U.S. patent application number 16/241227 was filed with the patent office on 2019-08-01 for devices and methods for treatment of anxiety and related disorders via delivery of mechanical stimulation to nerve, mechanorecep.
The applicant listed for this patent is Apex Neuro Inc.. Invention is credited to Alyssa Boasso, Zen Chu, Kelsey Fafara, Sean Hagberg, Francois Kress, Miles Thibault, Rohan Ajay Verma.
Application Number | 20190232047 16/241227 |
Document ID | / |
Family ID | 65269056 |
Filed Date | 2019-08-01 |
View All Diagrams
United States Patent
Application |
20190232047 |
Kind Code |
A1 |
Chu; Zen ; et al. |
August 1, 2019 |
DEVICES AND METHODS FOR TREATMENT OF ANXIETY AND RELATED DISORDERS
VIA DELIVERY OF MECHANICAL STIMULATION TO NERVE, MECHANORECEPTOR,
AND CELL TARGETS
Abstract
Presented herein are systems, methods, and devices that provide
for stimulation of nerves and/or targets such as mechanoreceptors,
tissue regions, mechanoresponsive proteins, and vascular targets
through generation and delivery of mechanical vibrational waves. In
certain embodiments, the approaches described herein utilize a
stimulation device (e.g., a wearable device) for generation and
delivery of the mechanical vibrational waves. As described herein,
the delivered vibrational waves can be tailored based on particular
targets (e.g., nerves, mechanoreceptors, vascular targets, tissue
regions) to stimulate and/or to elicited particular desired
responses in a subject. As described herein, in certain
embodiments, the delivery of mechanical stimulation to a subject
provides for treatment of anxiety.
Inventors: |
Chu; Zen; (Brookline,
MA) ; Thibault; Miles; (Boston, MA) ; Fafara;
Kelsey; (Watertown, MA) ; Kress; Francois;
(New York, NY) ; Verma; Rohan Ajay; (Boston,
MA) ; Boasso; Alyssa; (Brookline, MA) ;
Hagberg; Sean; (Cranston, RI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Apex Neuro Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
65269056 |
Appl. No.: |
16/241227 |
Filed: |
January 7, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62741758 |
Oct 5, 2018 |
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|
62680525 |
Jun 4, 2018 |
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62623977 |
Jan 30, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61H 23/0218 20130101;
A61H 2201/5097 20130101; A61H 2201/5007 20130101; A61H 2230/065
20130101; A61H 2201/1207 20130101; A61N 1/3603 20170801; A61H
2205/027 20130101; A61H 2230/085 20130101; A61H 23/00 20130101;
A61H 2201/501 20130101; A61H 2201/0157 20130101; A61H 2201/165
20130101; A61H 2201/5084 20130101; A61N 1/0456 20130101; A61H
2230/655 20130101; A61N 1/36025 20130101; A61H 2205/02 20130101;
A61N 1/37518 20170801 |
International
Class: |
A61N 1/04 20060101
A61N001/04; A61N 1/36 20060101 A61N001/36; A61N 1/375 20060101
A61N001/375 |
Claims
1. A transcutaneous neuromodulation device for treating anxiety
and/or an anxiety related disorder in a subject by promoting nerve
stimulation through mechanical vibration, comprising: one or more
mechanical transducers, a battery, and one or more controller
boards, wherein the one or more mechanical transducers, the battery
and the one or more controller boards are in communication, and
wherein the controller board controls waveform output through the
one or more mechanical transducers, thereby producing mechanical
vibration, and wherein the waveform output comprises an isochronic
wave
2-3. (canceled)
4. The neuromodulation device of claim 1, wherein the device
promotes stimulation of one or more nerves, and wherein the one or
more nerves comprises a C-tactile afferent.
5. The neuromodulation device of claim 1, wherein the device
promotes stimulation of one or more mechanoreceptors and/or
cutaneous sensory receptors in the skin.
6. The neuromodulation device of claim 5, wherein the one or more
mechanoreceptors and/or cutaneous sensory receptors comprise Piezo2
protein and/or Merkel cells.
7. The neuromodulation device of claim 1, wherein the one or more
controller boards modulate the waveform output to introduce
particular signals that include active or inactive pulse durations
and frequencies configured to accommodate particular
mechanoreceptor recovery periods, adaptation times, inactivation
times, sensitization and desensitization times, or latencies.
8. The neuromodulation device of claim 1, the device comprising one
or more ergonomic support components, wherein the one or more
transducers are supported by the one or more ergonomic support
component(s) and the one or more ergonomic support component(s)
is/are formed to maintain the transducer in substantial proximity
to one or more mastoid regions of a human subject.
9-17. (canceled)
18. The neuromodulation device of claim 1, wherein the isochronic
wave comprises a frequency component ranging from 5 to 15 Hz.
19. The neuromodulation device of claim 1, wherein one or more
low-amplitude sub-intervals of the isochronic wave have a duration
of greater than or approximately two seconds.
20-23. (canceled)
24. The neuromodulation device of claim 1, wherein a level of at
least a portion of the mechanical vibration is based on activation
thresholds of one or more target cells and/or proteins.
25. The neuromodulation device of claim 1, wherein an amplitude of
the mechanical vibration corresponds to a displacement ranging from
1 micron to 10 millimeters.
26. A method of treating anxiety and/or an anxiety related disorder
in a subject by providing transcutaneous mechanical stimulation to
the subject via a stimulation device, the method comprising:
generating a mechanical wave by a mechanical transducer of the
stimulation device in response to an applied electronic drive
signal; controlling a waveform of the electronic drive signal by a
controller board, wherein the waveform comprises an isochronic
wave; and delivering the mechanical wave to a body location of the
subject via the stimulation device, thereby providing the
transcutaneous mechanical stimulation to the subject.
27-28. (canceled)
29. The method of claim 26, wherein the mechanical wave promotes
stimulation of one or more nerves, and wherein the one or more
nerves comprises a C-tactile afferent.
30. The method of claim 26, wherein the mechanical wave promotes
stimulation of one or more mechanoreceptors and/or cutaneous
sensory receptors in the skin.
31. The method of claim 30, wherein the one or more
mechanoreceptors and/or cutaneous sensory receptors comprise Piezo2
protein and/or Merkel cells.
32. The method of claim 26, wherein the controlling the waveform of
the electronic drive signal comprises modulating the waveform to
introduce particular signals that include active or inactive pulse
durations and frequencies configured to accommodate particular
mechanoreceptor recovery periods, adaptation times, inactivation
times, sensitization and desensitization times, or latencies.
33. (canceled)
34. The method of claim 26, wherein the delivering the mechanical
wave to the body location comprises contacting the mechanical
transducer to a surface of the subject at the body location and
wherein the contacting the mechanical transducer to the surface of
the subject at the body location comprises using one or more
ergonomic support components, wherein the one or more transducers
are supported by the one or more ergonomic support component(s) and
the one or more ergonomic support component(s) is/are formed to
maintain the transducer in substantial proximity to one or more
mastoid regions of a human subject.
35-43. (canceled)
44. The method of claim 26, wherein the isochronic wave comprises a
frequency component ranging from 5 to 15 Hz.
45. The method of claim 26, wherein one or more low-amplitude
sub-intervals of the isochronic wave have a duration of greater
than or approximately two seconds.
46-49. (canceled)
50. The method of claim 26, wherein a level of at least a portion
of the mechanical wave is based on activation thresholds of one or
more target cells and/or proteins.
