U.S. patent application number 16/037974 was filed with the patent office on 2019-01-24 for device and method for non-invasive neuromodulation.
The applicant listed for this patent is The Board of Trustees of the Leland Stanford Junior University. Invention is credited to Karl Deisseroth, M. Bret Schneider.
Application Number | 20190022425 16/037974 |
Document ID | / |
Family ID | 40583766 |
Filed Date | 2019-01-24 |
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United States Patent
Application |
20190022425 |
Kind Code |
A1 |
Deisseroth; Karl ; et
al. |
January 24, 2019 |
Device And Method for Non-Invasive Neuromodulation
Abstract
One embodiment involves modifying neural transmission patterns
between neural structures and/or neural regions in a noninvasive
manner. In a related exemplary method, sound waves are directed
toward a first targeted neural structure and characteristics of the
sound waves are controlled at the first target neural structure
with respect to characteristics of sound waves at the second target
neural structure. In response, neural transmission patterns
modified to produce the intended effect (e.g., long-term
potentiation and long-term depression of the neural transmission
patterns). In a related embodiment, a transducer produces the sound
for stimulating the first neural structure and the second neural
structure, and an electronically-based control circuit is used to
control characteristics of the sound waves as described above to
modify the neural transmission patterns between the first and
second neural structures.
Inventors: |
Deisseroth; Karl; (Stanford,
CA) ; Schneider; M. Bret; (Portola Valley,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The Board of Trustees of the Leland Stanford Junior
University |
Stanford |
CA |
US |
|
|
Family ID: |
40583766 |
Appl. No.: |
16/037974 |
Filed: |
July 17, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12263026 |
Oct 31, 2008 |
10035027 |
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16037974 |
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60984225 |
Oct 31, 2007 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 7/00 20130101; A61N
2007/027 20130101; A61N 2007/0078 20130101; A61N 2007/0026
20130101; A61N 2007/0095 20130101 |
International
Class: |
A61N 7/00 20060101
A61N007/00 |
Claims
1. A system for modifying neural transmission patterns between a
first neural structure and a second neural structure, the system
comprising: a transducer arrangement configured and arranged to
produce sound for stimulating the first neural structure and the
second neural structure; a control circuit configured and arranged
to control of characteristics of sound waves at the first target
neural structure with respect to characteristics of sound waves at
the second target neural structure for modifying the neural
transmission patterns between a first neural structure and a second
neural structure; and implanted piezoelectric antennas configured
to produce an electrical current in response to the sound
waves.
2. The system of claim 1, wherein modifying the neural transmission
patterns includes one of long-term potentiation and long-term
depression of the neural transmission patterns.
3. The system of claim 1, wherein the sound waves at first target
neural structure sufficiently raise the temperature of the first
target neural structure so as to affect the firing rate of neurons
in the first target neural structure.
4. The system of claim 1, wherein the transducer arrangement
includes a plurality of transducers that are each configured and
arranged to be controlled by the control circuit.
5. A method for modifying neural transmission patterns between a
first neural structure and a second neural structure, the method
comprising: producing sound waves; directing the sound waves to
implanted piezoelectric antennas configured to produce an
electrical current in response to the sound waves at a first target
neural structure and a second target neural structure; and
controlling characteristics of sound waves at the first target
neural structure with respect to characteristics of sound waves at
the second target neural structure to modify neural transmission
patterns.
6. A device for neuromodulation comprising: one or more energy
emitters configured and arranged to emit energy that is focused to
a focal point; a targeting controller configured and arranged to
determine a location in space at which the focal point is desired;
and an aiming controller configured and arranged to direct the
focal point toward the location in space to non-destructively alter
a pattern of functional responsiveness of cells at the location in
space for a first time period to change responsiveness between two
groups of cells for a second period of time that is substantially
greater than the first period of time.
7. The device of claim 6, further including a secondary group of
one or more energy emitters, wherein each of the two groups of
cells is stimulated by one of the energy emitters.
8. The device of claim 6, wherein the responsiveness between two
groups of cells includes neural connectivity.
9. The device of claim 6, wherein the responsiveness between two
groups of cells is moderated by long-term potentiation (LTP).
10. The device of claim 6, wherein the responsiveness between two
groups of cells is moderated by long-term depression (LTD).
11. The device of claim 6, wherein the energy heats a first group
of cells of the two groups of cells thereby changing a spontaneous
firing rate of the first group of cells.
12. The device of claim 6, wherein the altering of a pattern of
functional responsiveness is due to mechanical perturbations of a
cell from the energy.
13. The device of claim 6, wherein the energy is focused using one
of a lens and a curved transducer portion.
