos activity (FIG. 15). This activated brain volume may have been
restricted by anatomical features along the dorsal-ventral US
transmission path implemented (for example the corpus callosum
restricting the depth of activation to the cortex). The 1.5-2.0 mm
lateral area of activation observed represents a more reliable
measure and is approximately five times better than the .apprxeq.1
cm lateral spatial resolution offered by transcranial magnetic
stimulation (TMS) (Barker, 1999). Due to the millimeter spatial
resolutions conferred by US, structured US fields may be used to
drive patterned activation in sparsely distributed brain circuits.
Similarly, focusing with acoustic meta-materials (having a negative
refractive index) enables subdiffraction spatial resolutions to be
achieved for US (Zhang et al., 2009). Brain regions <1.0 mm may
be accurately targeted for neurostimulation using 0.5 MHz US. Such
spatial scales make transcranial US for brain stimulation amenable
to a variety of research and clinical applications.
[0080] Focusing of US through skull bones, including those of
humans, can be achieved using transducers arranged in phased
arrays. A recent clinical study reported using trans-cranial
MRI-guided high-intensity focused ultrasound (0.65 MHz, >1000
W/cm.sup.2) to perform noninvasive thalamotomies (d=4.0 mm) for the
treatment of chronic neuropathic pain by focusing US through the
intact human skull to deep thalamic nuclei using phased arrays
(Martin et al., 2009). Pulsed US in the noninvasive stimulation of
human brain circuits is contemplated by the present invention.
[0081] The present invention comprises methods wherein two
modalities are used simultaneously or sequentially. As US is
readily compatible with magnetic resonance imaging (MRI) it is
feasible that pulsed US could be used for brain-circuit stimulation
during simultaneous MRI imaging in the functional brain mapping of
intact, normal or diseased brains. Aspects of methods comprise
pulsed US used to induce forms of endogenous brain plasticity as
shown with TMS (Pascual-Leone et al., 1994). In such an embodiment,
pulsed US drives specific brain activity patterns shown to underlie
certain cognitive processes like memory trace formation (Girardeau
et al., 2009; Nakashiba et al., 2009). For example, in mice,
transcranial US can promote sharp-wave ripple oscillations (FIG.
16C) and stimulate the activity of endogenous BDNF (FIG. 16D), an
important regulator of brain plasticity and hippocampal-dependent
memory consolidation (Tyler et al., 2002).
[0082] A method of the present invention comprises blocking memory
formation and memory consolidation to prevent the formation of
short- and/or long-term memories. Such methods include methods for
treating, ameliorating or reducing post-traumatic stress disorder
(PTSD), such as that resulting from combat stress. Other methods
include use of a device of the present invention in applications
where it is beneficial or necessary that the subject's memory is
altered or prevented from forming. A device may comprise an
anti-ballistic helmet and/or other head wearable device wherein the
ultrasound treatments are administered by the subject wearing the
device or by other personnel. A device may provide focused and/or
unfocused ultrasound ranging from 25 kHz to 50 MHz and an intensity
ranging from 0.025 to 250 W/cm.sup.2 in a treatment method to
modulate brain function in a manner that alters neuronal plasticity
such that the formation of memories related to specific events are
blocked. Such methods may comprise prior, concurrent or post
treatment with chemical, electrical, magnetic, or genetic methods
to enhance the memory control.
[0083] Methods of the present invention comprise altering synaptic
plasticity by providing ultrasound to memory centers of the brain.
Ultrasound methods are used to reduce synaptic plasticity or to
promote certain types of synaptic plasticity such as long-term
depression if a memory is to be forgotten, and synaptic plasticity
such as long-term potentiation is enhanced if a memory is to be
retained. Promotion of plasticity in memory centers is useful in
treatments for dementia, Alzheimer's disease, or loss of memory due
to other events, such as a stroke. Memory centers of the brain
comprise the limbic system, the prefrontal cortex, the hippocampus,
the amygdyla, the cerebellum and entorhinal cortex, including
Broadman's Areas 34 and 28.
[0084] Methods of the present invention comprise impeding or
inhibiting memory formation in a subject by providing an effective
amount of ultrasound to a brain region, wherein the brain region
comprises the hippocampal formation, hippocampus proper, limbic
system, amygdala, thalamus, cerebellum, striatum, entorhinal
cortex, perirhinal cortex, and cerebral cortex (including
prefrontal cortex, auditory cortex, visual cortex, somatosensory
cortex, and/or motor cortex), afferents or efferents of said
regions, or combinations thereof. Methods of the present invention
comprise providing ultrasound to a subject, optionally using an
ultrasound device described herein, prior to an event, for example,
about 1 minute, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 1
hour, 1.5 hours, 1.75 hours, 2 hours, 2.5 hours, 2.75 hours, 3
hours, 3.5 hours, 4 hours or for about 4.5 hours prior to an event
for which a subject's memory is to be impeded, and optionally,
providing ultrasound to a subject during an event, and optionally
after the event occurs, for example, for at least 1 minute, 10
minutes, 20 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5
hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours,
6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9
hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, 12
hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, or for a longer
time period if needed, after the event, and thereby inhibiting
memory formation or storage. Methods may also comprise providing
chemical, pharmaceutical, electrical, magnetic or light therapy
before, during or after ultrasound is provided. A method of the
present invention comprises providing ultrasound using a device
described herein.
[0085] Human brain targets where ultrasound is provided to prevent
the formation of memories include, but are not limited to, the
hippocampal formation, hippocampus proper, amygdala, thalamus,
cerebellum, striatum, entorhinal cortex, perirhinal cortex, and
cerebral cortex (including prefrontal cortex, auditory cortex,
visual cortex, somatosensory cortex, and/or motor cortex).
Embodiments of the present invention comprise use of a device of
the present invention to provide ultrasound to modify brain
activity in at least one, or in a combination of the aforementioned
anatomical areas in a manner that is effective to disrupt normal
neuronal plasticity including, for example, long-term potentiation
(LIP), long-term depression (LTD), spike-timing dependent
plasticity (STDP), and/or homeostatic plasticity by modulating the
spatiotemporal patterns of brain activity, which lead to the
formation of short- and/or long-term memories. Changes in brain
activity induced by ultrasound may act on calcium-dependent
biochemical processes, which include an increase and/or decrease in
either, or both, kinase and phosphotase activity to modulate the
activity of proteins, by modulating gene transcription, or protein
translation. Conversely, different ultrasound waveforms may be
projected to the aforementioned brain regions in a manner which
will promote neuronal plasticity (LTP/STDP) in order to enhance the
learning and/or memory of events as a therapeutic treatment method
for dementia, Alzheimer's disease or other age-related,
injury-related, and/or developmental memory disorders.
[0086] Methods of the present invention comprise administration of
ultrasound to the brain of an animal, including humans, such as by
transcranial routes, to modify cognitive processes. An aspect of
the invention comprises providing transcranial pulsed ultrasound to
modify cognitive processes in a human or animal. For example,
spatial learning and memory can be modified using methods of the
present invention (FIGS. 17 and 18A-18B). Methods of the present
invention comprise delivery of pulsed transcranial ultrasound to
the intact hippocampus and/or associated brain regions to modify
cognitive processes, including by not limited to, modifying normal
cognition or enhancing cognitive processes. Methods for increasing
the strength of synapses comprise providing transcranial ultrasound
to one or more brain regions.
[0087] The Morris Water Maze is a classic test used to assay
cognition in rodents. Intact mice hippocampi were stimulated using
ultrasound methods disclosed herein. If US stimulation occurred 5
minutes immediately before training the mice on the MWM task, the
mice do not learn as well and additionally, the mice have worse
memory of the escape location compared to sham controls. It is
currently believed that the disruption of learning and memory
consolidation is due to stimulating hippocampal activity in
patterns absent of context, which disrupts the formations of
associations amongst environmental cues, as well as alters the
neuronal firing code needed for normal learning and memory to
occur. Thus, by providing disruptive hippocampal stimulation with
pulsed ultrasound learning can be attenuated and memory can be
blocked. Methods of the present invention comprise providing
ultrasound to disrupt learning and/or interfere with memory
consolidation by stimulating one or more brain regions in the
absence of context (for the animal stimulated).
[0088] For example, if mice are stimulated for 5 minutes per day
for 7 days before training them on the MWM task (without
stimulating the day of or immediately before training on any
training day) then the mice receiving intact hippocampal
stimulation in this chronic paradigm perform better than sham
controls. They remember better and learn faster. It is believed
that traditional models of plasticity explain the findings, where
the synaptic strengths of hippocampal synapses are increased by
stimulating across repeated days in controlled environments.
Ultrasound stimulates the release of brain-derived neurotrophic
factor (BDNF) and BDNF induces plasticity and mediates learning,
thus, the repeated prolonged increase in BDNF signaling enhances
cognitive function. Methods of the present invention comprise
repeated stimulation of the hippocampus by transcranial ultrasound
to improve learning and memory. Methods of the present invention
comprise repeated stimulation of one or more brain regions by
transcranial ultrasound to improve learning and memory. Methods of
the present invention comprise repeated stimulation of the
hippocampus by transcranial ultrasound for treating a disease or
physiological condition where disrupted cognition is present in an
animal. For example, such diseases or physiological conditions
include, but are not limited to, mental retardation, Down's
syndrome, Fragile X, Alzheimer's disease, age-related cognitive
decline, and other conditions where cognition is delayed, faulty or
impaired. Methods comprising providing ultrasound to the brain of
an animal for the upregulation of neurotrophic factors may be used
treat diseases where different brain circuits are targeted. For
example, dysregulated BDNF signaling occurs in diseases or
physiological conditions including, but not limited to, epilepsy,
anxiety, depression, Alzheimer's disease, Parkinson's disease, and
following stroke and brain injury. Methods of the present invention
comprise upregulation of neurotrophic factors, including but not
limited to BDNF, Nerve Growth Factor, Neurotrophin-3, Fibroblast
Growth Factor, Insulin-like Growth Factor, by transcranial
ultrasound for treating a disease or physiological condition where
neurotrophic dysregulation or impaired neurotrophic signaling
occurs. For example, increasing BDNF signaling by performing
chronic repeated brain stimulation with ultrasound may encourage
plasticity which can have a profound effect on diseased, faulty or
impaired brain circuits Likewise, chronic repeated brain
stimulation with ultrasound may encourage plasticity to enhance
learning and memory in normal brain circuits. An ultrasonic method
of the present invention comprises enhancing learning or memory
formation in a subject, comprising providing an effective amount of
ultrasound to a brain region, wherein the brain region comprises
the hippocampal formation, hippocampus proper, amygdala, thalamus,
cerebellum, striatum, entorhinal cortex, perirhinal cortex, and
cerebral cortex, prefrontal cortex, auditory cortex, visual cortex,
somatosensory cortex, or motor cortex, afferents or efferents of
the regions, or combinations thereof.