51. The method of claim 26, wherein an amplitude of the mechanical
wave corresponds to a displacement ranging from 1 micron to 10
millimeters.
52-59. (canceled)
60. A method of adjusting a level of a stress hormone in a subject,
the method comprising transcutaneously delivering mechanical
stimulation to the subject using a mechanical wave having a
vibrational waveform selected to reduce the level of the stress
hormone in the subject upon and/or following the delivering of the
mechanical wave to the subject.
61. A kit comprising: a transcutaneous neuromodulation device for
treating anxiety and/or an anxiety related disorder in a subject by
promoting nerve stimulation through mechanical vibration,
comprising: one or more mechanical transducers, a battery, and one
or more controller boards, wherein the one or more mechanical
transducers, the battery and the one or more controller boards are
in communication, and wherein the controller board controls
waveform output through the one or more mechanical transducers,
thereby producing mechanical vibration, and wherein the waveform
output comprises an isochronic wave; and a label indicating that
the device is to be used for reducing stress in a user as measured
by a level of a stress hormone for the subject.
62-64. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to and benefit of U.S.
Provisional Patent Application No. 62/623,977, filed Jan. 30, 2018,
U.S. Provisional Patent Application No. 62/680,525, filed Jun. 4,
2018, and U.S. Provisional Patent Application No. 62/741,758, filed
Oct. 5, 2018, the contents of each of which are hereby incorporated
by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates generally to wearable
neuromodulation devices for promoting nerve stimulation through
mechanical vibration. In particular, in certain embodiments the
neuromodulation devices provide for treatment of anxiety and
related disorders.
BACKGROUND
[0003] Electrical stimulation of nerves in human subjects can alter
mood states, reduce the sensation of pain, and treat certain
diseases. While promising in this regard, patients subjected to
electrical stimulation often experience unpleasant and/or dangerous
side effects, including skin irritation resulting from gels needed
to maintain good contact between electrodes and the patient's skin,
burns and/or rashes, and pain or irritation at the stimulation
site. Such side effects are particularly problematic for
applications where nerve stimulation should be applied frequently
(e.g., daily), such as for stress management.
[0004] Accordingly, there is a need for systems, methods, and
devices that provide for convenient, regular nerve stimulation with
limited side effects and a robust safety profile. Such systems,
methods, and devices are of particular relevance to the treatment
of conditions where frequent nerve stimulation is desired.
SUMMARY OF THE INVENTION
[0005] Presented herein are systems, methods, and devices that
provide for stimulation of nerves and/or targets such as
mechanoreceptors, tissue regions, cellular mechanotransduction and
vascular targets through generation and delivery of mechanical
vibrational waves. In certain embodiments, the approaches described
herein utilize a stimulation device (e.g., a wearable or applied
device) for generation and delivery of the mechanical vibrational
waves. As described herein, the delivered vibrational waves can be
tailored based on particular targets (e.g., nerves,
mechanoreceptors, vascular targets, tissue regions) to stimulate
and/or to elicit particular desired responses in a subject. As
described herein, in certain embodiments, the delivery of
mechanical stimulation to a subject provides for treatment of
anxiety.
[0006] In certain embodiments, the properties of mechanical waves
generated are tailored by controlling a waveform of an electronic
drive signal that is applied to mechanical transducers in order to
generate a desired mechanical wave. By controlling and delivering
various specific mechanical waves in this manner, the approaches
described herein can be used to achieve a variety of health
benefits in subjects, for example by promoting relaxation,
preventing migraine headaches, facilitating stress management,
alleviating diseases exacerbated by stress, and improving
sleep.
[0007] In one aspect, the invention is directed to a transcutaneous
neuromodulation device [e.g., a wearable device; e.g., a
non-invasive device (e.g., not comprising any components that
penetrate skin)] for treating anxiety and/or an anxiety related
disorder in a subject by promoting nerve stimulation through
mechanical vibration, comprising: one or more mechanical
transducers, a battery, and one or more controller boards, wherein
the one or more mechanical transducers, the battery and the one or
more controller boards are in communication (e.g., through one or
more connectors; e.g., wirelessly), and wherein the controller
board controls waveform output through the one or more mechanical
transducers, thereby producing mechanical vibration, and wherein
the waveform output comprises an isochronic wave
[0008] In certain embodiments, the device promotes stimulation
(e.g., wherein the waveform is selected to promote stimulation) of
one or more nerves [e.g., a vagus nerve; e.g., a trigeminal nerve;
e.g., peripheral nerves; e.g., a greater auricular nerve; e.g., a
lesser occipital nerve; e.g., one or more cranial nerves (e.g.,
cranial nerve VII; e.g., cranial nerve IX; e.g., cranial nerve XI;
e.g., cranial nerve XII)]. In certain embodiments, the one or more
nerves comprises a vagus nerve and/or a trigeminal nerve. In
certain embodiments, the one or more nerves comprises a C-tactile
afferent.
[0009] In certain embodiments, the device promotes stimulation of
(e.g., wherein the waveform is selected to promote stimulation of)
one or more mechanoreceptors and/or cutaneous sensory receptors in
the skin (e.g., to stimulate an afferent sensory pathway and use
properties of receptive fields to propagate stimulation through
tissue and bone). In certain embodiments, the one or more
mechanoreceptors and/or cutaneous sensory receptors comprise Piezo2
protein and/or Merkel cells.
[0010] In certain embodiments, the one or more controller boards
modulate the waveform output to introduce particular signals that
include active or inactive pulse durations and frequencies
configured to accommodate particular mechanoreceptor recovery
periods, adaptation times, inactivation times, sensitization and
desensitization times, or latencies.
[0011] In certain embodiments, the one or more controller boards
modulate the waveform output to enhance or inhibit the expression
of presynaptic molecules essential for synaptic vesicle release in
neurons. In certain embodiments, the one or more controller boards
modulate the waveform output to enhance or inhibit the expression
of neuroactive substances that can act as fast excitatory
neurotransmitters or neuromodulators.
[0012] In certain embodiments, the one or more controller boards
modulates the waveform output to stimulate mechanoreceptor cell
associated with M-fibers and C-fibers (e.g., including C tactile
fibers) in order to stimulate nociceptive, thermoceptive and other
pathways modulated by these fibers.
[0013] In certain embodiments, the one or more controller boards
modulate the waveform output using dynamical systems methods to
produce a preferred response in neural network dynamics (e.g., via
modulation of signal timing).
[0014] In certain embodiments, the one or more controller boards
modulates the waveform output using dynamical systems measures to
assess response signals (e.g., electronic) to detect particular
network responses correlated with changes in mechanical wave
properties (e.g., and modulates the waveform output to
target/optimally enhance particular preferred responses).
[0015] In certain embodiments, the device comprises an adhesive
(e.g., a biocompatible adhesive) for adhering at least one of the
one or more mechanical transducers (e.g., up to all) to a subject
[e.g., skin (e.g., on a neck of; e.g., overlaying at least one
mastoid process of; e.g., of an outer or posterior of at least one
ear of) a human subject](e.g., wherein the at least one mechanical
transducer is embedded within the adhesive; e.g., wherein the at
least one mechanical transducer is surrounded by the adhesive).