14. The device of claim 6, wherein the energy is focused by aiming
an array of the energy emitters at the focal point.
15. A system for modifying neural transmission patterns between a
first neural structure and a second neural structure, the system
comprising: a transducer arrangement configured and arranged to
wirelessly stimulate the first neural structure and the second
neural structure; a control circuit configured and arranged to
control of characteristics of the stimulus at the first target
neural structure with respect to characteristics of sound waves at
the second target neural structure thereby modifying the neural
transmission patterns between a first neural structure and a second
neural structure; and an implanted piezoelectric antenna configured
to produce an electrical current in response to the sound
waves.
16. The system of claim 15 wherein the transducer arrangement
produces ultrasound for stimulating the first neural structure and
the second neural structure.
17. The system of claim 15 wherein the transducer arrangement
produces radio frequency energy for stimulating the first neural
structure and the second neural structure.
18. The system of claim 15 wherein the transducer arrangement
produces a magnetic field for stimulating the first neural
structure and the second neural structure.
19. The system of claim 15 wherein the transducer arrangement
produces ionizing radiation for stimulating the first neural
structure and the second neural structure.
Description
RELATED PATENT DOCUMENTS
[0001] This is a conversion of U.S. Provisional Patent Application
Ser. No. 60/984,225, entitled "Device and Method for Non-Invasive
Neuromodulation," and filed on Oct. 31, 2007, to which benefit is
claimed under 35 U.S.C. .sctn. 119.
FIELD OF THE INVENTION
[0002] The present invention relates generally to systems and
approaches for stimulation of neural circuits and more particularly
to facilitating long-term potentiation or long-term depression
between neural circuits.
BACKGROUND
[0003] Long-term potentiation (LTP) involves the process of
establishing an association between the firing of two cells or
groups of cells. For instance, Hebb's rule essentially states that
if an axon of cell A is near enough to excite a cell B and
repeatedly or persistently takes part in firing cell B, an increase
in the strength of the chemical synapse between the cells takes
place such that A's efficiency, as one of the cells firing B, is
increased. LTP has been shown to last from minutes to several
months. Conditions for establishing LTP are favorable when a
pre-synaptic neuron and a post-synaptic neuron are both depolarized
in a synchronous manner. An opposite effect, long-term depression
(LTD), has also been established. LTD is the weakening of a
neuronal synapse that lasts from hours to months. In the cerebellar
Purkinje cells, LTD results from strong synaptic stimulation. By
contrast, in the hippocampus, LTD results from persistent weak
synaptic stimulation, or when a pre-synaptic neuron and a
postsynaptic neuron discharge in an asynchronous manner. Since the
establishment of Hebb's original rule, additional "Hebb's Rules"
have been proposed for the prediction of self-organization of
neuronal systems, and these rules appear to govern the process by
which the brain is effectively sculpted over time in order to
master the demands of the environment.
[0004] Neurons and other electrically excitable cells (including
cardiac cells and some endocrine cells) have spontaneous firing
rates: they discharge action potentials at a baseline rate, in the
absence of external stimulation or suppression. This spontaneous
firing rate is affected by temperature. Generally, the warmer an
electrically excitable cell, the faster the spontaneous firing
rate, and the colder the cell, the slower the firing rate. When
cells become extremely warm, such as in a very high fever, they
have a high propensity to fire. At extremes, such an increase in
firing rates may manifest as a risk of a febrile seizure.
[0005] Neuromodulation is the control of nerve activity, and is
usually implemented for the purpose of treating disease. In the
strictest sense, neuromodulation may be accomplished with a
surgical intervention like cutting an aberrant nerve tract.
However, the semi-permanent nature of a surgical procedure leaves
little room for later adjustment and optimization. Likewise, it
could be asserted that neuromodulation can be accomplished with
chemical agents or medications. Chemical agents or medications may
be undesirable because, for example, many medications are difficult
to deliver to specific anatomy, and because the titration
(increasing or decreasing the dose of a medication) is a slow and
imprecise way to achieve a desired effect on a specific target.
Consequently, the term neuromodulation usually implies the use of
energy-delivering devices.
[0006] Several categories of device-based neuromodulation methods
are known in the art. These include electrical neuromodulation,
magnetic neuromodulation and opto-genetic neuromodulation.
[0007] Electrical nerve stimulation is well-established. Examples
of electrical approaches include transcutaneous electrical nerve
stimulation (TENS) units, and the surgically implanted electrodes
of deep brain stimulation (DBS). TENS units are used to lessen
superficial nerve pain within skin and muscle. Because the device
is non-invasive and has a low power output, its use involves little
risk. However, the efficacy of TENS is limited to nerve
distributions very close to the surface. Additionally, TENS has
little focusing ability for targeting with close tolerances.