[0089] Aspects of the present invention comprise methods and
devices to provide transcranial ultrasound to modify dysfunctional,
impaired or diseased brain circuits in humans and animals. Patients
with various types of brain impairments have been shown to benefit
from brain stimulation using electromagnetic energy, such as that
transduced using electrodes, lasers, magnetic coils, and other
energy emitting devices. Ultrasound for brain stimulation can
confer many advantages over electromagnetic-based brain stimulation
strategies. For example, aspects of ultrasound methods disclosed
herein do not require surgery and can confer a spatial resolution
at least 3-5 times better than that achieved with other noninvasive
techniques, such as transcranial magnetic stimulation. Further,
ultrasound can be rapidly deployed for brain stimulation, which can
facilitate the providing of first line interventions to treat
traumatic brain injuries or neurocritical care conditions such as
refractory seizure activity.
[0090] Methods disclosed herein attenuate seizure activity using
pulsed ultrasound.
[0091] Brain regulation devices disclosed herein can be used in
neurocritical care situations to rapidly provide a noninvasive
brain stimulation intervention using pulsed ultrasound. For
example, status epilepticus (SE) refractory to conventional
anti-epileptic drugs typically has a poor prognosis, but patients
may recover well if seizures can be terminated. Methods for using
transcranial pulsed ultrasound (TPU) to stimulate intact brain
activity are disclosed herein and can be used for treatment of
seizure activity. TPU can synchronize intact hippocampal
oscillations in high-frequency and gamma bands without producing
damage. Data disclosed herein shows TPU can disrupt kainic
acid-induced SE by providing a whole-brain stimulation interference
source. The studies showed acute and chronic effects of
transcranial ultrasound on healthy and kainic acid (KA) induced SE
mice.
[0092] Methods of the present invention comprise treatment of brain
dysfunction by modulating cortical and subcortical brain circuit
activity by providing ultrasound to the cortical and subcortical
regions of the brain. The present invention is useful for treating
neurocritical emergencies like SE that carry high morbidity.
SE-induced in rodents serves as a model of Temporal Lobe Epilepsy
with hippocampal sclerosis, the most frequent epilepsy in humans.
Aspects of the present invention comprise treating temporal lobe
epilepsy, optionally with hippocampal sclerosis, by providing
ultrasound to one or more brain regions. Such ultrasound may be
pulsed transcranial ultrasound.
[0093] Aspects of the methods of the present invention comprise use
of pulsed, transcranial ultrasound, continuous wave ultrasound or
both. Use of ultrasound devices disclosed herein may be used in
methods for acute treatment of brain diseases or impairment.
Devices for providing ultrasound as disclosed herein may be used
treating brain diseases or brain impairment by providing chronic
stimulation. For example, chronic stimulation with brain regulation
devices providing ultrasound may be used to increase plasticity and
enhance cognitive processes in animals to treat degenerative
diseases such as Alzheimer's disease. Such devices and methods may
be used to treat neurodevelopmental diseases in children or other
aged humans or animals, such as mental retardation, fragile x,
Down's syndrome, etc. Both diseased or impaired brain tissues and
normal brain tissues may be modulated using ultrasound devices
disclosed herein.
[0094] As shown in FIG. 19, continuous wave ultrasound, in contrast
to pulsed ultrasound, may be used to induce seizure activity in
normal brain circuits. In diseased or impaired brain circuits, such
as when seizure activity is present, continuous wave ultrasound or
pulsed ultrasound may be used to disrupt the aberrant activity,
such as seizures. The outcome is highly dependent on the initial
state of the brain. If aberrant activity is present, methods
providing ultrasound can interfere with aberrant activity. If
aberrant activity is not present, such as in normal brain tissue,
the induction of seizures may be used to functionally identify
epileptic circuits. Use of ultrasound devices and methods described
herein are useful prior to, during, or after surgical manipulation
of brain tissue, for example, to map functional and/or
dysfunctional brain circuits. For example, methods comprise use of
ultrasound to identify diseased brain circuits, such as epileptic
brain circuits which may require surgical removal.
[0095] Aspects of the present invention comprise methods and
devices to provide ultrasound to regulate or modify the activity of
certain brain circuits to reduce anxiety and stress responses
induced by environmental cues or other conditions, for example,
combat situations or operation of complex or sensitive machinery
such as a space shuttle, or other intra-/extra-atmospheric craft.
Though not wishing to be bound by any particular theory, it is
believed that stress responses are mediated in the brain and/or
nervous system by several neuromodulators, neurohormones, and
neurotransmitters including, but not limited to noradrenaline,
epinephrine, norepinephrine (NE), acetylcholine (ACh), cortisol,
corticotropin-releasing hormone (CRH), adrenocorticotropic hormone
(ACTH), and glucocorticoids. Brain circuits involved in mediating
responses to stressors include, but are not limited to, the locus
ceruleus, the paraventricular nucleus of the hypothalamus (PVN),
the autonomic nervous system, the sympathetic nervous system;
("fight-or-flight" response), hypothalamic-pituitary-adrenal axis
(HPA), adrenal medulla, and the pons. Methods of the present
invention comprise altering a stress response by a subject by
providing an effective amount of ultrasound to a brain region,
wherein the brain region comprises the locus ceruleus, the
paraventricular nucleus of the hypothalamus (PVN), the autonomic
nervous system, the sympathetic nervous system; ("fight-or-flight"
response), hypothalamic-pituitary-adrenal axis (HPA), adrenal
medulla, or the pons.
[0096] There are several different types of stress responses. The
"fight-or-flight" stress response is an acute stress response,
which is put into effect when a general alarm system in the brain
is activated by an increase in the activity of neurons in the locus
ceruleus. This increase in activity leads to an increase in
noradrenergic activity to increase awareness and attention. Other
acute stress responses include the actions of Ach to trigger the
release of epinephrine and NE from the medulla and adrenal glands,
as well as activation of the HPA to mediate appropriate behaviors.
Acute stress can be positive for the subject in situations where
the subject is challenged. Prolonged exposure to acute stress leads
to decreased cognitive and physiological functioning. This is due
to an abnormally high level of circulating stress hormones, such as
cortisol, CRH, ACTH, as well as maladaptive plasticity in local
brain circuits such as the locus ceruleus, PVN, hippocampus,
prefrontal cortex, and the amygdala.
[0097] Problems associated with prolonged chronic stress, such as
that seen in military or tactical personnel, presents major
problems and is termed combat stress reaction, which has been
previously called shell shock or battle fatigue. Combat stress
reaction can manifest itself leading to fatigue, slow response
times lack of ability to make decisions, lack of an ability to
carry out missions, disconnection, and other poor cognitive
abilities. Combat stress reaction can lead to other stress
disorders such as post-traumatic stress disorder, generalized
anxiety disorder, depression, and acute stress disorder. Subjects
other than military or combat personnel can present with combat
stress reaction or other stress disorders and be treated using
methods described herein.
[0098] An aspect of the present invention comprises use of a device
for providing ultrasound of the present invention to decrease the
deleterious effects of prolonged stress on physiological and
cognitive performance of a subject by providing ultrasound to
excite and/or inhibit the aforementioned brain stress systems. In
an aspect of the invention, the acute stress response is left
intact to maximize combat/tactical personnel efficiency during
hostile engagement, but the activity of the brain stress centers
are reduced by providing ultrasound following environmental
exposure to the stressors. For example, after a stressful event,
such as a battle or a patrol in a dangerous region, tactical,
military, or combat personnel activate the ultrasound device once
they have returned to a relatively safe environment. In an
embodiment, a sensor that detects circulating stress hormone levels
communicates information regarding the subject's physiological
state of stress hormones is in communication with an ultrasound
device worn by the such that the ultrasound device becomes active
and provides an effective amount of ultrasound to reduce prolonged
and/or chronic stress. Reduction of the stress response interrupts
the chronic state of stress which leads to the combat stress
reaction and underlies subsequent PTSD, depression, generalized
anxiety disorder, and acute stress disorder in many
individuals.
[0099] Methods of the present invention comprise use of an
ultrasound device to provide ultrasound to activate brain regions,
which increase arousal, attention, and awareness. Methods for
activation of brain regions may be employed by any subject where
arousal, attention or awareness are sought. For example, ultrasound
devices may be worn by operators of heavy machinery or equipment,
astronauts, pilots, and combat or tactical personnel where
increased attention, arousal, increased alertness and for long-term
wakefulness is desirable in order to improve performance and to
minimize risk of injury to the user and others and/or accidents.
Shift-workers or long-haul truck drivers may also benefit from such
methods.
[0100] There are numerous centers in the brain which are
responsible for regulating attention, arousal, and alertness.
Increasing activity in these brain regions can increase reaction
times, enhance cognitive performance, and promote appropriate
behavioral or physiological responses. Some of the neurotransmitter
and neuromodulator systems involved in the regulation of arousal
and alertness are acetylcholine, dopamine, histamine, hypocretin,
serotonin, and norepinephrine. Brain circuits, which mediate
arousal and attention include, but are not limited to the
prefrontal cortex, basal forebrain, the hypothalamus,
tuberomamillary nuclei, basolateral amygdala, ventral tegmental
area, medial forebrain bundle, locus ceruleus, the thalamus, and
the dorsal raphe nucleus. Specific thalamocortical oscillations
(.about.40 Hz) are known to occur during wakefulness or alertness
and can be detected using EEG and or MEG. There are other patterns
of brain activity, which indicate enhanced arousal, alertness, and
attention and these can also be detected using MEG and or EEG.
[0101] Methods of the present invention comprise activating arousal
brain regions to increase alertness, awareness, attention or
long-term wakefulness in a subject by providing an effective amount
of ultrasound to a brain region, wherein the brain region comprises
prefrontal cortex, basal forebrain, the hypothalamus,
tuberomamillary nuclei, basolateral amygdala, ventral tegmental
area, medial forebrain bundle, locus ceruleus, the thalamus, and
the dorsal raphe nucleus. Ultrasound may be provided by a device of
the present invention. A device may provide focused and/or
unfocused ultrasound ranging from 25 kHz to 50 MHz and an intensity
ranging from 0.025 to 250 W/cm.sup.2 in a treatment method to
modulate brain function in a manner that alters alertness,
wakefulness, and/or attention. Methods of the present invention
comprise providing ultrasound to effect release of acetylcholine,
dopamine, histamine, hypocretin, serotonin, and norepinephrine. For
example, an ultrasound device of the present invention may provide
ultrasound to a subject to activate to activate arousal brain
regions in the subject to increase alertness, awareness, attention,
and long-term wakefulness for enhanced attention and alertness
during sensitive operations, such as during combat environments,
while operating heavy machinery, for astronauts, or pilots.
[0102] Methods of providing ultrasound to activate arousal brain
regions may be used to promote long-term wakefulness by using
ultrasound to stimulate one of more of the arousal brain regions,
systems, circuits and/or for neurotransmitter release. Subjects
engaged in long-term activity activate an ultrasound device of the
present invention to reduce the likelihood of entering sleep cycles
or to prevent microsleep. Methods comprise use of an ultrasound
device of the present invention in combination with EEG and/or MEG
sensors to monitor brainwave activity. The sensors can relay
information regarding the brainwave patterns to an onboard
microprocessor or a remote processor such that when brainwaves show
the user is entering a reduced awareness/alertness or sleep cycle
the ultrasound device is activated, such as by a microcontroller,
to begin transmitting ultrasound to one or more arousal-related
brain regions which increases wakefulness such that the subject
returns to an awake state. Methods of providing ultrasound to
activate arousal brain regions or neurotransmitters in a subject
for arousal include treating subjects in reduced consciousness
states, such as those in a coma or a minimally conscious state
where thalamocortical activity and oscillations are impaired or
disrupted.