[0016] In certain embodiments, device comprises one or more
ergonomic support components, wherein the one or more transducers
are supported by (e.g., housed within; e.g., mounted on) the one or
more ergonomic support component(s) (e.g., collectively) and the
one or more ergonomic support component(s) is/are formed (e.g.,
molded) to maintain the transducer in substantial proximity to one
or more mastoid regions of a human subject (e.g., by maintaining
substantial contact with skin overlaying the one or more mastoid
regions).
[0017] In certain embodiments, the device comprises a first
ergonomic support component, the first ergonomic support component
comprising: (a) a first housing comprising a casing (e.g., molded
casing) of sufficient size to at least partially house (i) a first
transducer set comprising at least a portion (e.g., half; e.g.,
all) of the one or more mechanical transducers and (ii) a first
controller board set comprising at least a portion (e.g., half;
e.g., all) of the one or more controller boards, wherein the first
transducer set is disposed adjacent to a window in the first
housing [e.g., an insulated region of the first housing that
contacts skin of the human subject in substantial proximity to a
first mastoid region (e.g., on a first (e.g., left; e.g., right)
side of head of the subject); e.g., wherein the window comprises
fabric, adhesive, etc. placed in between a surface of the
transducers of the first transducer set and skin of the subject so
as to prevent direct contact with skin]; and (b) a first
elastomeric arm comprising a resilient material and formed (e.g.,
molded) to engage an first ear of the subject and thereby support
(e.g., fully) the first housing (e.g., and first transducer set and
first controller board set housed therein), wherein the first
housing is coupled to a distal end of the first elastomeric arm,
wherein the distal end of the first elastomeric arm substantially
aligns the window of the first housing with a first body location
on the subject in substantial proximity to a first mastoid region
(e.g., on a first side of the subject's head; e.g., on a left side;
e.g., on a right side), and wherein the resilient material provides
a force to hold the first housing against the first body
location.
[0018] In certain embodiments, the device further comprises a
second ergonomic support component, the second ergonomic support
component comprising: (a) a second housing comprising a casing
(e.g., molded casing) of sufficient size to at least partially
house (i) a second transducer set comprising at least a portion
(e.g., half; e.g., all) of the one or more mechanical transducers
and (ii) a second controller board set comprising at least a
portion (e.g., half; e.g., all) of the one or more controller
boards, wherein the second transducer set is disposed adjacent to a
window in the second housing [e.g., an insulated region of the
second housing that contacts skin of the human subject in
substantial proximity to a second mastoid region (e.g., on a second
(e.g., left; e.g., right) side of head of the subject); e.g.,
wherein the window comprises fabric, adhesive, etc. placed in
between a surface of the transducers of the second transducer set
and skin of the subject so as to prevent direct contact with skin];
and (b) a second elastomeric arm comprising a resilient material
and formed (e.g., molded) to engage an ear of the subject and
thereby support (e.g., fully) the second housing (e.g., and second
transducer set and second controller board set housed therein),
wherein the second housing is coupled to a distal end of the second
elastomeric arm, wherein the distal end of the second elastomeric
arm substantially aligns the window of the second housing with a
second body location on the subject in substantial proximity to a
second mastoid region (e.g., on a second side of the subject's
head; e.g., on a right side; e.g., on a left side), and wherein the
resilient material provides a force to hold the second housing
against the second body location.
[0019] In certain embodiments, the first and second ergonomic
support components are in wireless communication with each other
(e.g., via near-field magnetic induction (NFMI) e.g., so as to
avoid/overcome interference from the subject's head) for
synchronizing delivery of the mechanical vibration to the first and
second mastoid regions of the subject (e.g., for synchronizing
delivery of a first mechanical vibration produced by the first
transducer set and delivery of a second mechanical vibration
produced by the second transducer set).
[0020] In certain embodiments, the one or more ergonomic support
components comprises: a linkage component formed to engage (e.g.,
wrap around a top of) a head of the subject; two housings disposed
at opposite ends of the linkage component so as to be positioned on
opposite sides of the head of the subject, wherein each housing
comprising a casing (e.g., a molded casing) of sufficient size to
at least partially house a corresponding transducer set comprising
at least a portion (e.g., one; e.g., half; e.g., all) of the one or
more mechanical transducers, wherein the mechanical transducers are
disposed adjacent to a window in each housing; and two elastomeric
hinges, each disposed at the opposite ends of the linkage component
and mounted to flexibly couple a housings to the linkage component,
wherein at least one of the elastomeric hinges is formed and
positioned to substantially align the window of each housing with
and against opposing mastoid regions on opposite sides of the head
of the subject.
[0021] In certain embodiments, the linkage component comprises an
adjustment mechanism comprising two partially overlaid,
interlocking, and sliding curved arms (e.g., curved elastomeric
arms), wherein said curved arms are maintained in alignment with
each other to form an arc (e.g., approximately matching an average
arc of a human head) and slide with respect to each other so as to
vary an amount of overlap, thereby varying a size of the arc (e.g.,
to match different size human heads), and wherein the two
elastomeric hinges are disposed on opposing ends of the arc formed
by the two sliding arms.
[0022] In certain embodiments, the device comprises at least one
transducer array comprising a plurality of (e.g., two or more)
mechanical transducers maintained in a fixed spatial arrangement in
relation to each other (e.g., in substantial proximity to each
other; e.g., spaced along a straight or curved line segment) and
wherein at least a portion of the one or more controller boards
(e.g., a single controller board; e.g., two or more controller
boards) are in communication with the mechanical transducers of the
transducer array to control output of the mechanical transducers of
the transducer array in relation to each other [e.g., wherein the
at least a portion of the one or more controller boards
synchronizes mechanical vibration produced by each mechanical
transducer of the transducer array (e.g., such that each mechanical
transducer begins and/or ends producing mechanical vibration at a
particular delay with respect to one or more other mechanical
transducers of the array; e.g., such that the mechanical
transducers are sequentially triggered, one after the other; e.g.,
wherein the mechanical transducers are spaced along a straight or
curved line segment and triggered sequentially along the line
segment, such that an apparent source of mechanical vibration moves
along the line segment to mimic a stroking motion)] [e.g., wherein
a first portion of the mechanical transducers outputs a different
frequency mechanical vibration from a second portion of the
mechanical transducers of the transducer array (e.g., wherein each
mechanical transducer of the transducer array outputs a different
frequency mechanical vibration)].
[0023] In certain embodiments, the transducer is a linear
transducer (e.g., operable to produce mechanical vibration
comprising a longitudinal component (e.g., a longitudinal
vibration)).
[0024] In certain embodiments, the device is incorporated into a
headphone (e.g., an in-ear headphone; e.g., an over-the-ear
headphone).
[0025] In certain embodiments, the device comprises a receiver in
communication with the one or more controller boards, wherein the
receiver is operable to receive a signal from and/or transmit a
signal (e.g., wirelessly; e.g., via a wired connection) to a
personal computing device (e.g., a smart phone; e.g., a personal
computer; e.g., a laptop computer; e.g., a tablet computer; e.g., a
smartwatch; e.g., a fitness tracker; e.g., a smart charger)(e.g.,
to upload new waveforms and/or settings for waveforms).
[0026] In certain embodiments, the one or more controller boards
is/are operable to modulate and/or select the waveform output in
response to (e.g., based on) the signal received from the personal
computing device by the receiver.
[0027] In certain embodiments, the device is non-invasive (e.g.,
does not comprise any components for penetrating skin).