Moreover, its therapeutic use shows a fairly small effective
treatment area. DBS is a useful approach for treating conditions
including Parkinson's disease, essential tremor, epilepsy, chronic
pain, depression and obsessive-compulsive disorder. In the case of
Parkinson's disease, a multi-contact electrode may be
neurosurgically implanted in the subthalamic nucleus of a patient.
Once connected to a pulse generation unit similar to a cardiac
pacemaker device, the electrodes may be electrically pulsed at
various rates, effectively driving the activity of the neurons
immediately adjacent to the electrode contacts, using currents of
about 3 amps and voltages between 1 and 10. Subsequently, various
configurations of electrode pairs or monopolar configurations may
be empirically tested on the patient for effect and tolerability.
At a later time, the circuit configuration or pulse parameters may
be changed by the physician in charge, usually without the need to
physically disturb the implanted electrode. One disadvantage of DBS
is that, by definition, it requires a highly invasive and risky
neurosurgical implantation procedure. If the site of implantation
is later deemed suboptimal, or if the device physically fails, more
surgery is required.
[0008] Magnetic stimulation involves the discharge of large
capacitors into an electrically conductive coil placed external to
a patient's brain or body. As electrical current runs through the
coil, a magnetic field is induced, which in turn, induces an
electric field in nerve membranes and surrounding fluid. This
forces nerves to depolarize with each discharge of the capacitors
in the machine. Magnetic stimulation, when delivered at rates of
5-20 Hz, tend to be stimulating to nerves that it affects, for some
time after the magnetic pulse delivery has stopped. Pulse rates of
less than 1 Hz tend to suppress the activity of affected nerves
after stimulation has ended. Very fast pulse trains (e.g., 50 Hz),
punctuated by absence of pulses 6-9 times per second ("theta
rhythm") also tend to suppress the activity of affected neurons.
Magnetic neuromodulation, in the form of repetitive transcranial
magnetic stimulation, is useful for the treatment of depression,
and likely several other neurological and psychiatric conditions.
The derived effects may last from minutes to months after the end
of magnetic treatment. One limitation of magnetic neuromodulation
is the difficulty in achieving tight focus of the effect, since
magnetic fields capable of penetrating to useful depth tend to be
large in footprint, as dictated by the Biot-Savart Law.
[0009] Opto-genetic neuromodulation is a newly discovered approach
which has the advantages of being neuron-type specific. Using this
approach, light-sensitive ion channels or pumps are genetically
transferred to the targeted neurons of the brain to be stimulated.
A flashing light from an implanted device provides a signal to
these channels or pumps to activate. This leads to either neuronal
depolarization, or neuronal hyperpolarization, depending upon the
nature of the light-sensitive channel or pump. Opto-genetic
approaches lend themselves to both neuronal up-regulation and
down-regulation. Disadvantages include the requirement of implanted
hardware, and the need for the genetic modification of targeted
neurons.
[0010] Ultrasound is mechanical vibration at frequencies above the
range of human hearing, or above 16 kHz. Most medical uses for
ultrasound use frequencies in the range of 1 to 20 MHz. Low to
medium intensity ultrasound products are widely used by physicians,
nurses, physical therapists, masseurs and athletic trainers. The
most common applications are probably wanning stiff, swollen or
painful joints or muscles in a manner similar to a hot compress,
but with better penetration. Many ultrasound products have been
commercially available for years, including consumer-grade massage
machines. By design, the power on these devices is designed to be
too low to warm or otherwise affect structures more than two
centimeters or so below the surface. Also, these devices are not
capable of tight focus at depth, nor are there means for accurately
aiming such devices toward precise structural coordinates within
the body. As ultrasound of sufficient strength can cause pain in
peripheral nerves with each pulse, it is likely that mechanical
perturbations caused by ultrasound can cause nerves to
discharge.
SUMMARY OF THE INVENTION
[0011] Various aspects of the present invention are directed to
addressing the above issues and/or generally advancing technology
in the above-discussed contexts and other contexts.
[0012] In accordance with one embodiment, the present invention is
directed to methods, devices and systems that are used to modify
neural transmission patterns between neural structures and/or
regions. Consistent herewith, one exemplary method involves
directing sound waves toward a first targeted neural structure,
controlling characteristics of the sound waves at the first target
neural structure with respect to characteristics of sound waves at
the second target neural structure, and in response, modifying
neural transmission patterns. In a related embodiment, a transducer
produces the sound for stimulating the first neural structure and
the second neural structure, and an electronically-based control
circuit is used to control characteristics of the sound waves as
described above to modify the neural transmission patterns between
the first and second neural structures.