[0103] A device of the present invention may comprise multiple
components for activating brain structures. For example, a device
may comprise laser diodes and MEG/EEG sensors, in addition to
ultrasound transducers and optionally magnetic transducers.
Scattered photons from the laser diodes are provided at the inner
surface of the body of the device so that the photons are between
the inner surface of the device and the outer surface of the head.
The scattered photons are detected by ultrasound transducers
present on the inner surface of the body of the device. The
interaction with the photons provides information about brain
activity regarding blood flow and blood oxygenation via
photoacoustic tomography. In an alternative aspect, sensors that
provide information about the scattered photons can be used in
functional near-infrared spectroscopy (fNIRS). MEG
(magnetoencepholography) or EEG sensors may be used in a device of
the present invention to detect electrical brain activity, or to
detect changes in brain electrical activity. The data regarding
brain activity acquired from these sensors can be relayed to a
remote or local microprocessor. A local microprocessor may one that
is integrated directly in or on the body of the device. The relayed
data may be used by the microprocessor to return instructions to
components in the device, such as ultrasound transducers, such as
to modulate the ultrasound waveform, adjust the frequency,
intensity or waveform characteristics to fine tune the ultrasound
being delivered to the subject.
[0104] Methods of the present invention comprise activation of
reward pathways in a subject by providing an effective amount of
ultrasound to a brain region, wherein the brain region comprises
the mesolimbic and mesocortical pathways, including connections
between the medial forebrain bundle (MFB) and its connections to
the nucleus accumbens (NA) wherein dopamine (DA) acts as a
neuromodulator, the prefrontal cortex, the anterior cingulate
cortex (ACC), basolateral amygdaia (BLA), or the ventral tegmental
area (VTA), as well as dopaminergic, glutamtergic, serotonergic,
and cholinergic systems. Ultrasound may be provided by an
ultrasound device of the present invention. Activation of reward
pathways may be used to condition and/or reinforce certain desired
attributes and/or to motivate specific behavioral actions. The
major anatomical pathways responsible for "reward" in the nervous
system are the mesolimbic and mesocortical pathways, which include
connections between the medial forebrain bundle (MFB) and its
connections to the nucleus accumbens (NA) wherein dopamine DA acts
as a neuromodulator. Other areas crucial to reward pathways involve
the prefrontal cortex, the anterior cingulate cortex (ACC),
basolateral amygdaia (BLA), and the ventral tegmental area (VTA).
These reward (pleasure) centers of the brain have powerful
functions in reinforcing certain behaviors. These pathways mediate
addiction to drugs of abuse and/or other appetitive behaviors. For
example, in rats conditioned to press a bar to receive intracranial
self-stimulation (ICSS) of the VTA, MFB, and/or NA will lead to
reinforcing behaviors such that the rat ignores all other
environmental cues and will engage in repeated bar pressing
behaviors in order to gain the reinforcing/pleasure inducing ICSS
of those brain nuclei.
[0105] Methods of the present invention comprise ultrasound devices
that deliver ultrasound waveforms to any one or a combination of
the reward brain regions in order to reinforce desired behavioral
actions. A device may provide focused and/or unfocused ultrasound
ranging from 25 kHz to 50 MHz and an intensity ranging from 0.025
to 250 W/cm.sup.2 in a treatment method to modulate brain function
in a manner that rewards behaviors and/or increases the motivation
to engage in certain behaviors. Since temporal contiguity of the
reinforcement (brain stimulation) with the behavioral action is
needed for the activation of reward pathways to promote behaviors,
timing of the delivery of ultrasound waveforms to the reward brain
regions may affect the behavioral response. Better behavioral
responses are found when the delivery of reinforcing ultrasound
stimulus waveforms occurs in close temporal contiguity with the
behavior to be reinforced. Ultrasound stimulus waveforms may be
provided from about one hour prior to the occurrence of the
behavior to be reinforced to about one hour following the
behavioral actions to be reinforced. Longer or shorter time ranges
for ultrasound provision may be appropriate for some behaviors, or
for later stages of treatment, and such ranges may be determined by
those skilled in the art. More specific and restricted timing
windows for providing ultrasound may lead to more robust behavioral
conditioning. The activation of the ultrasound device of the
present invention may be controlled by the subject or may be
remotely controlled via various communication ports.
[0106] Methods for activation of reward pathways can be used for
training a desired behavior or response. For example, ultrasound
devices of the present invention may be used to provide ultrasound
to a reward pathway to reinforce behaviors that are beneficial for
military/combat/tactical personnel, machine operators, systems
engineers, or other technical personnel to train the subjects to
respond with specific behavioral routines and/or sensitive
procedures. This will reduce job-specific learning curves and to
increase job-performance. Such training can also be used to train
athletes or any other subject where conditioned responses would be
beneficial. Such training may also be used to change deleterious
behaviors by providing reward stimulation that substitutes for the
deleterious behavior. For example, when tempted to engage in a
deleterious behavior such as an addictive behavior, a reward
pathway is activated and the subject is "distracted" from the
deleterious behavior.
[0107] Methods of the present invention comprise providing
ultrasound to the prefrontal cortex and a device of the present
invention may be used to provide the ultrasound. Providing
ultrasound to the prefrontal cortex, alone or in combination with
other treatments, such as transcranial magnetic stimulation, may be
used to activate that brain region and may be useful for treatments
of drug-resistant depression or clinical depression. Such
ultrasound may be focused or unfocused.
[0108] Methods of the present invention comprise modulating
cerebrovascular dynamics by providing ultrasound to brain regions.
Ultrasound induces vasodilation or vasoconstriction in peripheral
tissues by activating nitric oxide/nitric oxide synthetase. Data of
the inventor showed that air-coupled ultrasound transducers induced
vasodilation in the brains of rodents. Pulsed ultrasound remotely
modulated brain hemodynamics by inducing cerebrovascular
vasodilation in an intact brain. An ultrasound device of the
present invention may alter brain activity by altering
cerebrovascular blood flow and indirectly increase or decrease
neuronal activity, altering energy utilization and metabolism, or
increase oxygen to brain regions. The application of ultrasound
through treatment devices may be used to regulate the
cerebrovascular dynamics of the brain such that the blood-brain
barrier is modified in order to allow the better absorption of one
or more active agents, such as drugs or pharmaceuticals, to
specific brain regions, for example, so that the active agent is
effective in local brain regions while not affecting other
surrounding brain regions. Application of ultrasound waves to a
brain region can increase and or decrease linear blood cell density
as well as cerebrovascular flux. The modulation of blood flow can
be coupled to brain activity, but it can also be uncoupled from the
effects on brain activity. Methods of the present invention
comprise modulating blood vessel diameter in the brain of a human
or animal, comprising providing an effective amount of ultrasound,
in pulsed or continuous form, to a brain region, wherein an
effective amount of ultrasound causes vasodilation or
vasoconstriction of blood vessels in the area of the brain where
the ultrasound waves impinge.
[0109] Methods of the present invention comprise activating sensory
or motor brain regions in a subject by providing an effective
amount of ultrasound to a brain region, wherein the brain region
comprises all or part of a vestibular system, an aural region, a
visual region, an olfactory region, a proprioperceptive region,
afferents or efferents of one or more regions, or combinations
thereof. Ultrasound may be provided by an ultrasound device of the
present invention. An aspect of the present invention comprises
methods and devices that allow a human-machine interface for
communications with the subject operably attached to an ultrasound
device of the present invention to activate sensory or motor brain
regions of the subject to produce movement or to create synthetic
brain imagery. For example, such methods and devices are used for
projections of virtual sounds to auditory regions of the brain,
ability to generate virtual maps/images onto visual brain regions,
ability to control body movement patterns of an individual. Such
brain stimulation may be effected either directly or indirectly.
For example, an operator or the subject may stimulate the
vestibular system to cause the subject to make a turning motion in
order to guide that subject via GPS or other feedback from
navigation technology, or stimulate motor areas of the subject's
brain to cause the subject to make a motor action. Such methods and
devices may be used for any application, including but not limited
to, recreational, entertainment, and/or video gaming
applications.
[0110] Methods of the present invention comprise harvesting energy,
for example, to power a device of the present invention. For
example, mechanical energy generated by a physical activity such as
walking, jogging, running, peddling, etc. is converted to
electrical energy using piezopolymers or piezoelectric fiber
composites. The electrical energy produced charges or re-charges
the capacitive or battery elements which may be powering the
ultrasound transducer microcontrollers or other components of a
device. For example, a subject's footwear, i.e., boot, shoe, etc.
comprises PVDF piezopolymers or piezoelectric fiber composites
(e.g., Piezoflex from Airmar Technology Corp.). The subject's
footwear may comprise one or more microcontrollers for harvesting
the energy that is generated during the physical activity. The
electrical energy then supplies power to a device via at least one
microcontroller and at least one battery. Voltage traces confirm
energy harvesting or conversion of mechanical energy into
electrical energy using piezopolymers. FIGS. 9A and B are graphs
showing the energy produced in the conversion of mechanical energy
to electrical energy using piezopolymers.
[0111] Methods of the present invention comprise methods of
facilitating uni- and bi-directional communication between a
subject wearing an ultrasound device of the present invention and a
remote control unit or processor. The remote control unit/processor
includes but is not limited to a central command location or unit,
or its equivalents, a monitoring station for vital functions, or
its equivalents, or some type of console (e.g., gaming console). A
device of the present invention may send information or data to a
remote control unit/processor for further analysis and evaluation,
using communication networks, including but not limited to, radio
frequency (RF), wi-fi, wi-max, Bluetooth, ultrasound, and infrared
radiation. Such data include but are not limited to information
related to the subject's brain activity, vital functions such as
EEG and MEG, and the subject's global positioning. Other data
include photoacoustic tomography, information regarding the timing
of events, and force/blast information. Software and algorithms may
be used to analyze the data transmitted from the subject. Based on
the computational analysis of the data, a device may alter one or
more stimuli, such as ultrasound, being provided to the subject,
for example, provide modified ultrasound waveform patterns.
Modifications may include changes in acoustic frequency and
intensity and changes in ultrasound focusing. The changes in
ultrasound waveform patterns modify brain function to achieve a
desired outcome
[0112] The disclosed methods and devices achieve acoustic impedance
matching between water-matched ultrasound transducers and the
surface of the head of the subject. For example, one or more
water-matched ultrasound transducers are coupled to ultrasound
coupling pads and installed into an ultrasound device. The
water-matched ultrasound transducer receives voltage pulses from at
least one microcontroller of an ultrasound device. For example, the
ultrasound transducer is in electrical communication with a
microcontroller at one position of the transducer, and contacts an
ultrasound coupling pad at a different location of the transducer.