[0028] In certain embodiments, the device comprises a secondary
stimulation device for providing one or more external
stimulus/stimuli (e.g., visual stimulus; e.g., acoustic stimulus;
e.g., limbic priming; e.g., a secondary tactile signal).
[0029] In certain embodiments, the isochronic wave comprises a
frequency component ranging from 5 to 15 Hz (e.g., ranging from
approximately 7 to approximately 13 Hz; e.g., a frequency range
matching an alpha brain wave frequency range; e.g., approximately
10 Hz).
[0030] In certain embodiments, the isochronic wave comprises a
frequency component ranging from 0 to 49 Hz (e.g., from 18 to 48
Hz; e.g., from 15 to 40 Hz; e.g. from 8 to 14 Hz).
[0031] In certain embodiments, one or more low-amplitude
sub-intervals of the isochronic wave have a duration of greater
than or approximately two seconds (e.g., wherein the one or more
low-amplitude sub-intervals have a duration of approximately two
seconds; e.g., wherein the one or more low-amplitude sub-intervals
have a duration ranging from approximately two seconds to
approximately 10 seconds; e.g., wherein the one or more low
amplitude sub-intervals have a duration ranging from approximately
two seconds to approximately 4 seconds).
[0032] In certain embodiments, the isochronic wave comprises a
carrier wave [e.g., a periodic wave having a substantially constant
frequency (e.g., ranging from 5 to 15 Hz; e.g., ranging from
approximately 7 to approximately 13 Hz; e.g., a frequency range
matching an alpha brain wave frequency range; e.g., approximately
10 Hz)] modulated by an envelope function having one or more
low-amplitude sub-intervals [e.g., a periodic envelope function
(e.g., a square wave; e.g., a 0.5 Hz square wave); e.g., the one or
more low-amplitude sub-intervals having a duration of greater than
or approximately equal to two seconds; e.g., the one or more
low-amplitude sub-intervals having a duration of approximately two
seconds].
[0033] In certain embodiments, the isochronic wave is also a
transformed time-varying wave. In certain embodiments, the
isochronic wave comprises a chirped wave. In certain embodiments,
the waveform output comprises a transformed time-varying wave
having a functional form corresponding to a carrier wave within an
envelope {e.g., wherein the transformed-time varying wave is the
carrier wave and is further modulated by an envelope [e.g., wherein
the envelope is a sinusoidal wave; e.g., wherein the envelope has a
monotonically increasing (in time) amplitude (e.g., wherein the
envelope has a functional form corresponding to an increasing (in
time) exponential)]; e.g., wherein the transformed time-varying
wave is the envelope that modulates a carrier wave [e.g., wherein
the carrier wave is a periodic wave (e.g., a sinusoidal wave; e.g.,
a square wave; e.g., a sawtooth wave)(e.g., having a higher
frequency than the envelope)]}.
[0034] In certain embodiments, a functional form of the waveform
output is based on one or more recorded natural sounds (e.g.,
running water; e.g., ocean waves; e.g., purring; e.g., breathing;
e.g., chanting; e.g., gongs; e.g., bells).
[0035] In certain embodiments, the device comprises a receiver in
communication with the one or more controller boards, wherein the
receiver is operable to receive a signal from and/or transmit a
signal to a monitoring device (e.g., directly from and/or to the
monitoring device; e.g., via one or more intermediate server(s)
and/or computing device(s))(e.g., a wearable monitoring device;
e.g., a personal computing device; e.g., a fitness tracker; e.g., a
heart-rate monitor; e.g., an electrocardiograph (EKG) monitor;
e.g., an electroencephalography (EEG) monitor; e.g., an
accelerometer; e.g., a blood-pressure monitor; e.g., a galvanic
skin response (GSR) monitor) and wherein the one or more controller
boards is/are operable to modulate and/or select the waveform
output in response to (e.g., based on) the signal from the wearable
monitoring device received by the receiver.
[0036] In certain embodiments, the device is operable to record
usage data (e.g., parameters such as a record of when the device
was used, duration of use, etc.) and/or one or more biofeedback
signals for a human subject [e.g., wherein the device comprises one
or more sensors, each operable to measure and record one or more
biofeedback signals (e.g., a galvanic skin response (GSR) sensor;
e.g., a heart-rate monitor; e.g., an accelerometer)][e.g., wherein
the device is operable to store the recorded usage data and/or
biofeedback signals for further processing and/or transmission to
an external computing device, e.g., for computation (e.g., using a
machine learning algorithm that receives the one or more
biofeedback signals as input, along with, optionally, user reported
information) and display of one or more performance metrics (e.g.,
a stress index) to a subject using the device].
[0037] In certain embodiments, the one or more controller boards
is/are operable to automatically modulate and/or select the
waveform output in response to (e.g., based on) the recorded usage
data and/or biofeedback signals (e.g., using a machine learning
algorithm that receives the one or more biofeedback signals as
input, along with, optionally, user reported information, to
optimize the waveform output).
[0038] In certain embodiments, a level [e.g., amplitude (e.g., a
force; e.g., a displacement)] of at least a portion of the
mechanical vibration is based on activation thresholds of one or
more target cells and/or proteins (e.g., mechanoreceptors (e.g., C
tactile afferents); e.g., nerves; e.g., sensory thresholds
corresponding to a level of tactile sensation) [e.g., wherein the
one or more controller boards modulate the waveform output based on
sub-activation thresholds (e.g., accounting for the response of the
mechanical transducers)].
[0039] In certain embodiments, an amplitude of the mechanical
vibration corresponds to a displacement ranging from 1 micron to 10
millimeters (e.g., approximately 25 microns)(e.g., wherein the
amplitude is adjustable over the displacement ranging from 1 micron
to 10 millimeters) [e.g., wherein the amplitude corresponds to a
force of approximately 0.4N][e.g., thereby matching the amplitude
to activation thresholds of C tactile afferents].
[0040] In certain embodiments, the isochronic wave comprises one or
more components (e.g., additive noise; e.g., stochastic resonance
signals) that, when transduced by the transducer to produce the
mechanical wave, correspond to sub-threshold signals that are below
an activation threshold of one or more target cells and/or proteins
(e.g., below a level of tactile sensation).
[0041] In certain embodiments, the isochronic wave comprises one or
more components (e.g., additive noise; e.g., stochastic resonance
signals) that, when transduced by the transducer to produce the
mechanical wave, correspond to supra-threshold signals that are
above an activation threshold of one or more target cells and/or
proteins (e.g., above a level of tactile sensation).
[0042] In another aspect, the invention is directed to a
transcutaneous neuromodulation device [e.g., a wearable device;
e.g., a non-invasive device (e.g., not comprising any components
that penetrate skin)] for treating anxiety and/or an anxiety
related disorder in a human subject by promoting nerve stimulation
through mechanical vibration, comprising: one or more mechanical
transducers, a battery, and one or more controller boards, wherein
the one or more mechanical transducers, the battery and the one or
more controller boards are in communication (e.g., through one or
more connectors; e.g., wirelessly), and wherein the one or more
controller boards control waveform output through the one or more
mechanical transducers, and the one or more mechanical transducers
transcutaneously stimulate one or more nerves of a human subject
and wherein the waveform output comprises an isochronic wave.