[0013] In accordance with one embodiment, the present invention is
directed to methods, devices and systems that are used to modify
neural transmission patterns between neural structures and/or
regions. Consistent herewith, one exemplary method involves
directing stimuli toward a first targeted neural structure,
controlling characteristics of the stimulus at the first target
neural structure with respect to characteristics of stimulus at the
second target neural structure, and in response, modifying neural
transmission patterns. In a related embodiment, a transducer
produces the stimulus for the first neural structure and the second
neural structure, and an electronically-based control circuit is
used to control characteristics of the stimulus as described above
to modify the neural transmission patterns between the first and
second neural structures.
[0014] As discussed with the detailed description that follows,
more specific embodiments of the present invention concern various
levels of detail for controlling the neural-transmission
modulation.
[0015] The above summary of the present invention is not intended
to describe each illustrated embodiment or every implementation of
the present invention. The figures in the detailed description that
follow more particularly exemplify these embodiments.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] The invention may be more completely understood in
consideration of the detailed description of various embodiments of
the invention that follows in connection with the accompanying
drawings, in which:
[0017] FIG. 1 shows a system for altering neural patterns between
two groups of cells, according to an example embodiment of the
present invention;
[0018] FIG. 2A shows the use of two focused-beam ultrasound
transducers physiologically suppressing the connection between two
regions, according to an example embodiment of the present
invention;
[0019] FIG. 2B shows the use of an electronically focused
ultrasound transducer array to physiologically augment the
connection between two regions, according to an example embodiment
of the present invention;
[0020] FIG. 3A shows a specific application of the present
invention in which LTP is facilitated within the "trisynaptic
circuit" of the human hippocampus, according to an example
embodiment of the present invention;
[0021] FIG. 3B shows the use of the present invention, to produce
LTP between the entorhinal cortex and the CA3 fields of a human
hippocampus, as can be used to augment the encoding of memory,
according to an example embodiment of the present invention;
[0022] FIG. 4A shows the use of two focused-beam ultrasound
transducers, each focused upon a different, but connected neural
target, according to an example embodiment of the present
invention; and
[0023] FIG. 4B shows an array of multiple small ultrasound
transducers which may be electronically directed at one or more
target regions within a patient's brain via a coordinated phase and
power adjustment, also according to the present invention.
[0024] While the invention is amenable to various modifications and
alternative forms, specifics thereof have been shown by way of
example in the drawings and will be described in detail. It should
be understood, however, that the intention is not to limit the
invention to the particular embodiments described. On the contrary,
the intention is to cover all modifications, equivalents, and
alternatives falling within the spirit and scope of the
invention.
DETAILED DESCRIPTION
[0025] The present invention is believed to be useful for enabling
practical application of a variety of LTP and LTD systems, and the
invention has been found to be particularly suited for use in
systems and methods dealing with generating LTP or LTD effects in
neural circuits through the use of sounds waves (which may include
high-intensity focused ultrasound), radio frequency (RF)
transmissions, electrical current, magnetic fields or ionizing
radiation. In the context of this invention, the terms "sound" and
"ultrasound" are used interchangeably. For simplicity, while the
present invention is not necessarily limited to such applications,
various aspects of the invention may be appreciated through a
discussion of various examples using this context.
[0026] Various embodiments of the present invention are directed
toward the use of ultrasound to produce LTP or LTD within a living
subject. Sound waves are used to stimulate a first portion of
neurons. For LTP, the sound waves are used to concurrently
stimulate a second portion of neurons in a synchronous manner. For
LTD, the sound waves are used to stimulate a second portion of
neurons in an asynchronous manner. Sound waves provide stimulation
both in terms of thermal properties and mechanical jarring. While
specific embodiments and applications thereof involve sound waves
being in the ultrasound frequency range, they need not be so
limited. For example, aspects of the present invention can employ
frequencies that are outside of the ultrasound frequency range.
[0027] In accordance with one embodiment, the present invention is
directed to a method for modifying neural transmission patterns
between neural structures. The method involves producing and
directing sound waves or RF transmissions toward a first targeted
neural structure, controlling characteristics of the sound waves or
RF transmissions at the first target neural structure with respect
to characteristics of sound waves or RF transmissions at the second
target neural structure, and thereby modifying neural transmission
patterns. In a related embodiment, a transducer produces the sound
for stimulating the first neural structure and the second neural
structure, and an electronically-based control circuit is used to
control characteristics of the sound waves as described above to
modify the neural transmission patterns between the first and
second neural structures. In another related embodiment, a RF
transmitter is used to produce RF transmissions and to focus the
transmissions toward a first target neural structure.