The ultrasound coupling pad is in contact with the transducer in
one location and, in another location of the pad, is in contact
with the surface of the head of the wearer of the device. For
example, the transducer transits from the outside of the body of
the device to the inner surface of the device. At the outer surface
of the body of the device, the transducer is operably connected to
a microcontroller, either remotely or by an electrical means such
as a wire. At the inner surface of the body of the device, the
transducer is in contact with the ultrasound coupling pad. The use
of ultrasound coupling pads helps provide optimal power transfer
during ultrasound transmission. Ultrasound coupling pads include
but are not limited to degassed water in a polymer bladder. One or
more ultrasound coupling pads mounted within an ultrasound device
serve to couple water-matched ultrasound transducers directly to
the subject's head surface.
[0113] The methods of providing ultrasound waves to neural tissue
or the brain to modulate brain activity may further comprise
providing other elements or treatments, such as providing
pharmaceutical or chemical compounds, and/or electrical or light
waves in conjunction with ultrasound waves. Such other elements or
treatments may be provided to a subject before, concurrently with,
or after ultrasound is provided to the subject. Methods comprising
combinations of one or more types of treatments or elements, for
example, such as ultrasound and pharmaceutical treatments, are
contemplated by the present invention.
Definitions
[0114] As used in the specification and the appended claims, the
singular forms "a," "an," and "the" include plural referents unless
the context clearly dictates otherwise. Thus, for example,
reference to "a pharmaceutical carrier" includes mixtures of two or
more such carriers, and the like.
[0115] Ranges can be expressed herein as from "about" one
particular value, and/or to "about" another particular value. When
such a range is expressed, another embodiment includes from the one
particular value and/or to the other particular value. Similarly,
when values are expressed as approximations, by use of the
antecedent "about," it will be understood that the particular value
forms another embodiment. It will be further understood that the
endpoints of each of the ranges are significant both in relation to
the other endpoint, and independently of the other endpoint. It is
also understood that there are a number of values disclosed herein,
and that each value is also herein disclosed as "about" that
particular value in addition to the value itself. For example, if
the value "10" is disclosed, then "about 10" is also disclosed. It
is also understood that when a value is disclosed that "less than
or equal to" the value, "greater than or equal to the value" and
possible ranges between values are also disclosed, as appropriately
understood by the skilled artisan. For example, if the value "10"
is disclosed the "less than or equal to 10" as well as "greater
than or equal to 10" is also disclosed. It is also understood that
the throughout the application, data is provided in a number of
different formats, and that this data, represents endpoints and
starting points, and ranges for any combination of the data points.
For example, if a particular data point "10" and a particular data
point 15 are disclosed, it is understood that greater than, greater
than or equal to, less than, less than or equal to, and equal to 10
and 15 are considered disclosed as well as between 10 and 15. It is
also understood that each unit between two particular units are
also disclosed. For example, if 10 and 15 are disclosed, then 11,
12, 13, and 14 are also disclosed.
[0116] In this specification and in the claims which follow,
reference will be made to a number of terms which shall be defined
to have the following meanings:
[0117] "Optional" or "optionally" means that the subsequently
described event or circumstance may or may not occur, and that the
description includes instances where said event or circumstance
occurs and instances where it does not.
[0118] The term "treating" refers to inhibiting, preventing,
curing, reversing, attenuating, alleviating, minimizing,
suppressing or halting the deleterious effects of a disease and/or
causing the reduction, remission, or regression of a disease. Those
of skill in the art will understand that various methodologies and
assays can be used to assess the development of a disease, and
similarly, various methodologies and assays may be used to assess
the reduction, remission or regression of the disease.
[0119] "Increase" is defined throughout as 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 21, 22, 23, 24, 25,
26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,
43, 44, 45, 46, 47, 48, 49, 50 51, 52, 53, 54, 55, 56, 57, 58, 59,
60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,
77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,
94, 95, 96, 97, 98, 99, 100, 150, 200, 250, 300, 400, or 500 times
increase as compared with basal levels or a control.
EXAMPLES
Example 1
Treatment of TBI
[0120] A person is injured and has traumatic brain injury resulting
from exposure to a blast from an explosion. Because this person is
a military service member, the person is wearing an anti-ballistic
helmet comprising ultrasound transducers. The ultrasound
transducers are located in a phased array or as single transducer
elements. A sensor in the helmet registers the pressure force of
the blast and communicates wirelessly to a remote control position
located a distance from the blast zone that a blast has occurred. A
GPS signal is sent that provides data about the location of device.
A sensor, located in the attachment straps of the helmet, relays
data that the device is still attached to the subject. Other
sensors relay data about the subject's physical condition such as
heart rate, brain activity, blood pressure, etc. The EEG data shows
a location of injury to the brain that indicates traumatic brain
injury. In some embodiments, treatment may be provided by way of
transducers that are not comprised in an anti-ballistic helmet, but
through a portable treatment unit that can be administered by
emergency responding personnel such as a combat medic. Such a
portable treatment unit may be comprised of one or more ultrasound
transducers and can be handheld or not. A portable treatment unit
may also comprise EEG electrodes in order to monitor brain
activity.
[0121] Upon receiving the data, the remote site responds by
transmitting data and ultrasound wave process data to the
transducers in the phased array of the helmet. A microcontroller
changes the orientation of some of the transducers in and adjacent
to the phased array. The ultrasound transducers provide a focused
ultrasound treatment to the site of traumatic brain injury,
comprising providing ultrasound waves at 0.5 MHz and 100
mW/cm.sup.2. The ultrasound transducers also provide focused and
unfocused ultrasound waves ranging from 25 kHz to 50 MHz to areas
around the injury site to ameliorate secondary effects from the
traumatic brain injury. Medical personnel are sent to the blast
site and the subject using GPS locational data. While undergoing
ultrasound treatment, the subject is transported to a hospital.
Example 2
Alteration of Memory
[0122] A human with post-traumatic stress disorder (PTSD), such as
that resulting from combat stress, presents to a psychiatrist
requesting relief from disturbing memories. An ultrasound device of
the present invention is placed on the human subject's head and
unfocused ultrasound ranging from 25 kHz to 50 MHz is applied in
multiple treatments to modulate brain function in a manner that
alters neuronal plasticity such that the formation of memories
related to specific events are blocked. Concurrently with
ultrasound therapy, the subject is administered anti-anxiety
medication, a serotonin release inhibitor, SRI. The ultrasound
waves target one or more brain regions, comprising the hippocampal
formation, hippocampus proper, limbic system, amygdala, thalamus,
cerebellum, striatum, etorhinal cortex, perirhinal cortex, and
cerebral cortex (including prefrontal cortex, auditory cortex,
visual cortex, somatosensory cortex, and/or motor cortex), brain
afferents or brain efferents of said regions, or combinations
thereof. One treatment comprises providing ultrasound waves at 30
MHz and 300 mW/cm.sup.2 to the amygdala in multiples of 250
milliseconds with a rest period of 500 milliseconds for 10 minutes,
evoking the memory by recall of the events, and repeating the
treatment when the memory is evoked. In other treatments ultrasound
ranging in single or multiple frequencies ranging from 25 kHz to 50
MHz can be used to treat the brain in a pulsed or continuous wave
mode at intensities less than 1 W/cm.sup.2 in single or multiple
repeat sessions as needed. After several days to weeks of
treatment, the subject reports less depression, fewer panic
attacks, and is able to return to many every day activities such as
socializing with friends.
Example 3
Reduction of Anxiety
[0123] A person is being trained to operate a space craft and a
reduction in stress responses is sought in performing emergency
response training. While training in performing specific emergency
response activities, the person wears an ultrasound device
comprising an astronaut helmet and ultrasound transducers.
Ultrasound waves are provided to the person's brain to modulate one
or more of noradrenaline, epinephrine, norepinephrine (NE),
acetylcholine (ACh), cortisol, corticotropin-releasing hormone
(CRH), adrenocorticotropic hormone (ACTH), or glucocorticoids, and
brain structures including the locus ceruleus, the paraventricular
nucleus of the hypothalamus (PVN), the autonomic nervous system,
the sympathetic nervous system; ("fight-or-flight" response),
hypothalamic-pituitary-adrenal axis (HPA), adrenal medulla, and the
pons. For example, one treatment comprises providing unfocused
ultrasound waves at 50 MHz and 40 mW/cm.sup.2 by sweeping the
hypothalamic-pituitary-adrenal axis (HPA), and providing focused
ultrasound waves through an acoustic hyperlens to the pons at 200
kHz and 40 W/cm.sup.2. After several training sessions during which
ultrasound treatments are provided, the stress response, as
measured by physiological data such as respiration rate, heart rate
and blood pressure, and by levels of adrenalin, is lowered in the
person.
Example 4
Activation of Brain Regions for Arousal and Attention
[0124] A pilot flying airline routes from New York to Tokyo wears
an ultrasound device of the present invention. The body of the
device is formed so that a phased array of ultrasound transducers
is positioned to provide ultrasound waves to the prefrontal cortex,
basal forebrain, the hypothalamus, tuberomamillary nuclei,
basolateral amygdala, ventral tegmental area, medial forebrain
bundle, locus ceruleus, the thalamus, and the dorsal raphe nucleus.
A sensor in the device, for example, an MEG or EEG sensor can
detect specific thalamocortical oscillations (.about.40 Hz) known
to occur during wakefulness or alertness. When the MEG or EEG
sensor detects fewer thalamocortical oscillations or other
frequency band oscillations that indicate lessened wakefulness, the
sensor data activates a controller imbedded in the device body to
activate the ultrasound array to provide unfocused ultrasound waves
from about 100 kHz to about 2.5 MHz in a sweeping frequency
arrangement and an intensity of 250 mW/cm.sup.2 to the
hypothalamus, basolateral amygdala, medial forebrain bundle, locus
ceruleus, the thalamus, and the dorsal raphe nucleus. The pilot is
restored to a wakeful state and continues to fly the airplane in an
alert condition.
Example 5
Reward Behaviors
[0125] A person has road rage attacks and experiences a road rage
attack every day while driving to work. In treatment of this
condition, the person begins wearing an ultrasound device of the
present invention. When the person controls the rage response
successfully, the person then activates the ultrasound device to
provide ultrasound waves to a brain region for reward pathways,
such as the mesolimbic and mesocortical pathways, including
connections between the medial forebrain bundle (MFB) and its
connections to the nucleus accumbens (NA) wherein dopamine DA acts
as a neuromodulator, the prefrontal cortex, the anterior cingulate
cortex (ACC), basolateral amygdaia (BLA), or the ventral tegmental
area (VTA), as well as depaminergic, glutamtergic, serotonergic,
and cholinergic systems to gain the reinforcing/pleasure inducing
ICSS of those brain nuclei. Ultrasounds waves at 200 kHz and 300
mW/cm.sup.2 are provided in 100 millisecond pulses for 3 minutes. A
cooling unit is provided in the device that also functions as an
ultrasound coupling pad to aid in transmission of the ultrasound
waves. Occasionally when tempted to engage in the deleterious road
rage behavior, a reward pathway is activated and the subject is
distracted from the road rage.