[0043] In another aspect, the invention is directed to a
transcutaneous stimulation device [e.g., a wearable device; e.g., a
non-invasive device (e.g., not comprising any components that
penetrate skin)] for treating anxiety and/or an anxiety related
disorder in a human subject by promoting mechanoreceptor
stimulation through mechanical vibration, comprising: one or more
mechanical transducers, a battery, and one or more controller
boards, wherein the one or more mechanical transducers, the battery
and the one or more controller boards are in communication (e.g.,
through one or more connectors; e.g., wirelessly), and wherein the
one or more controller boards control waveform output through the
transducer, and the one or more mechanical transducers
transcutaneously stimulate one or more mechanoreceptors of a human
subject and wherein the waveform output comprises an isochronic
wave.
[0044] In another aspect, the invention is directed to a method of
treating anxiety and/or an anxiety related disorder in a subject by
providing transcutaneous mechanical stimulation (e.g., non-invasive
mechanical stimulation) to the subject via a stimulation device
(e.g., a wearable device), the method comprising: generating a
mechanical wave by a mechanical transducer of the stimulation
device in response to an applied electronic drive signal;
controlling a waveform of the electronic drive signal by a
controller board (e.g., a controller board of the stimulation
device; e.g., a remote controller board), wherein the waveform
comprises an isochronic wave; and delivering the mechanical wave to
a body location of the subject via the stimulation device, thereby
providing the transcutaneous mechanical stimulation to the
subject.
[0045] In certain embodiments, the mechanical wave promotes
stimulation (e.g., wherein the waveform is selected to promote
stimulation) of one or more nerves [e.g., a vagus nerve; e.g., a
trigeminal nerve; e.g., peripheral nerves; e.g., a greater
auricular nerve; e.g., a lesser occipital nerve; e.g., one or more
cranial nerves (e.g., cranial nerve VII; e.g., cranial nerve IX;
e.g., cranial nerve XI; e.g., cranial nerve XII)]. In certain
embodiments, the one or more nerves comprises a vagus nerve and/or
a trigeminal nerve. In certain embodiments, the one or more nerves
comprises a C-tactile afferent.
[0046] In certain embodiments, the mechanical wave promotes
stimulation of (e.g., wherein the waveform is selected to promote
stimulation of) one or more mechanoreceptors and/or cutaneous
sensory receptors in the skin (e.g., to stimulate an afferent
sensory pathway and use properties of receptive fields to propagate
stimulation through tissue and bone). In certain embodiments, the
one or more mechanoreceptors and/or cutaneous sensory receptors
comprise Piezo2 protein and/or Merkel cells.
[0047] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform to
introduce particular signals that include active or inactive pulse
durations and frequencies configured to accommodate particular
mechanoreceptor recovery periods, adaptation times, inactivation
times, sensitization and desensitization times, or latencies.
[0048] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform to
enhance or inhibit the expression of presynaptic molecules
essential for synaptic vesicle release in neurons.
[0049] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform to
enhance or inhibit the expression of neuroactive substances that
can act as fast excitatory neurotransmitters or
neuromodulators.
[0050] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform to
stimulate mechanoreceptor cells associated with A.delta.-fibers and
C-fibers (e.g., including C tactile fibers) in order to stimulate
nociceptive, thermoceptive, interoceptive and/or other pathways
modulated by these fibers.
[0051] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform using
dynamical systems methods to produce a preferred response in neural
network dynamics (e.g., via modulation of signal timing).
[0052] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform using
dynamical systems measures to assess response signals (e.g.,
electronic) to detect particular network responses correlated with
changes in mechanical wave properties (e.g., and modulates the
waveform output to target/optimally enhance particular preferred
responses).
[0053] In certain embodiments, the delivering the mechanical wave
to the body location comprises contacting the mechanical transducer
to a surface (e.g., skin) of the subject at the body location.
[0054] In certain embodiments, the contacting the mechanical
transducer to the surface of the subject at the body location
comprises using an adhesive (e.g., a biocompatible adhesive) for
adhering at least one of the one or more mechanical transducers
(e.g., up to all) to a subject [e.g., skin (e.g., on a neck of;
e.g., overlaying at least one mastoid process of; e.g., of an outer
or posterior of at least one ear of) a human subject](e.g., wherein
the at least one mechanical transducer is embedded within the
adhesive; e.g., wherein the at least one mechanical transducer is
surrounded by the adhesive).
[0055] In certain embodiments, the contacting the mechanical
transducer to the surface of the subject at the body location
comprises using one or more ergonomic support components, wherein
the one or more transducers are supported by (e.g., housed within;
e.g., mounted on) the one or more ergonomic support component(s)
(e.g., collectively) and the one or more ergonomic support
component(s) is/are formed (e.g., molded) to maintain the
transducer in substantial proximity to one or more mastoid regions
of a human subject (e.g., by maintaining substantial contact with
skin overlaying the one or more mastoid regions).
[0056] In certain embodiments, the one or more ergonomic support
components comprise(s) a first ergonomic support component, the
first ergonomic support component comprising: (a) a first housing
comprising a casing (e.g., molded casing) of sufficient size to at
least partially house (i) a first transducer set comprising at
least a portion (e.g., half; e.g., all) of the one or more
mechanical transducers and (ii) a first controller board set
comprising at least a portion (e.g., half; e.g., all) of the one or
more controller boards, wherein the first transducer set is
disposed adjacent to a window in the first housing [e.g., an
insulated region of the first housing that contacts skin of the
human subject in substantial proximity to a first mastoid region
(e.g., on a first (e.g., left; e.g., right) side of head of the
subject); e.g., wherein the window comprises fabric, adhesive, etc.
placed in between a surface of the transducers of the first
transducer set and skin of the subject so as to prevent direct
contact with skin]; and (b) a first elastomeric arm comprising a
resilient material and formed (e.g., molded) to engage an first ear
of the subject and thereby support (e.g., fully) the first housing
(e.g., and first transducer set and first controller board set
housed therein), wherein the first housing is coupled to a distal
end of the first elastomeric arm, wherein the distal end of the
first elastomeric arm substantially aligns the window of the first
housing with a first body location on the subject in substantial
proximity to a first mastoid region (e.g., on a first side of the
subject's head; e.g., on a left side; e.g., on a right side), and
wherein the resilient material provides a force to hold the first
housing against the first body location.
[0057] In certain embodiments, the one or more ergonomic support
components further comprise(s) a second ergonomic support
component, the second ergonomic support component comprising: (a) a
second housing comprising a casing (e.g., molded casing) of
sufficient size to at least partially house (i) a second transducer
set comprising at least a portion (e.g., half; e.g., all) of the
one or more mechanical transducers and (ii) a second controller
board set comprising at least a portion (e.g., half; e.g., all) of
the one or more controller boards, wherein the second transducer
set is disposed adjacent to a window in the second housing [e.g.,
an insulated region of the second housing that contacts skin of the
human subject in substantial proximity to a second mastoid region
(e.g., on a second (e.g., left; e.g., right) side of head of the
subject); e.g., wherein the window comprises fabric, adhesive, etc.
placed in between a surface of the transducers of the second
transducer set and skin of the subject so as to prevent direct
contact with skin]; and (b) a second elastomeric arm comprising a
resilient material and formed (e.g., molded) to engage an ear of
the subject and thereby support (e.g., fully) the second housing
(e.g., and second transducer set and second controller board set
housed therein), wherein the second housing is coupled to a distal
end of the second elastomeric arm, wherein the distal end of the
second elastomeric arm substantially aligns the window of the
second housing with a second body location on the subject in
substantial proximity to a second mastoid region (e.g., on a second
side of the subject's head; e.g., on a right side; e.g., on a left
side), and wherein the resilient material provides a force to hold
the second housing against the second body location.