[0028] In a more specific embodiment, the present invention uses
High-intensity Focused Ultrasound (HIFU) as a powerful ultrasound
emitter. In connection herewith, ultrasound waves are aimed and
focused at a targeted depth geometrically, for example, by using a
lens at the emitting end, or by using a curved transducer portion
(e.g., a partial sphere). Ultrasound may also be aimed and focused
electronically, by coordinating the phase and intensity of
individual transducer elements within an array, thereby steering
the location of greatest intensity, and even correcting for
transmission distortions created, for example by inhomogeneities in
the skull. As an ultrasound wave travels through tissue, the
mechanical excitation of the tissue generates heat. Thus, the focal
point of a HIFU system may be heated substantially in response to
the ultrasound. Excessive heat may cause cell damage or even cell
death. The threshold for cell death is generally bringing the
targeted tissue to 56 degrees Celsius for one second, or 52 degrees
Celsius for a longer period of time. Also, tissues held above 43
degrees Celsius for more than an hour or so may have their
physiological processes (including cell division) interrupted.
Accordingly, to change the firing patterns of targeted neurons, the
temperature can be raised to a more moderate temperature above the
normal 37 degrees Celsius. In another example, the targeted neurons
may be raised to 40-42 degrees Celsius for repeated, brief periods
of time, resulting in an increased spontaneous firing rate, and
enabling one step of the LTP/LTD induction process.
[0029] For further information on the use of such HIFU, and related
systems, reference may be made to various literature including, for
example, U.S. Pat. No. 4,616,231, filed on Mar. 26, 1984 to Autrey
et al. and entitled "Narrow-band beam steering system," U.S. Pat.
No. 4,865,042, filed on Aug. 8, 1986 to Umemura et al. and entitled
"Ultrasonic irradiation system," U.S. Pat. No. 5,520,188, filed on
Nov. 2, 1994 to Hennige et al. and entitled "Annular array
transducer," U.S. Pat. No. 7,175,596 filed on Oct. 29, 2001 to
Vitek et al. and entitled "System and method for sensing and
locating disturbances in an energy path of a focused ultrasound
system," U.S. Pat. No. 6,805,129 filed on Oct. 27, 2000 to Pless et
al. and entitled "Apparatus and method for ablating tissue," and
U.S. Pat. No. 6,506,154 filed on Nov. 28, 2000 to Ezion et al. and
entitled "Systems and methods for controlling a phased array
focused ultrasound system," each of which is fully incorporated
herein by reference. An MRI guided approach to beam aiming with
improved phase adjustment focusing techniques incorporates
stereotactic capabilities into HIFU. Some of the focused ultrasound
systems have shown effectiveness for accurately targeting small
lesions within the brain, thermally destroying the targeted tissue,
and leaving surrounding tissue unharmed. A few devices allow for
the destruction of brain tumors in a non-invasive manner (i.e.,
through an intact skull).
[0030] According to yet another embodiment of the present
invention, HIFU is used to stimulate two different areas of the
brain. The stimulation of each area is coordinated in order to
facilitate the development of either LTP or LTD between the two
different areas of the brain. For example, each of the areas can be
stimulated in a synchronous fashion to produce LTP. If the
stimulation results in an increased rate of depolarization of the
neurons, the probability that both areas of the brain will fire at
the same time is likewise increased. Moreover, LTP may be developed
where the stimulation results in one of the areas generating action
potentials more readily in response to stimulus from the other area
(e.g., by having a lower depolarization threshold). In order to
produce LTD, the areas may be stimulated in an asynchronous fashion
to produce an increased probability of the different areas firing
independently from one another.
[0031] In accordance with the present invention, it has been
discovered that not all neurons react in the same fashion to
temperature variations. For instance, some neurons increase their
firing rate in response to a decrease in temperature and such a
response impacts expected efforts in developing LTP or LTD.
According to certain embodiments of the present invention,
temperature data regarding these neuron-regions are used in
developing LTP or LTD between the areas of the brain. In a
particular instance, an area of the brain containing neurons that
increase their rate of fire due to the stimulation is targeted, and
at the same time, another area of the brain containing neurons that
decrease their rate of fire due to stimulation is also targeted.
This may be particularly useful for facilitating LTD between the
targeted areas.