Example 6
Virtual Applications and Peripheral and Cranial Nerves
[0126] A device of the present invention is used to provide a
virtual experience to a person by providing ultrasound waves that
modulate brain activity in the vestibular system, aural region, and
a visual region. The subject wears an ultrasound device of the
present invention that provides ultrasound waves in a focused
manner from about 100 kHz to 10 MHz while the virtual experience is
desired. The subject may visually follows a display unit of a
computer running software that provides the visual cues of the
experience, for example a training exercise or a video game. The
subject responds with movements or the sensation of movement, hears
sounds and/or sees aspects of the training program when the
ultrasound waves are impinging on the brain regions or the
periphery. In an embodiment, ultrasound may be delivered to the
vestibular nerve or the vestibular system to alter the sensation of
balance. The modulation of the sense of balance can be coupled to a
visual display during the virtual experience such that the subject
experiences motion or the sense of movement.
[0127] In an embodiment, a device of the present invention is used
to provide somatosensory feedback to the hands or feet of the
subject by delivering pulsed or continuous wave ultrasound to the
periphery. In such an embodiment the ultrasound can be delivered to
at least one hand by a glove or other handheld device such as a
videogame controller, cellular/mobile telephone or PDA, or to a
foot by a shoe, or videogame controller, cellular/mobile telephone
or PDA. The pulsed or continuous wave ultrasound can be delivered
at acoustic frequencies ranging from 25 kHz to 50 MHz at
intensities ranging from 30 mW/cm.sup.2 to 1 W/cm.sup.2 from air-
or water-matched transducers arranged as single elements or phased
arrays to produce painful, mechanical, or thermal sensations in
peripheral body structures, separate from the brain, such that
interactive experiences can be modulated. In such an embodiment,
stimulation of peripheral nerve structures with pulsed or
continuous wave ultrasound will modulate somatosensory experiences
by modulating brain activity through direct peripheral nerve
stimulation in the hands, feet, or other body part. See FIG. 20
wherein an embodiment of an ultrasound device for stimulating
peripheral nerves in the hand is shown. The stimulation of the
peripheral nerve will provide somatosensory feedback to the subject
by changing brain activity in areas of the brain responsible for
processing pain, mechanical, or thermal stimuli such as the
somatosensory cortex. The materials for the transducers can be
piezoceramics, piezopolymers, gas matrix piezoelectric transducers,
or CMUTs. These devices can also be used to characterize peripheral
nerve function by stimulating peripheral nerves to assess damage or
function and or to map body receptive fields or they can be used in
conjunction with electrical and/or magnetic stimulation to overcome
neural recruitment issues in clinical situations or for prosthetic
devices. FIG. 20A shows a glove-like device although this could be
a cell phone, pda, iPad, or video game controller. Peripheral nerve
stimulation will modify brain activity in a way other than direct
application of ultrasound to the brain. FIG. 20B shows a picture of
human skin with anatomical illustration of hair and nerve endings
for detection of heat, cold, pain, proprioperception, etc.
[0128] In a like manner, methods of the present invention comprise
stimulating cranial nerves, which are nerves that are primarily
outside the brain structure itself, for example, but not as a
limitation, the vestibular nerve, vestibulocochlear nerve, and the
trigeminal nerve. The pulsed or continuous wave ultrasound can be
delivered at acoustic frequencies ranging from 25 kHz to 50 MHz at
intensities ranging from 30 mW/cm.sup.2 to 1 W/cm.sup.2 from air-
or water-matched transducers arranged as single elements or phased
arrays.
[0129] For example, a device for modulating peripheral or cranial
nerve activity of a human or animal user using ultrasound, may
comprise an article configured to be placed on at least a portion
of the body of the user, and at least one ultrasonic transducer
coupled to the article and configured to emit ultrasound, also
referred to as acoustic energy, wherein the portion of the body of
the user that is contacted by the ultrasound is not the brain. The
article may comprise a glove, a shoe, a piece of clothing, a scarf,
a game controller, a cellular telephone, a personal digital
assistant, an iPad, a computer, a flexible material, or a
non-flexible material. The article may be shaped to be adaptable to
the portion of the body to which the ultrasound is applied. There
may be one or more ultrasound transducers coupled to the article,
and at least one ultrasound transducer is at least one of an
ultrasonic emitter, piezoelectric transducer, piezocomposite
transducer, piezopolymer, or a capacitive micromachined ultrasound
transducer. The device may comprise at least one electromagnetic
wave producing component. The device may comprise a global
positioning component. The device may comprise a controller coupled
to at least one ultrasonic transducer, wherein the controller
controls waveform and power emitted by at least one ultrasonic
transducer. The controller may be attached to the article. The
controller may be located remote to the article. The device may
comprise a plurality of ultrasonic transducers positioned in an
array of transducers. An array may be in any configuration, for
example an array of transducers may be a circular array of
transducers. The device may comprise components for focusing the
acoustical energy to one or more sites in the brain of the user.
Such focusing components are known, and include, but are not
limited to, an acoustic hyperlens or acoustic metamaterial. The
intensity of the acoustical energy is less than about 500
mW/cm.sup.2. The intensity of the acoustical energy is less than
about 100 W/cm.sup.2. The frequency of the acoustical energy is
between about 0.02 MHz and 10.0 MHz. The frequency of the
acoustical energy is between about 25 kHz and 50 MHz.
[0130] The device may comprise at least one motion control
component coupled to the article, and/or may be coupled to at least
one ultrasonic transducer, and a motion control component may be
configured to change the orientation of at least one transducer
relative to its base. The device may be configured for stimulation
of peripheral nerves. The device may be configured for stimulation
of cranial nerves. For example, the device may stimulate cranial
nerves which are distinct from brain, including, but not limited
to, the vestibular nerve, the vestibulocochlear nerve or the
trigeminal nerve. The device may provide pulsed ultrasound
waveforms, continuous ultrasound waveforms or both.
Example 7
Energy Production
[0131] A device of the present invention is powered when mechanical
energy generated by a physical activity such as walking, is
converted to electrical energy using piezopolymers or piezoelectric
fiber composites located in the shoes of the person wearing the
ultrasound device. The electrical energy produced charges or
re-charges the capacitive or battery elements which are powering
the ultrasound transducer microcontrollers or other components of a
device. The subject's shoe comprises PVDF piezopolymers and three
microcontrollers for capturing the energy that is generated during
walking. The electrical energy then supplies power to the device
where it is stored in a capacitor or battery. Two hours later,
while undergoing training, the person uses the stored power to run
the ultrasound phased array or single element transducers.
Example 8
Generation and Characterization of Pulsed US Waveforms
[0132] Immersion-type US transducers having a center frequency of
0.5 MHz (V301-SU, Olympus NDT, Waltham, Mass.) or 0.3 MHz
(GS-300-D19, Ultran, State College, PA) were used to produce US
waveforms. US pulses were generated by brief bursts of square waves
(0.2 .mu.s; 0.5 mV peak-to-peak) using an Agilent 33220A function
generator (Agilent Technologies, Inc., Santa Clara, Calif., USA).
Square waves were further amplified (50 dB gain) using a 40 W ENI
240L RF amplifier. Square waves were delivered between 0.25 and
0.50 MHz depending on the acoustic frequency desired. US pulses
were repeated at a pulse repetition frequency by triggering the
above-referenced function generator with square waves produced
using a second Agilent 33220A function generator.
[0133] The intensity characteristics of pulsed US stimulus
waveforms were characterized by recording voltage traces produced
by US pressure waves using a calibrated needle hydrophone (HNR 500,
Onda Corporation, Sunnyvale, Calif., USA) and an Agilent DS06012A
100 MHz digital oscilloscope connected to a PC. Intensity
measurements were made from targeted points inside fresh ex vivo
mouse heads corresponding to the brain region targeted. The
transcranial US waveforms were transmitted to intact brain circuits
from US transducers using custom-designed acoustic collimators
consisting of 3.0 or 4.7 mm (1 ml syringe) diameter polyethylene
tubing or 5.0 mm diameter tubing tapered to a 2.0 mm diameter
output aperture. Collimating guides were constructed so stimulated
regions of the brain were in the far field of US transmission paths
and filled with ultrasound coupling gel.
[0134] Using measurements recorded from calibrated hydrophones,
several acoustic intensity characteristics of pulsed US stimulus
waveforms were calculated based on published and industry accepted
standards (NEMA, 2004).
[0135] The pulse intensity integral (P//) was defined as
P // = .intg. p 2 ( t ) z .smallcircle. dt ##EQU00001##
where p is the instantaneous peak pressure, Z.sub.0 is the
characteristic acoustic impedance in Pa s/m defined as .rho.c where
.rho. is the density of the medium, and c is the speed of sound in
the medium. We estimated .rho. to be 1028 kg/m.sup.3 and c to be
1515 m/s for brain tissue based on previous reports (Ludwig, 1950).
The spatial-peak, pulse-average intensity (/.sub.SPPA) was defined
as
/ SPPA = P // PD ##EQU00002##
where PD is the pulse duration defined as (t)(0.9P//-0.1 P//) 1.25
as outlined by technical standards established by AIUM and NEMA
(NEMA, 2004).
[0136] The spatial-peak temporal-average intensity (/.sub.sPTA) was
defined as /.sub.SPTA=P//(PRF), where PRF is equal to the pulse
repetition frequency in hertz.
[0137] The mechanical index (MI) was defined as
MI = P r f . ##EQU00003##
In Vivo US Stimulation
[0138] Wild-type mice were used in accordance with animal-use
protocols approved by the Institutional Animal Care and Use
Committee at Arizona State University. To conduct transcranial US
stimulation of intact motor cortex, mice were anesthetized using a
ketamine-xylazine cocktail (70 mg/kg ketamine, 7 mg/kg xylazine)
administered intraperitoneally. The hair on the dorsal surface of
the head over regions corresponding to targeted brain regions was
trimmed. Mice were then placed in a custom-designed or Cunningham
mouse stereo-tax. US transducers with affixed collimators were
lowered to points above the skin corresponding to brain regions
using standard stereotactic coordinates. Collimators or transducers
were then placed on the surface of the skin above the targeted
brain region and coupled to the skin using ultrasound gel.
Transcranial pulsed US stimulus waveforms were delivered to the
targeted motor cortex or hippocampus using standard TTL triggering
protocols. Digital signal markers indicated the onset and length of
US stimulus waveforms. During some experiments, simultaneous
electrophysiological data were acquired (see below). Only in
experiments where in vivo extracellular recordings of brain
activity or brain temperature were made was a craniotomy performed.
Since cranial windows and electrode insertions were made at sites
adjacent to angled US projection lines targeting specific brain
regions, in these cases the US was still transmitted through skull
bone, although not covered by overlying skin. All other experiments
were conducted in wholly intact mice, except for some mapping
experiments that required retraction of the skin to identify
landmarks on the mouse skull. Following stimulation, animals were
either allowed to recover from anesthesia or processed as described
below.