[0058] In certain embodiments, the first and second ergonomic
support components are in wireless communication with each other
(e.g., via near-field magnetic induction (NFMI) e.g., so as to
avoid/overcome interference from the subject's head) for
synchronizing delivery of the mechanical vibration to the first and
second mastoid regions of the subject (e.g., for synchronizing
delivery of a first mechanical vibration produced by the first
transducer set and delivery of a second mechanical vibration
produced by the second transducer set).
[0059] In certain embodiments, the one or more ergonomic support
components comprises: a linkage component formed to engage (e.g.,
wrap around a top of) a head of the subject; two housings disposed
at opposite ends of the linkage component so as to be positioned on
opposite sides of the head of the subject, wherein each housing
comprising a casing (e.g., a molded casing) of sufficient size to
at least partially house a corresponding transducer set comprising
at least a portion (e.g., one; e.g., half; e.g., all) of the one or
more mechanical transducers, wherein the mechanical transducers are
disposed adjacent to a window in each housing; and two elastomeric
hinges, each disposed at the opposite ends of the linkage component
and mounted to flexibly couple a housings to the linkage component,
wherein at least one of the elastomeric hinges is formed and
positioned to substantially align the window of each housing with
and against opposing mastoid regions on opposite sides of the head
of the subject.
[0060] In certain embodiments, the linkage component comprises an
adjustment mechanism comprising two partially overlaid,
interlocking, and sliding curved arms (e.g., curved elastomeric
arms), wherein said curved arms are maintained in alignment with
each other to form an arc (e.g., approximately matching an average
arc of a human head) and slide with respect to each other so as to
vary an amount of overlap, thereby varying a size of the arc (e.g.,
to match different size human heads), and wherein the two
elastomeric hinges are disposed on opposing ends of the arc formed
by the two sliding arms.
[0061] In certain embodiments, the mechanical transducer is a
member of a transducer array comprising a plurality of (e.g., two
or more) mechanical transducers maintained in a fixed spatial
arrangement in relation to each other (e.g., in substantial
proximity to each other; e.g., spaced along a straight or curved
line segment) and wherein the controller board controls output of
the mechanical transducer in relation to other mechanical
transducers of the array [e.g., so as to synchronize mechanical
vibration produced by each mechanical transducer of the transducer
array (e.g., such that each mechanical transducer begins and/or
ends producing mechanical vibration at a particular delay with
respect to one or more other mechanical transducers of the array;
e.g., such that the mechanical transducers are sequentially
triggered, one after the other; e.g., wherein the mechanical
transducers are spaced along a straight or curved line segment and
triggered sequentially along the line segment, such that an
apparent source of mechanical vibration moves along the line
segment to mimic a stroking motion)][e.g., wherein a first portion
of the mechanical transducers outputs a different frequency
mechanical vibration from a second portion of the mechanical
transducers of the transducer array (e.g., wherein each mechanical
transducer of the transducer array outputs a different frequency
mechanical vibration)].
[0062] In certain embodiments, the transducer is a linear
transducer (e.g., operable to produce mechanical vibration
comprising a longitudinal component (e.g., a longitudinal
vibration)).
[0063] In certain embodiments, the mechanical transducer is
incorporated into a headphone (e.g., an in-ear headphone; e.g., an
over-the-ear headphone).
[0064] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises receiving (e.g., by a receiver in
communication with the controller board) a signal from a personal
computing device (e.g., a smart phone; e.g., a personal computer;
e.g., a laptop computer; e.g., a tablet computer; e.g., a
smartwatch; e.g., a fitness tracker; e.g., a smart charger)(e.g.,
to upload new waveforms and/or settings for waveforms).
[0065] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating and/or selecting the
waveform in response to (e.g., based on) the signal received from
the personal computing device by the receiver.
[0066] In certain embodiments, the delivering the mechanical wave
to the body location is performed in a non-invasive fashion (e.g.,
without penetrating skin of the subject).
[0067] In certain embodiments, the method comprising providing, by
a secondary stimulation device, one or more external
stimulus/stimuli (e.g., visual stimulus; e.g., acoustic stimulus;
e.g., limbic priming; e.g., a secondary tactile signal).
[0068] In certain embodiments, the isochronic wave comprises a
frequency component ranging from 5 to 15 Hz (e.g., ranging from
approximately 7 to approximately 13 Hz; e.g., a frequency range
matching an alpha brain wave frequency range; e.g., approximately
10 Hz).
[0069] In certain embodiments, the isochronic wave comprises a
frequency component ranging from 0 to 49 Hz (e.g., from 18 to 48
Hz; e.g., from 15 to 40 Hz; e.g. from 8 to 14 Hz).
[0070] In certain embodiments, one or more low-amplitude
sub-intervals of the isochronic wave have a duration of greater
than or approximately two seconds (e.g., wherein the one or more
low-amplitude sub-intervals have a duration of approximately two
seconds; e.g., wherein the one or more low-amplitude sub-intervals
have a duration ranging from approximately two seconds to
approximately 10 seconds; e.g., wherein the one or more low
amplitude sub-intervals have a duration ranging from approximately
two seconds to approximately 4 seconds).
[0071] In certain embodiments, the isochronic wave comprises a
carrier wave [e.g., a periodic wave having a substantially constant
frequency (e.g., ranging from 5 to 15 Hz; e.g., ranging from
approximately 7 to approximately 13 Hz; e.g., a frequency range
matching an alpha brain wave frequency range; e.g., approximately
10 Hz)] modulated by an envelope function having one or more
low-amplitude sub-intervals [e.g., a periodic envelope function
(e.g., a square wave; e.g., a 0.5 Hz square wave); e.g., the one or
more low-amplitude sub-intervals having a duration of greater than
or approximately equal to two seconds; e.g., the one or more
low-amplitude sub-intervals having a duration of approximately two
seconds].
[0072] In certain embodiments, the isochronic wave is also a
transformed time-varying wave. In certain embodiments, the
isochronic wave comprises a chirped wave. In certain embodiments,
the waveform of the electronic drive signal comprises a transformed
time-varying wave having a functional form corresponding to a
carrier wave within an envelope {e.g., wherein the transformed-time
varying wave is the carrier wave and is further modulated by an
envelope [e.g., wherein the envelope is a sinusoidal wave; e.g.,
wherein the envelope has a monotonically increasing (in time)
amplitude (e.g., wherein the envelope has a functional form
corresponding to an increasing (in time) exponential)]; e.g.,
wherein the transformed time-varying wave is the envelope that
modulates a carrier wave [e.g., wherein the carrier wave is a
periodic wave (e.g., a sinusoidal wave; e.g., a square wave; e.g.,
a sawtooth wave)(e.g., having a higher frequency than the
envelope)]}. In certain embodiments, a functional form of the
waveform of the electronic drive signal is based on one or more
recorded natural sounds (e.g., running water; e.g., ocean waves;
e.g., purring; e.g., breathing; e.g., chanting; e.g., gongs; e.g.,
bells).