[0032] For further information on the use of RF transmitters to
elevate temperatures of target cells, reference can be made to Kato
H., Ishida T. "Present and future status of noninvasive selective
deep heating using RF in hyperthermia" Med Biol Eng Comput. 1993
Jul.; 31 Suppl:S2-11 and to Gelvich E A, Mazokhin V N "Contact
flexible microstrip applicators (CFMA) in a range from microwaves
up to short waves" IEEE Trans Biomed Eng. 2002 Sept.;
49(9):1015-23), which are fully incorporated herein by reference.
For simplicity, much of the discussion is limited to ultrasound
energy; however, the invention is not so limited. For instance, it
should be apparent that for many applications the use of RF
frequency energy could be used in place of ultrasound energy.
Whether by ultrasound, radio frequency energy, or other stimuli,
neural effects of the delivered stimulus may be produced by induced
temperature alteration, electrical stimulation, or by mechanical
perturbation.
[0033] FIG. 1 shows a system for altering neural patterns between
two groups of cells, according to an example embodiment of the
present invention. Ultrasound (or RF) source 104 focuses the
ultrasound (or RF) 106, 108 at locations 110 and 114. In some
instances, the ultrasound can be focused at only one of the
locations, or at one location at a time (e.g., for developing LTD).
Control 102 controls the ultrasound produced by ultrasound source
104. In a particular instance, control 102 is responsive to input
from monitor device 116. The stimulation from sound (or RF) 106,
108 can be used to effect (e.g., facilitate or frustrate through
LTP or LTD) a pathway 112 between locations 110 and 114.
[0034] Ultrasound source 104 can be implemented using a number of
different techniques and mechanisms. According to one embodiment,
ultrasound source 104 is implemented using one single transducer
for each of location 110 and 114. Such a transducer acts as a lens
to focus the ultrasound waves at a point in space. The control 104
can modify various aspects of the transducer including, but not
limited to, direction of focus, distance from the target location,
strength of the ultrasound waves or the frequency of the ultrasound
waves. Such aspects allow for precise aiming of the focal point of
the ultrasound waves. This can be particularly useful for reducing
unintended stimulation of cells while increasing stimulation at the
target location. In some instances, the transducers can be aimed
using piezoelectric devices. Piezoelectric devices allow for minute
movements of the transducers in response to electrical signals.
[0035] According to another embodiment, ultrasound source 104 is
implemented using an array of transducers. In one instance, the
array can be implemented as one or more two-dimensional arrays of
transducers. In another instance, the array can be implemented
using a three-dimensional array, such as an array placed upon the
skull of a patient. Similar to the single transducer
implementation, the control 104 can modify various aspects of the
transducers. In one instance, the transducers are similar to those
used by the single transducer implementation in that they function
to focus the ultrasound waves at a point in space. The array
provides a summation of the effects from the transducers in order
to further focus ultrasound waves. In one instance, each transducer
can be individually calibrated so as to focus the ultrasound waves
at the desired location. Control 104 can then alter the phase of
each transducer such that the ultrasound waves provide constructive
interference rather than destructive interference so as to increase
the effectiveness of the delivered ultrasound energy. In another
instance, the individual transducers of the array of transducers
offer little directional or focusing effect when used in isolation.
Control 104 modifies the aspects of the ultrasound waves of the
array so as to effectively focus the ultrasound waves at the target
location.
[0036] In various embodiments of the invention, control 104 can use
monitoring device 116 to determine the appropriate aspects for the
transducer(s). For instance, monitoring device 116 may be
implemented using, for example, the ExAblate.RTM. system (InSightec
Ltd. Haifa, Israel). The input from such device provides a
determination as to the effectiveness of the current settings of
transducer(s).
[0037] Although not shown, various embodiments of the invention may
also be implemented using devices or methods to effectively
determine the target location. These implementations can be
particularly useful for providing improved accuracy of the
ultrasound waves by precisely targeting the desired location. An
example of a possible targeting method and system includes the
targeting system of the ExAblate .RTM. (InSightec Ltd. Haifa,
Israel). Alternatively, the system may be targeted by registering
the ultrasound probes to a commercially available user-configurable
tool or "universal tool" on a neuronavigation system such as the
StealthStation by the Surgical Navigation Technologies division of
Medtronic, Inc. (Minneapolis, Minn.). Targeting may also be
achieved by affixing ultrasonic transducers to a stereotactic
frame, and moving them into correct targeting position via
frame-based techniques, such as those used for neurosurgery.
[0038] The display of the effect at the target may be augmented
with a registration and display of calculated or measured
temperature at the target site, or a measurement or calculation of
neuronal activity at the target site. Temperature displays, e.g.,
obtained from thermal tomography systems, may be derived from
measured values or from projected/calculated values. Examples of
measurements and display of neuronal activity include multichannel
EEG (for example Brain Electrical Activity Monitoring or BEAM) or
mangetoencephalography (MEG).