Extracellular Recording
[0139] Extracellular activity was recorded using standard
approaches with tungsten microelectrodes (500 k.OMEGA. to 1
M.OMEGA., FHC, Inc., Bowdoin, Me., USA). Tungsten microelectrodes
were driven to recording sites through cranial windows (d=1.5 mm)
based on stereotactic coordinates and confirmed by
electrophysiological signatures. Tungsten microelectrodes were
connected to a Medusa PreAmp (RA16PA; Tucker-Davis Technologies,
Aluchua, Fla., USA) and a multichannel neurophysiology workstation
(Tucker-Davis Technologies) or a 16 channel DataWave Experimenter
and SciWorks (DataWave Technologies, Berthoud, Colo.) to acquire
extracellular activity. Raw extracellular activity in response to
pulsed US was acquired at a sampling frequency of 24.414 kHz in 10
s trial epochs. The MUA signal was resampled at 1.017 kHz and
bandpass filtered between 0.3 to 6 kHz, the LFP signal was filtered
between 1 and 120 Hz, wideband activity was filtered between 0.001
and 10 kHz, gamma band activity was filtered between 40 and 100 Hz,
and the SWP ripple band was filtered between 160 and 200 Hz. Data
analyses were subsequently performed offline.
EMG Recordings
[0140] Fine-wire EMG recordings were made using standard approaches
and a four-channel differential AC amplifier (model 1700, A-M
Systems, Inc., Sequim, Wash., USA) with 10-1000 Hz band-pass filter
and a 100.times. gain applied. Electrical interference was rejected
using a 60 Hz notch filter. EMG signals were acquired at 2 kHz
using a Digidata 1440A and pClamp or a 16 channel Data-Wave
Experimenter and SciWorks. Briefly, small barbs were made in a 2 mm
uncoated end of Teflon-coated steel wire (California Fine Wire,
Co., Grover Beach, Calif., USA). Single recording wires were then
inserted into the appropriate muscles using a 30 gauge hypodermic
syringe before being connected to the amplifier. Ground wires were
similarly constructed and subcutaneously inserted into the dorsal
surface of the neck.
Brain Temperature Recordings and Estimated Changes
[0141] Prior to US stimulation in some experiments, a small
craniotomy (d.apprxeq.2 mm) was performed on mouse temporal bone.
Following removal of dura, a 0.87 mm diameter thermocouple (TA-29,
Warner Instruments, LLC, Hamden, Conn., USA) was inserted into
motor cortex through the cranial window. The thermocouple was
connected to a monitoring device (TC-324B, Warner Instruments) and
to a Digidata 1440A to record temperature (calibrated voltage
signal=100 mV/.degree. C.) using pClamp.
[0142] The influence of US stimulus waveforms on brain temperature
change was estimated using a set of previously described equations
valid for short exposure times (O'Brien, 2007). Briefly, the
maximum temperature change (.DELTA.Tmax) was estimated to be
.DELTA. t max Q .DELTA. t C v ##EQU00004##
where .DELTA.t is the pulse exposure time, where C.sub.v is the
specific heat capacity for brain tissue .apprxeq.3.6 J/g/K (Cooper
and Trezek, 1972), and where Q is the rate at which heat is
produced defined by Nyborg (1981):
Q .smallcircle. = ap 0 2 pc ##EQU00005##
where p is the density of the medium, c is the speed of sound in
the medium as described above, where .alpha. is the absorption
coefficient of brain (.apprxeq.0.03 Np/cm for 0.5 MHz US; Goss et
al., 1978), and p.sub.0 is the pressure amplitude of US stimulus
waveforms.
Data Analyses
[0143] All electrophysiological data (MUA, LFP, and EMG) were
processed and analyzed using custom-written routines in Matlab (The
Mathworks, Natick, Mass., USA) or Clampfit (Molecular Devices).
Single spikes were isolated using a standard thresholding window.
Ultrasound waveform characteristics were analyzed using hydrophone
voltage traces and custom-written routines in Matlab and Origin
(OriginLab Corp., Northampton, Mass., USA). All histological
confocal and transmitted light images were processed and analyzed
using ImageJ (http://rsb.info.nih.gov/ij/). Electron microscopy
data were also quantified using ImageJ. All statistical analyses
were performed using SPSS (SPSS, Inc., Chicago, Ill., USA). Data
shown are mean.+-.SEM unless indicated otherwise.
Example 9
Construction and Transmission of Pulsed Ultrasound Stimulus
Waveforms into Intact Brain Circuits
[0144] US stimulus waveforms were constructed and transmitted into
the intact brains of anesthetized mice (n=192; FIG. 11A). The
optimal gains between transcranial transmission and brain
absorption occurs for US at acoustic frequencies (f)<0.65 MHz
(Hayner and Hynynen, 2001; White et al., 2006). Herein transcranial
stimulus waveforms were constructed with US having f=0.25-0.50 MHz.
Intensity characteristics of US stimulus waveforms were calculated
based on industry standards and published equations developed by
the American Institute of Ultrasound Medicine, the National
Electronics Manufacturers Association, and the United Stated Food
and Drug Administration (NEMA, 2004; see above description).
[0145] Single US pulses contained between 80 and 225 acoustic
cycles per pulse (c/p) for pulse durations (PD) lasting 0.16-0.57
ms. Single US Pulses were repeated at pulse repetition frequencies
(PRF) ranging from 1.2 to 3.0 kHz to produce spatial-peak
temporal-average intensities (/.sub.SPTA) of 21-163 mW/cm.sup.2 for
total stimulus duration ranging between 26 and 333 ms. Pulsed US
waveforms had peak rarefactional pressures (pr) of 0.070-0.097 MPa,
pulse intensity integrals (P//) of 0.017-0.095 mJ/cm.sup.2, and
spatial-peak pulse-average intensities (/.sub.SPPA) of 0.075-0.229
W/cm.sup.2. FIGS. 11A and 11B illustrate the strategy developed for
stimulating intact brain circuits with trans-cranial pulsed US. The
attenuation of US due to propagation through the hair, skin, skull,
and dura of mice was <10% (FIG. 11C), and all intensity values
reported were calculated from US pressure measurements acquired
using a calibrated hydrophone positioned with a micromanipulator
inside fresh ex vivo mouse heads at locations corresponding to the
brain circuit being targeted.
Example 10
Functional Stimulation of Intact Brain Circuits Using Pulsed
Ultrasound
[0146] The influence of pulsed US on intact motor cortex was
studied because it enables electrophysiological and behavioral
measures of brain activation. Local field potentials (LFP) and
multiunit activity (MUA) were recorded in primary motor cortex (M1)
while transmitting pulsed US (0.35 MHz, 80 c/p, 1.5 kHz PRF, 100
pulses) having an /.sub.SPTA=36.20 mW/cm.sup.2 through acoustic
collimators (d=4 7 mm) to the recording locations in anesthetized
mice (n=8; FIGS. 12A and 12B). Pulsed US triggered an LFP in M1
with a mean amplitude of -350.59.+-.43.34 .mu.V (FIG. 2B, 25 trials
each). The LFP was associated with an increase in the frequency of
cortical spikes (FIGS. 12C and 12D). This increase in spiking
evoked by pulsed US was temporally precise and apparent within 50
ms of stimulus onset (FIG. 12D). A broad range of pulsed US
waveforms were found were equally capable of stimulating intact
brain circuits as discussed below. Application of TTX (100 .mu.M)
to M1 (n=4 mice) attenuated US-evoked increases in cortical
activity, indicating that transcranial US stimulated neuronal
activity mediated by action potentials (FIG. 12B). These data
provided evidence that pulsed US can be used to directly stimulate
neuronal activity and action potentials in intact brain
circuits.
[0147] Fine-wire electromyograms (EMG) and videos of muscle
contractions in response to US stimulation of motor cortex in skin
and skull-intact were acquired in anesthetized mice. Using
transcranial US to stimulate motor cortex, muscle contraction and
movements were evoked in 92% of the mice tested. The muscle
activity triggered by US stimulation of motor cortex produced EMG
responses similar to those acquired during spontaneous muscle
twitches (FIG. 13A).
[0148] When using transducers directly coupled to the skin of mice,
bilateral stimulation with transcranial US produced the
near-simultaneous activation of several muscle groups, indicated by
tail, forepaw, and whisker movements. By using acoustic collimators
having an output aperture of d=2.0, 3.0, or 4 7 mm and by making
small (.apprxeq.2 mm) adjustments to the positioning of transducers
or collimators over motor cortex within a subject, the activity of
isolated muscle groups was differentially evoked. Despite these
intriguing observations, it was difficult to reliably generate fine
maps of mouse motor cortex using US for brain stimulation. The
likeliest explanation for this difficulty is that the
topographical/spatial segregation of different motor areas
represented on the mouse cortex are below the resolution limits of
US.
Example 11
The Influence of US Brain Stimulation Parameters on Motor Circuit
Response Properties
[0149] When bilaterally targeted to motor cortex, pulsed US (0.50
MHz, 100 cycles per pulse, 1.5 kHz PRF, 80 pulses) having an
/.sub.SPTA=64.53 mW/cm.sup.2 triggered tail twitches and EMG
activity in the lumbosacrocaudalis dorsalis lateralis muscle with a
mean response latency of 22.65.+-.1.70 ms (n=26 mice). When
unilaterally transmitted to targeted regions of motor cortex using
a collimator (d=3 mm), pulsed US (0.35 MHz, 80 c/p, 2.5 kHz PRF,
150 pulses) having an /.sub.SPTA=42.90 mW/cm.sup.2 triggered an EMG
response in the contralateral triceps brachii muscle with a mean
response with latency of 20.88.+-.1.46 ms (n=17 mice). With nearly
identical response latencies (21.29.+-.1.58 ms), activation of the
ipsilateral triceps brachii was also observed in .about.70% of
these unilateral stimulation cases. Although consistent from trial
to trial (FIG. 13B), the EMG response latencies produced by US
brain stimulation were .apprxeq.10 ms slower those obtained using
optogenetic methods and intracranial electrodes to stimulate motor
cortex (Ayling et al., 2009). Several reports show that TMS also
produces response latencies slower than those obtained with
intracranial electrodes (Barker, 1999). Discrepancies among the
response latencies observed between electrical and US methods of
brain stimulation are possibly due to differences in the
time-varying energy profiles that these methods impact on brain
circuits. The underlying core mechanisms of action responsible for
mediating each brain-stimulation method are additional factors
likely to influence the different response times.
[0150] The baseline failure rate in obtaining US-evoked motor
responses was <5% when multiple stimulus trials were repeated
once every 4-10 s for time periods up to 50 min (FIG. 13B). As
observed for response latencies in acute experiments, the peak
amplitudes of EMG responses evoked by transcranial pulsed US were
stable across trial number (FIG. 13B). In more chronic situations,
repeated US stimulation experiments were performed within
individual subjects (n=5 mice) on days 0, 7, and 14 using a trial
repetition frequency of 0.1 Hz for 12-15 min each day. In these
experiments, there were no differences in the peak amplitudes of
the US-evoked EMG responses across days (day 0 mean peak EMG
amplitude=40.26.+-.0.99 .mu.V, day 7=43.06.+-.1.52 .mu.V, day
14=42.50.+-.1.42 .mu.V; ANOVA F2 1303=1.47, p=0.23; FIG. 54A).