[0073] In certain embodiments, the method comprises receiving an
electronic response signal from a monitoring device (e.g., directly
from and/or to the monitoring device; e.g., via one or more
intermediate server(s) and/or computing device(s))(e.g., a wearable
monitoring device; e.g., a personal computing device; e.g., a
fitness tracker; e.g., a heart-rate monitor; e.g., an
electrocardiograph (EKG) monitor; e.g., an electroencephalography
(EEG) monitor; e.g., an accelerometer; e.g., a blood-pressure
monitor; e.g., a galvanic skin response (GSR) monitor) and), and
wherein the controlling the waveform of the electronic drive signal
comprises adjusting and/or selecting the waveform in response to
(e.g., based on) the received electronic response signal.
[0074] In certain embodiments, the method comprises recording usage
data (e.g., parameters such as a record of when the device was
used, duration of use, etc.) and/or one or more biofeedback signals
for a human subject [e.g., using one or more sensors, each operable
to measure and record one or more biofeedback signals (e.g., a
galvanic skin response (GSR) sensor; e.g., a heart-rate monitor;
e.g., an accelerometer)][e.g., storing and/or providing the
recorded usage data and/or biofeedback signals for further
processing and/or transmission to an external computing device,
e.g., for computation (e.g., using a machine learning algorithm
that receives the one or more biofeedback signals as input, along
with, optionally, user reported information) and display of one or
more performance metrics (e.g., a stress index) to a subject].
[0075] In certain embodiments, the method comprises automatically
modulating and/or selecting the waveform of the electronic drive
signal in response to (e.g., based on) the recorded usage data
and/or biofeedback signals (e.g., using a machine learning
algorithm that receives the one or more biofeedback signals as
input, along with, optionally, user reported information, to
optimize the waveform output).
[0076] In certain embodiments, a level [e.g., amplitude (e.g., a
force; e.g., a displacement)] of at least a portion of the
mechanical wave is (e.g., modulated and/or selected) based on
activation thresholds of one or more target cells and/or proteins
(e.g., mechanoreceptors (e.g., C tactile afferents); e.g., nerves;
e.g., sensory thresholds corresponding to a level of tactile
sensation) [e.g., wherein the one or more controller boards
modulate the waveform output based on sub-activation thresholds
(e.g., accounting for the response of the mechanical
transducers)].
[0077] In certain embodiments, an amplitude of the mechanical wave
corresponds to a displacement ranging from 1 micron to 10
millimeters (e.g., approximately 25 microns)(e.g., wherein the
amplitude is adjustable over the displacement ranging from 1 micron
to 10 millimeters)[e.g., wherein the amplitude corresponds to a
force of approximately 0.4N][e.g., thereby matching the amplitude
to activation thresholds of C tactile afferents].
[0078] In another aspect, the invention is directed to a method of
treating anxiety and/or an anxiety related disorder in a subject by
providing transcutaneous mechanical stimulation (e.g., non-invasive
mechanical stimulation) to the subject via a stimulation device
(e.g., a wearable device), the method comprising: generating a
mechanical wave by a mechanical transducer of the stimulation
device in response to an applied electronic drive signal;
controlling a waveform of the electronic drive signal by a
controller board (e.g., a controller board of the stimulation
device; e.g., a remote controller board); and delivering the
mechanical wave to a body location of the subject via the
stimulation device, wherein the body location is in proximity to a
mastoid of the subject (e.g., wherein the mastoid lies directly
beneath the body location), thereby providing the transcutaneous
mechanical stimulation to the subject.
[0079] In another aspect, the invention is directed to a method of
treating anxiety and/or an anxiety related disorder in a subject by
providing transcutaneous mechanical stimulation (e.g., non-invasive
mechanical stimulation) to one or more nerves of the subject via a
stimulation device (e.g., a wearable device), the method
comprising: generating a mechanical wave by a mechanical transducer
of the stimulation device in response to an applied electronic
drive signal; controlling a waveform of the electronic drive signal
by a controller board (e.g., of the stimulation device; e.g., a
remote controller board); and delivering the mechanical wave to a
body location of the subject via the wearable stimulation device,
thereby stimulating the one or more nerves, wherein the one or more
nerves comprise(s) a cranial nerve (e.g., vagus nerve; e.g.,
trigeminal nerve; e.g., facial nerve) of the subject.
[0080] In another aspect, the invention is directed to a method of
treating anxiety and/or an anxiety related disorder in a subject by
providing transcutaneous mechanical stimulation (e.g., non-invasive
mechanical stimulation) to one or more nerves and/or
mechanoreceptors of the subject via a stimulation device (e.g., a
wearable device), the method comprising: generating a mechanical
wave by a mechanical transducer of the stimulation device in
response to an applied electronic drive signal; controlling a
waveform of the electronic drive signal by a controller board
(e.g., a controller board of the wearable stimulation device; e.g.,
a remote controller board), wherein the waveform comprises a
frequency component ranging from approximately 5 Hz to 15 Hz (e.g.,
approximately 10 Hz; e.g., ranging from approximately 7 Hz to
approximately 13 Hz; e.g., a frequency range matching an alpha
brain wave frequency); and delivering the mechanical wave to a body
location of the subject via the stimulation device, thereby
providing the transcutaneous mechanical stimulation of the one or
more nerves and/or mechanoreceptors of the subject.
[0081] In another aspect, the invention is directed to a method of
treating anxiety and/or an anxiety related disorder in a subject by
providing transcutaneous mechanical stimulation (e.g., non-invasive
mechanical stimulation) to the subject via a stimulation device
(e.g., a wearable device), the method comprising: generating a
mechanical wave by a mechanical transducer of the stimulation
device in response to an applied electronic drive signal; receiving
an electronic response signal from a monitoring device (e.g., a
wearable monitoring device) operable to monitor one or more
physiological signals from the subject and generate, in response to
the one or more physiological signals from the subject, the
electronic response signal (e.g., wherein the electronic response
signal is received directly from the monitoring device; e.g.,
wherein the electronic response signal is received from the
wearable monitoring device via one or more intermediate servers
and/or processors); responsive to the receiving the electronic
response signal, controlling, via a controller board (e.g., a
controller board of the stimulation device; e.g., a remote
controller board), a waveform of the electronic drive signal to
adjust and/or select the waveform based at least in part on the
received electronic response signal; and delivering the mechanical
wave to a body location of the subject via the stimulation device,
thereby providing the transcutaneous mechanical stimulation to the
subject.
[0082] In another aspect, the invention is directed to a method of
treating anxiety and/or an anxiety related disorder in a subject by
providing transcutaneous mechanical stimulation (e.g., non-invasive
mechanical stimulation) to the subject via a stimulation device
(e.g., a wearable device), the method comprising: (a) generating a
mechanical wave by a mechanical transducer of the stimulation
device in response to an applied electronic drive signal; (b)
accessing and/or receiving [e.g., by a processor of a computing
device, of and/or in communication with the stimulation device,
e.g., an intermediate server and/or processor (e.g., of a mobile
computing device in communication with the stimulation device)]
subject response data (e.g., entered by the subjects themselves or
biofeedback data recorded via sensors) and/or initialization
setting data [e.g., physical characteristics of the subject (e.g.,
age, height, weight, gender, body-mass index (BMI), and the like);
e.g., activity levels (e.g., physical activity levels); e.g.,
biofeedback data recorded by one or more sensors (e.g., included
within the device and/or external to and in communication with the
device)(e.g., a heart rate; e.g., a galvanic skin response; e.g.,
physical movement (e.g., recorded by an accelerometer)); e.g.,
results of a preliminary survey (e.g., entered by the subject
themselves, e.g., via a mobile computing device, an app, and/or
online portal; e.g., provided by a therapist/physician treating the
subject for a disorder)]; (c) responsive to the accessed and/or
received subject response data and/or initialization setting data,
controlling, via a controller board (e.g., a controller board of
the stimulation device; e.g., a remote controller board), a
waveform of the electronic drive signal to adjust and/or select the
waveform based at least in part on the subject response data and/or
initialization setting data (e.g., using a machine learning
algorithm that receives one or more biofeedback signals as input,
along with, optionally, user reported information, to optimize the
waveform output); and (d) delivering the mechanical wave to a body
location of the subject via the stimulation device, thereby
providing the transcutaneous mechanical stimulation to the
subject.