[0039] FIG. 2A shows the use of two focused-beam ultrasound
transducers physiologically suppressing the connection between the
two regions by virtue of a mechanism such as long-term depression
(LTD). An ultrasound transducer 205 delivers ultrasound energy to
neural target 210 via ultrasound vectors 206. Ultrasound transducer
215 also delivers energy to neural target 220 via ultrasound
vectors 216. Neural target 220 is connected to neural target 210
via neuronal tract 225. As target 220 and target 210 are stimulated
in a slow-pulse rate, asynchronous fashion, long-term depression
(LTD) process 226 is initiated within tract 225. The presence of
LTD makes tract 225 less excitable than it would be under normal
circumstances. In many instances, such a depressed excitability
level is maintained for a period of weeks. Conversely, LTP may be
induced with these focused-beam transducers by changing to a more
rapid, regular and strong pulse pattern.
[0040] FIG. 2B shows the use of an electronically focused
ultrasound transducer array to physiologically augment the
connection between the two regions by virtue of a mechanism such as
LTP, according to an example embodiment of the present invention.
Neural target 265 is connected via neural tract 270, to neural
target 260. Ultrasound transducers 251, 252, 253, 254 and 255
contribute to the total energy delivered to both neural target 260
(via dashed lines 257) and to neural target 265 (via solid lines
256), by virtue of electronic focusing techniques. Neural target
265 and target 260 are stimulated in a rapid and regular fashion to
initiate an LTP process 275 within tract 270. In a specific
example, the target areas are regularly pulsed at a rate of 1 Hz or
more, or mildly heated at the same time thereby increasing the
neuronal firing rate in tract 270. This allows for the creating of
LTP, or enduring enhancement of the stimulation, along tract 270.
The presence of LTP increases the excitability level of tract 270
relative to normal circumstances. In certain instances, such an
increased excitability level can be maintained for a period of
weeks. Conversely, LTD may also be produced with this
electronically focused transducer array by changing to a weaker,
slow, asynchronous pattern of pulsing.
[0041] FIG. 3A shows a specific application of the present
invention in which LTP is facilitated within the "trisynaptic
circuit" of the human hippocampus according to an example
embodiment of the present invention. In the trisynaptic circuit,
cerebral cortical regions (not shown) have connections 310 to
entorhinal cortex 315. Entorhinal cortex 315 is connected to CA3
field 320 via connection 317. CA3 field 320 relays signals to CA1
field 325, via connection 322. CA1 field 325 relays back to
entorhinal cortex 315 via connection 327. Finally, entorhinal
cortex 315 relays data back to cerebral cortex regions via
connections 310. When rapid and strong stimulations are applied to
entorhinal cortex 315, long-terra potentiation (318) is established
along connection 317 between entorhinal cortex 315 and CA3 field
320. Moreover, it is believed that the application of stimulation
to both entorhinal cortex 315 and CA3 field 320 may improve the
speed at which the LTP effect is created and also improve the
length that the LTP effect is sustained.
[0042] FIG. 3B shows the use of the present invention, (in a form
similar to that shown in FIG. 2B) to produce LTP between the
entorhinal cortex and the CA3 fields of a human hippocampus, as can
be used to augment the encoding of memory. Specifically, entorhinal
cortex 375 is connected to CA3 field 380 (same as 315 and 320,
respectively, in FIG. 3A). Ultrasound transducers 351, 352, 353 and
354 are arranged around a patient's scalp 360 in order to stimulate
both the CA3 field 380 (via dashed lines 366) and the entorhinal
cortex 375 (via solid lines 365), by virtue of electronic focusing
techniques. By stimulating the entorhinal cortex 375 and CA3 field
380 in a rapid and regular fashion, a LTP process 318 is initiated
within connecting tract 317 as shown in FIG. 3A.
[0043] FIG. 4A shows the use of two focused-beam ultrasound
transducers, each focused upon a different, but connected neural
target, according to an example embodiment of the present
invention. Transducer 415 and 430 each focuses ultrasound waves 420
and 435, respectively, to specific points within the brain 410 of
patient 400. More specifically, transducer 415 focuses the
ultrasound to target point 427 and transducer 430 focuses the
ultrasound at target point 445.