These data demonstrate the ability of transcranial US to
successfully stimulate brain circuit activity across multiple time
periods spanning minutes (FIG. 13B) to weeks.
[0151] By examining EMG failure rates in eight mice, the success of
achieving motor activation was affected when stimulus trials were
repeated in more rapid succession was studied. The mean EMG failure
probability significantly increased (p<0.001) as the rate of US
stimulus delivery increased from 0.25 to 5 Hz (FIG. 13C). These
data suggest that brain stimulation with US may not be useful at
stimulation frequencies above 5 Hz.
[0152] Application of TTX to motor cortex blocked EMG activity,
which indicates that pulsed US triggers cortical action potentials
to drive peripheral mustcle contractions (n=4 mice; FIG. 13D). The
intensities of US stimuli studied were <500 mW/cm.sup.2, where
mechanical bioeffects have been well documented in the absence of
thermal effects (Dalecki, 2004; Dinno et al., 1989; O'Brien, 2007;
ter Haar, 2007). To confirm these observations in brain tissue, the
temperature of motor cortex in response to US waveforms having
different pulse duration (PD) times were monitored. Equations for
estimating thermal absorption of US in biological tissues indicated
that PD times are a critical factor for heat generation (O'Brien,
2007) and predict that 0.5 MHz US pulses exerting a .rho..sub.r of
0.097 MPa for a PD of 0.57 ms should produce a temperature increase
of 2.8.times.10-6.degree. C. in brain. All US stimulus waveforms
used in this study had .rho..sub.r values <0.097 MPa and PD
times <0.57 ms. None of the US waveforms used to stimulate
cortex elicited a significant change in cortical temperature within
our 0.01.degree. C. resolution limits (FIG. 13E). US pulses with
.rho..sub.r values of 0.1 MPa and PD times >50 ms were required
to produce a nominal temperature change (.DELTA.T) of 0.02.degree.
C. (FIG. 13E).
[0153] Acoustic frequencies and intensities across the ranges
studied influenced US-evoked EMG responses from the triceps brachii
of mice (n=20). Motor cortex was stimulated using 20 distinct
pulsed US waveforms composed with different US frequencies (0.25,
0.35, 0.425, and 0.5 MHz) and having varied intensities. The
sequence of which different waveforms were used were randomized in
individual stimulus trials to avoid order effects. Relative
comparisons of EMG amplitudes across animals can be influenced by
many factors, including electrode placement, number of fibers
recorded from, variation in noise levels, and differential fiber
recruitment, which can be handled using normalization techniques to
reduce intersubject variability. To examine US-evoked EMG responses
having the same dynamic range across animals, the peak amplitude of
individual EMG responses was normalized to the maximum-peak
amplitude EMG obtained for an animal and forced its minimum-peak
amplitude EMG response through zero. A two-way ANOVA revealed a
significant main effect of US frequency on EMG amplitude, where
lower frequencies produced more robust EMG responses (F3 1085=3.95,
p<0.01; FIG. 14A). The two-way ANOVA also revealed a significant
main effect of intensity (/.sub.SPTA) on EMG amplitudes (F19,
1085=9.78, p<0.001; FIG. 4B), indicating that lower intensities
triggered more robust EMG responses. The two-way ANOVA also
revealed a significant frequency x intensity interaction (F3,
1085=7.25, p<0.01; FIG. 4C), indicating differential effects of
US waveforms on neuronal activity as a function of frequency and
intensity. The EMG response latencies were not affected by either
frequency or intensity (data not shown).
Example 12
Spatial Distribution of Brain Circuit Activation with Transcranial
Pulsed Ultrasound
[0154] To characterize the spatial distribution of US-evoked
activity, functional activity maps were constructed using
antibodies against c-fos (n=4 mice). To facilitate data
interpretation, intact brain tissue having a relatively planar
surface and prominent subcortical structures was stimulated. The
acoustic collimators (d=2 mm) were centered over the skull covering
the right hemisphere from 1.2 mm to 3.2 mm of Bregma and 0.5 mm to
2 5 mm lateral of the midline using stereo-tactic coordinates (FIG.
15A; Franklin and Paxinos, 2007). The smallest-diameter collimator
was used to characterize the minimal resolution of the
brain-stimulation method since it is expected that larger
collimators will produce larger areas of brain activation. Pulsed
US (0.35 MHz, 50 c/p, 1.5 kHz PRF, 500 pulses) having an
/.sub.SPTA=36.20 mW/cm.sup.2 was transmitted along a vertical axis
parallel to the sagittal plane through underlying brain regions
once every 2 s for 30 min. Following a 45 min recovery period, mice
were sacrificed and their brains were harvested for histology.
[0155] Coronal sections from brain regions spanning +0.25 mm to
4.20 mm of Bregma were prepared (FIG. 15A). Individual sections
spaced every 125 .mu.m were then immunolabeled using antibodies
against c-fos and imaged using transmitted light microscopy. c-fos+
cell densities in 250.times.250 .mu.m squares were quantified for
entire coronal sections, corrected for tissue shrinkage, and
developed brain activity maps by plotting c-fos+ cell densities in
250.times.250.mu.m pixels onto their corresponding anatomical
locations using mouse brain atlas plates (Franklin and Paxinos,
2007). Representative raw data and functional activity maps coding
c-fos+ cell density using a pseudocolor lookup table for
visualization purposes are shown in FIGS. 15B-15D. The lateral
resolution of pulsed US along the rostral-caudal brain axis was
estimated by analyzing regions of dorsal cortex (0.25-1.0 mm deep;
0.75-1.50 mm lateral of the midline) for each coronal section
(FIGS. 15A-15D). An ANOVA comparing the mean c-fos+ cell densities
for each 250.times.250 .mu.m square region collapsed across animals
revealed that pulsed US produced a significant increase in the
density of c-fos+ cells (ANOVA, F646=73.39, p<0.001;
contralateral control hemisphere mean c-fos+ cell
density=16.29.+-.0.20 cells/6.25.times.10-2 mm2 compared to US
stim=19.82.+-.0.36 cells/6.25.times.10-2 mm2) Subsequent pairwise
comparisons of stimulated versus contralateral control cortex
revealed that US stimulation produced a significant increase in
c-fos+ cell densities for a 1 5 mm region along the rostral-caudal
axis (1.38 mm to -2.88 mm of Bregma) under the 2.0 mm diameter
stimulation zone (FIG. 15E). Similar analyses along the
medial-lateral axis of dorsal cortex revealed a significant
increase (p<0.05) in c-fos+ cell densities for a 2.0 mm wide
region of brain tissue under the stimulation zone. A smearing of
elevated c-fos+ cell densities was observed lateral to the
stimulation zone, which could be attributed to nonlinearities in
the acoustic collimators the corticocortical lateral spread of
activity, and/or slight lateral variations in the positioning of
our collimators.
[0156] By examining the effects of pulsed US along the
dorsal-ventral axis within the stimulation zone (0.5-2.5 mm medial
to lateral; -1.2 to 3 2 mm of Bregma), the density of c-fos+ cells
was found to be significantly higher (p<0.05) compared to
contralateral controls in the superficial 1.0 mm of tissue. While
there were trends of higher c-fos+ cell densities in some deeper
nuclei of stimulated hemispheres, only one significant difference
was observed in a deep-brain region.
[0157] The elevated c-fos here may have been produced by standing
waves or reflections, since higher c-fos+ cell densities were
generally observed near the skull base. It was expected to observe
elevated c-fos+ levels uniformly along the dorsal-ventral axis of
stimulated regions due to the transmission/absorption properties of
US in brain tissue. For >1.5 mm of the 2 0 mm diameter cortical
area targeted with US in these mapping studies, regions deeper than
.apprxeq.1 mm were ventral to dense white matter tracts (corpus
callosum) in the brain. Interestingly, unmyelinated C-fibers have
been shown to be more sensitive to US than myelinated
A.differential. fibers (Young and Henneman, 1961). Effectively
blocking US-evoked activity in subcortical regions, it was thought
that low-intensity US fields may have been absorbed/scattered by
dense white matter tracts in these mapping studies as a function of
the US transmission path implemented. It was possible to stimulate
subcortical brain regions with transcranial US by employing
different targeting approaches.
Example 13
Remote Stimulation of the Intact Mouse Hippocampus Using
Transcranial Pulsed US
[0158] To address the issue of subcortical stimulation of deep
brain circuits, the intact mouse hippocampus was used, since pulsed
US waveforms have been shown to elicit action potentials and
synaptic transmission in hippocampal slices (Tyler et al., 2008).
Extracellular recordings of US-evoked activity in the CA1 stratum
pyramidale (s.p.) cell body layer of dorsal hippocampus (n=7 mice)
were performed. Prompted by observations regarding the potential
disruption of US fields by dense white matter tracts, a targeting
approach bypassing the dense white matter of the corpus callosum
was used when transmitting pulsed US to the hippocampus.
[0159] An angled line of US transmission through the brain was used
by positioning acoustic collimators 50.degree. from a vertical axis
along the sagittal plane. The output aperture of collimators (d=2
mm) were unilaterally centered over 4.5 mm of Bregma and 1.5 mm
lateral of the midline (FIG. 16A). A 30.degree. approach angle was
used to drive tungsten microelectrodes to the CA1 s.p. region of
hippocampus through cranial windows (d=1.5 mm) centered
approximately 1.0 mm of Bregma (FIG. 16A). Pulsed US (0.25 MHz, 40
cycles per pulse, 2.0 kHz PRF, 650 pulses) having an
/.sub.SPTA=84.32 mW/cm.sup.2 reliably triggered an initial LFP with
a mean amplitude of 168.94.+-.0.04 .mu.V (50 trials each) and a
mean response latency of 123.24.+-.4.44 ms following stimulus onset
(FIG. 16B). This initial LFP was followed by a period of
after-discharge activity lasting <3 s (FIG. 16B). These
short-lived after-discharges did not appear to reflect abnormal
circuit activity as observed during epileptogenesis (Bragin et al.,
1997; McNamara, 1994; Racine, 1972). In fact, hippocampal
after-discharges lasting more than 10 s are indicative of seizure
activity (Racine, 1972).
[0160] Pulsed US produced a significant (p<0.01) increase in
spike frequency lasting 1.73.+-.0.12 s (FIG. 7B). Natural activity
patterns in the CA1 region of hippocampus exhibit gamma (40-100
Hz), sharp-wave (SPW) "ripple" (160-200 Hz), and other
frequency-band oscillations reflecting specific behavioral states
of an animal (Bragin et al., 1995; Buzsaki, 1989, 1996; Buzsaki et
al., 1992). Sharp-wave ripples (.apprxeq.20 ms oscillations at
.apprxeq.200 Hz) in CA1 result from the synchronized bursting of
small populations of CA1 pyramidal neurons (Buzsaki et al., 1992;
Ylinen et al., 1995) and have recently been shown to underlie
memory storage in behaving rodents (Girardeau et al., 2009;
Nakashiba et al., 2009). On the other hand, the consequences of
gamma oscillations in the CA1 region of the hippocampus are not as
well understood but are believed to stem from the intrinsic
oscillatory properties of inhibitory interneurons (Bragin et al.,
1995; Buzsaki, 1996). By decomposing the frequency components of
wideband (1-10,000 Hz) activity patterns evoked by pulsed US, it
was found that all after-discharges contained both gamma
oscillations and SWP ripple oscillations lasting <3 s (FIG.
16C). These data demonstrated that pulsed US stimulated intact
mouse hippocampus while evoking synchronous activity patterns and
network oscillations; hallmark features of intrinsic hippocampal
circuitry.
[0161] Brain-derived neurotrophic factor (BDNF) is one of the most
potent neuromodulators of hippocampal plasticity, and its
expression/secretion is known to be regulated by neuronal activity
(Lessmann et al., 2003; Poo, 2001). BDNF protein expression levels
in the hippocampus were examined following transcranial stimulation
with pulsed US. Unilateral hippocampi of mice (n=7) were targeted
and stimulated with pulsed US (0.35 MHz, 50 cycles per pulse, 1.5
kHz PRF, 500 pulses) having an /.sub.SPTA=36.20 mW/cm.sup.2 every 2
s for 30 min. Following a 45 min recovery period, mice were
sacrificed and their brains removed, sectioned, and immunolabeled
with antibodies against BDNF. Pulsed US induced a significant
increase in the density of BDNF+ puncta in CA1 s.p. (contralateral
control=149.64.+-.11.49 BDNF+ puncta/7.5.times.10.sup.-2 mm2 from
0.61 mm2 CA1 region/mouse versus US stim=221.50.+-.8.75 BDNF+
puncta/7.5.times.10.sup.-2 mm.sup.2 from 0.61 mm2 CA1 region/mouse;
t test, p<0.001; FIG. 16D). Similar significant increases were
observed in the CA3 s.p. region (contralateral
control=206.20.+-.19.68 BDNF+ puncta/7.5.times.10-2 mm2 from 0.61
mm2 CA3 region/mouse versus US stim=324.82.+-.27.94 BDNF+
puncta/7.5.times.10.sup.-2 mm.sup.2 from 0.61 mm.sup.2 CA3
region/mouse; t test, p<0.005; FIG. 16D). These data
demonstrated that pulsed US can be used to remotely stimulate
neuronal activity in the intact mouse hippocampus. The increased
synchronous activity and elevated BDNF expression patterns produced
by pulsed US show that transcranial US can be used to promote
endogenous brain plasticity.
Example 14
Modifying Cognitive Performance
[0162] Referring to FIG. 17, a stimulus method for modifying
cognitive performance was performed. Mice (n=4) were stimulated for
five minutes with transcranial ultrasound using the pulse
parameters shown in FIG. 17A, or sham treated the mice (n=3). Mice
were allowed to rest for one minute then they were placed in a
Morris Water Maze (MWM) with a hidden platform and allowed to swim
in the MWM until they a) found the escape platform or b) three
minutes had elapsed at which point they were moved to the platform.
The mice then rested 30 minutes before undergoing the stimulation
or sham procedure again for a total of 4 trials per day for three
consecutive days. On day four, mice were not stimulated or sham
treated and were placed in the MWM where the platform had been
removed. The time the mice spent swimming in the correct quadrant
was recorded. Longer times in the correct quadrant indicated a
better memory of where the escape platform had been located. As
shown in the plot on the far right of FIG. 17B, stimulated mice
spent less time in the correct quadrant indicating that had not
learned or remembered where the platform was as well as sham mice.
The first two plots from left (17B) show stimulated mice take
longer to find the escape platform across days (far left plot shows
impaired learning). The slower task acquisition curve on the far
left for stimulated animals shows it took the mice longer to learn
the task compared to sham controls which had a faster acquisition
curve. Upon closer examination of trial to trial data within days
(middle plot), stimulated mice did not remember where the platform
was from trial to trial or from day to day as well as control mice.
The two figures at far left show stimulated mice took longer to
locate the escape platform due to learning and memory impairments
evoked by brain stimulation with ultrasound. More specifically, the
data in FIG. 17B show that mice receiving hippocampal stimulation
in the absence of task context just prior to the context-dependent
spatial learning task could not perform as well as sham controls.
The data indicated that pulsed ultrasonic stimulation of the
hippocampus delivered close in time to a task requiring specific
brain wave activity patterns to perform optimally was used to
disrupt cognition by providing a masking pattern of brain wave
activity. Such a strategy can enable the use of pulsed ultrasound
to disrupt cognitive processes such as learning and memory. Brain
regulation devices of various embodiments described herein can be
used to deliver pulsed ultrasound to the intact hippocampus and
associated brain regions in order to modify cognitive processes
including but not limited to disrupting normal cognition. These
data show that pulsed ultrasound can be delivered through brain
regulation devices disclosed herein to enhance cognitive processes
or improve learning and memory. An aspect of the invention
comprises use of chronic repeated ultrasound stimulation to
increase the strength of synapses such that learning and memory is
improved. Methods of the present invention comprise use of brain
regulation devices to deliver ultrasound targeted to the
hippocampus and modify cognitive performance by impairing and or
enhancing learning and memory, depending on the desired need to
modify brain function and performance
Example 15
Use of Ultrasound for Enhancing Cognitive Processes
[0163] Referring to FIG. 18A-18B, methods disclosed herein were
used for enhancing cognitive processes. Transcranial ultrasound was
used to noninvasively enhance cognitive processes, such as learning
and memory. Pulsed ultrasound can stimulate the intact hippocampus
by driving synchronous oscillations in the gamma and sharp-wave
ripple bands, which are known to underlie hippocampal plasticity
and learning and memory.
[0164] Transcranial ultrasound can upregulate BDNF signaling in the
hippocampus. BDNF is one of the most potent modulators of brain
plasticity. Very specific temporal patterns of brain activity are
required to learn and remember. Disruption of such patterns with
pulsed ultrasound occurred when the brain was stimulated with a
brain regulation device using ultrasound at times very close to the
training task. In order to enhance cognition, the intact
hippocampus of mice (n=3) was stimulated with US for five minutes
per day for 7 days prior to the mice undergoing training on the
Morris Water Maze task. See FIG. 18A for ultrasound parameters. The
mice were not stimulated with US immediately before training,
instead mice were only stimulated on days 1-7 prior to training. On
day 8, mice were trained on the MWM task. As shown in the left line
plot of FIG. 18B, mice receiving stimulation learned the MWM task
faster than sham controls (n=3). Further, stimulated mice
remembered where the platform was better than sham controls as
indicated by the time spent in the correct quadrant when the escape
platform was removed on day 4 (histogram right).
Example 16
Noninvasive Ultrasound Neuromodulation for Status Epilepticus
(SE)
[0165] Status epilepticus (SE) refractory to conventional
anti-epileptic drugs typically has a poor prognosis, but patients
may recover well if seizures can be stopped. Nearly 40% of patient
with SE will be refractory to first line of therapy.
[0166] Recent pioneering studies illustrate the ability of pulsed
ultrasound in remotely modulating intact brain circuit activity
(Tufail et al., 2010), herein incorporated in its entirety.
Transcranial pulsed ultrasound (TPU) can also synchronize intact
hippocampal oscillations in high-frequency and gamma bands without
producing damage or rise in brain temperature (Tufail et al.,
2010). Though not wishing to be bound by any particular theory, it
is thought that epileptic seizures are attributed to runaway
excitation of certain brain circuitries and since electrical and
magnetic brain stimulation have been shown capable of terminating
electrographic seizure activity (Andrews, 2003; Hamani et al.,
2009), pulsed or continuous wave US stimulation can be used
interfere with or stop abnormal activity associated with SE.
[0167] FIG. 19 illustrates that transcranial pulsed ultrasound can
be used to modulate brain activity to study and or treat
neurological diseases. (A) Shows EMG recordings in response to
transcranial ultrasound stimuli delivered to the brain of normal
mice in a continuous wave mode for 5 seconds. The brain activity
pattern stimulated by continuous wave transcranial ultrasound is
indicative of that observed during epileptic seizure activity. Such
seizure activity patterns are known to occur for ten seconds or
longer following the onset of a brain stimulus as shown by the EMG
traces in response to transcranial stimulation of brain tissues
with continuous wave ultrasound. Evoking such seizure activity
patterns can be helpful in studying epilepsy by mapping diseased or
prone circuits, as well as by using ultrasound to modulate abnormal
brain activity patterns to screen for pharmacological compounds or
genes useful for treating such dysfunctional brain activity. The
data in panel (A) triggered with continuous wave ultrasound showed
that transcranial ultrasound can influence brain activity depending
on the ultrasound stimulus waveform used and depending on the
desired outcome. (B) A mouse is shown at left immediately after
being injected with kainic acid to produce a standard model of
epilepsy. EMG activity before (top right) and after (bottom right)
the onset of epileptic seizure activity is illustrated. The EMG
traces on the bottom right show the presence of seizure activity as
indicated by the increased persistent EMG activity compared to the
pre-seizure trace on the top right. (C) EMG traces showing that
brain stimulation achieved with transcranial ultrasound was used to
terminate seizure activity in a mouse model of epilepsy. Four
different examples (FIG. 19C) illustrate the delivery of
transcranial ultrasound was capable of quickly attenuating
pronounced seizure activity as indicated by the decreasing EMG
amplitude soon after the delivery of a transcranial ultrasound
stimulus waveform. Such an effect of focused and or unfocused
ultrasound on diseased brain activity can be administered manually
in response to seizures detected visually or by way of EEG or EMG
activity.
[0168] In an embodiment of the present invention, methods and
devices disclosed herein for the delivery of ultrasound to the
brain can be controlled automatically to provide US to the brain in
response to seizure activity detected by EEG, EMG, MEG, MRI, or
other readout of brain activity. An advantage of using ultrasound
to modulate abnormal brain activity such as SE is that it is rapid
and noninvasive. As taught here to treat epileptic seizure
activity, the rapid response times and fast ability to treat
diseased brain circuits with either focused or unfocused ultrasound
provide a life saving treatment or may lead to improved recovery
outcomes due to its rapid intervention to prevent excitotoxicity or
other metabolic dysfunction arising from injured brain. When
provided for the treatment of epilepsy or other diseased or injury
states such as those suffered by mild or severe traumatic brain
injuries, ultrasound can provide a first line of treatment to
dampen abnormal brain activity or to increase neuroprotective
factor activity. Ultrasound for the treatment of diseased or
injured brains can be delivered by emergency response personnel or
in neurocritical care situations in the emergency room, operating
room, a physician's office, a battlefield medical clinic, during
transport to a medical facility, or at the scene of an accident.
Here, the data on epilepsy are used as just one example of a
disease where ultrasound can be rapidly applied to the head for
modulating brain activity in a rapid response manner to provide
benefit.
* * * * *
References