[0044] The focus points of the transducers can be controlled by
modifying direction of the ultrasound waves 420 and 435. For
instance, transducers having different curvatures may be used to
provide different depths of convergence. Likewise, the transducer's
position on the skull and distance therefrom can be modified to set
the convergence point within the brain 410. The direction of the
ultrasound waves can be modified by controlling the angle of the
transducers 415 and 430 relative to brain 410. This can be
accomplished using a variety of approaches. One such approach
involves setting the angle using a structure that supports the
transducers and allows for adjustment of the angle. The patient's
skull can then be immobilized relative to the structure. Another
approach involves attaching the transducers directly to the
patient's scalp, skull, or by surgically implanting them upon or
within the brain itself. The angle may be set accordingly.
[0045] FIG. 4B shows the use of an array of multiple small
ultrasound transducers which may be electronically focused upon one
or more targets within a patient's brain by virtue of a coordinated
phase and power adjustment to the transducers in the array,
according to an example embodiment of the present invention. An
array of transducers 470 is attached to patient 450 for the purpose
of stimulating brain 460. Individual control of the transducers is
provided through communication connections 480, which are shown as
wires in FIG. 4B. Examples of suitable communications connections
include electrical wires, wireless transmissions and optical
fibers. In some instances, power is delivered to transducers 470
through the same (or similar) connections.
[0046] According to one embodiment of the invention, the power,
frequency and phase of the transducers can be modified to pinpoint
the desired target locations. The delay from the time that the
ultrasound wave is first transmitted to the time the ultrasound
wave arrives at the target location may vary from transducer to
transducer (e.g., due to differences in the location and
orientation of the transducers). For instance, the distance and
type of tissue can directly affect the propagation time of the
ultrasound wave. A control device can compensate for differences
between the transducers to ensure that the ultrasound waves add to
the power of the stimulation at the desired location. In some
instances, one or more of the transducers may not provide any
appreciable addition to the amount of stimulation at the target
location. In other instances, one or more of the transducers may
create undesirable effects, such as stimulation of areas other than
the target locations. For such instances, the transducer power may
be reduced or removed completely. The ineffectiveness of a few of
such transducers may be offset by increasing the power of the other
transducers or by providing a sufficiently large array of
transducers. Other variations are possible including grouping
control of a number of transducers together rather than
individually controlling each transducer. This may be particularly
useful for reducing the complexity of the communications and the
complexity of various control parameters.
[0047] Once the selected phase, frequency and other constraints are
set, the transducers can be used to stimulate two different target
areas in a synchronous or asynchronous manner to produce LTP or
LTD, respectively, between the different target areas. The
invention need not be limited to only two target areas. For
instance, three or more areas of the brain may be stimulated for
the purposes of facilitating LTP or LTD therebetween. In another
instance, a number of different target areas may be sequentially
stimulated to produce an LTP communication pathway of related
target areas. Similarly, a sequence of different target areas may
be stimulated to disrupt a communication pathway by producing LTD
between the sequential target areas. Various combinations thereof
are also possible.
[0048] In conjunction with a specific embodiment of the present
invention, the thermal properties of sound waves are supplemented
with electrical impulses generated by implanted devices that
respond to mechanical motion produced by the sound waves. For
instance a device, implanted surgically in proximity to a group of
neurons that one wishes to affect, electrically stimulates those
neurons when in receipt of sound waves.
[0049] In one such embodiment, implanted piezoelectric antennas are
surgically implanted adjacent to the neural structure that is the
target of the modulation. Such antennae produce electrical current
via the piezoelectric effect of an implanted piezoelectric
generator, which is rapidly moved back and forth by externally
applied ultrasound. The electric current from the piezoelectric
generator serves to stimulate neurons electrically, in response to
the externally applied ultrasonic waves. All other principles of
synchrony and asynchrony as they apply to the induction of LTP and
LTD, respectively, still hold under this paradigm. The implanted
ultrasound-to-electrical current conversion device serves to
enhance the same processes as previously described herein. For
further information regarding implanted piezoelectric antennas,
reference may be made to recent publications including, for
example, Wang X, Song J, Liu J, Wang Z L, in Direct-current
Nanogenerator Driven By Ultrasonic Waves, Science, 2007, Apr.
6-316(5821):102-5, which is fully incorporated herein by
reference.
[0050] In another embodiment of the present invention, such
implantable devices can be implemented as the primary source of
stimulation (e.g., with minimal thermal heating).
[0051] The various embodiments described above are provided by way
of illustration only and should not be construed to limit the
invention. Based on the above discussion and illustrations, those
skilled in the art will readily recognize that various
modifications and changes may be made to the present invention
without strictly following the exemplary embodiments and
applications illustrated and described herein. For instance, such
changes may include variations in the duration and frequency of the
stimulation between target areas. Such modifications and changes do
not depart from the true spirit and scope of the present invention,
which is set forth in the following claims.
* * * * *