[0083] In certain embodiments, step (b) comprises receiving and/or
accessing subject response data [e.g., results of a survey recorded
for the subject (e.g., entered by the subject themselves, e.g., via
a mobile computing device, an app, and/or online portal; e.g.,
provided by a therapist/physician treating the subject for a
disorder); e.g., biofeedback data recorded by one or more sensors
(e.g., included within the device and/or external to and in
communication with the device)(e.g., a heart rate; e.g., a galvanic
skin response; e.g., physical movement (e.g., recorded by an
accelerometer))] provided following their receipt of a round (e.g.,
a duration) of the transcutaneous mechanical stimulation provided
by the stimulation device; and step (c) comprises controlling the
waveform of the electronic drive signal based at least in part on
the subject feedback, thereby modifying the transcutaneous
mechanical stimulation provided to the subject based on subject
response data.
[0084] In another aspect, the invention is directed to a method of
treating anxiety and/or an anxiety related disorder in a subject by
providing transcutaneous mechanical stimulation (e.g., non-invasive
mechanical stimulation) to the subject via a stimulation device
(e.g., a wearable device), the method comprising: generating a
first mechanical wave by a first mechanical transducer of the
stimulation device in response to a first applied electronic drive
signal; controlling a first waveform of the first electronic drive
signal by a controller board (e.g., a controller board of the
stimulation device; e.g., a remote controller board); delivering
the first mechanical wave to a first body location (e.g., on a
right side; e.g., a location behind a right ear) of the subject via
the stimulation device; generating a second mechanical wave by a
second mechanical transducer of the stimulation device in response
to a second applied electronic drive signal; controlling a second
waveform of the second electronic drive signal by the controller
board; and delivering the second mechanical wave to a second body
location (e.g., on a left side; e.g., a location behind a left ear)
of the subject via the stimulation device, thereby providing the
transcutaneous mechanical stimulation to the subject.
[0085] In another aspect, the invention is directed to a method of
treating anxiety and/or an anxiety related disorder in a subject by
providing transcutaneous mechanical stimulation (e.g., non-invasive
mechanical stimulation) to the subject via a stimulation device
(e.g., a wearable device), the method comprising: generating a
first mechanical wave by a first mechanical transducer of the
stimulation device in response to an applied electronic drive
signal; controlling a waveform of the first electronic drive signal
by a controller board (e.g., a controller board of the stimulation
device; e.g., a remote controller board); delivering the first
mechanical wave to a first body location (e.g., on a right side;
e.g., a location behind a right ear) of the subject via the
stimulation device; generating a second mechanical wave by a second
mechanical transducer of the stimulation device in response to the
applied electronic drive signal; delivering the second mechanical
wave to a second body location (e.g., on a left side; e.g., a
location behind a left ear) of the subject via the stimulation
device, thereby providing the transcutaneous mechanical stimulation
to the subject.
[0086] In another aspect, the invention is directed to a method of
treating anxiety and/or an anxiety related disorder in a subject by
providing transcutaneous mechanical stimulation (e.g., non-invasive
mechanical stimulation) to one or more nerves and/or
mechanoreceptors of the subject via a stimulation device (e.g., a
wearable device), in combination with one or more rounds of a
therapy [e.g., psychotherapy; e.g., exposure therapy (e.g., for
treatment of various phobias such as fear of heights, fear of
public speaking, social phobia, panic attack, fear of flying, germ
phobia, and the like); e.g., cognitive behavioral therapy (CBT);
e.g., acceptance and commitment therapy (ACT)] the method
comprising: generating a mechanical wave by a mechanical transducer
of the stimulation device in response to an applied electronic
drive signal;
[0087] controlling a waveform of the electronic drive signal by a
controller board (e.g., a controller board of the wearable
stimulation device; e.g., a remote controller board); and
[0088] delivering the mechanical wave to a body location of the
subject via the stimulation device at one or more times each in
proximity to and/or during a round of the therapy received by the
subject [e.g., prior to the round of therapy (e.g., such that the
subject is in a more relaxed state prior to the round of the
therapy; e.g., such that the subject is in a more responsive state
prior to the round of the therapy; e.g., such that the subject is
more open to an exposure; e.g., such that the subject is in a state
of improved receptiveness and/or readiness to change); e.g., during
the round of the therapy; e.g., following (e.g., immediately
following) the round of the therapy; e.g., in between two or more
rounds of therapy], thereby providing the transcutaneous mechanical
stimulation of the one or more nerves and/or mechanoreceptors of
the subject in combination with one or more rounds of the
therapy.
[0089] In another aspect, the invention is directed to a method of
treating anxiety and/or an anxiety related disorder in a subject by
stimulating one or more nerves and/or mechanoreceptors of the
subject (e.g., a human subject), the method comprising: using the
device method comprising: using the device articulated in any of
paragraphs [007]-[0043], for stimulation of the one or more nerves
and/or mechanoreceptors of the subject.
[0090] In another aspect, the invention is directed to a method of
treating anxiety and/or an anxiety related disorder in a human
subject by stimulating one or more nerves of the human subject
using a transcutaneous, neuromodulation device [e.g., a wearable
device; e.g., a non-invasive device (e.g., not comprising any
components that penetrate skin)], the device comprising one or more
transducers (e.g., mechanical transducers), a battery, connectors,
and one or more controller boards, wherein the one or more
controller boards control waveform output through the connectors
and the transducers, and wherein the transducers transcutaneously
applied stimulates the one or more nerves, the method comprising:
contacting the one or more transducers of the device to the human
subject, generating the waveform output signal, activating the
transducers using the waveform output signal (e.g., by applying the
waveform output signal to the transducers to generate a mechanical
wave), and stimulating the one or more nerves of the human subject,
wherein the waveform output comprises an isochronic wave.
[0091] In another aspect, the invention is directed to a method of
treating anxiety and/or an anxiety related disorder in a human
subject by stimulating one or more mechanoreceptors of the human
subject using transcutaneous stimulation device [e.g., a wearable
device; e.g., a non-invasive device (e.g., not comprising any
components that penetrate skin)], the device comprising one or more
mechanical transducers, a battery, connectors, and one or more
controller boards, wherein the one or more controller boards
control waveform output through the connectors and the one or more
mechanical transducers, and wherein the one or more mechanical
transducers transcutaneously applied stimulate the one or more
mechanoreceptors, the method comprising: contacting the one or more
mechanical transducers of the device to the human subject,
generating the waveform output signal, activating the mechanical
transducers using the waveform output signal (e.g., by applying the
waveform output signal to the transducers to generate a mechanical
wave), and stimulating the one or more mechanoreceptors of the
human subject, wherein the waveform output comprises an isochronic
wave.
[0092] In another aspect, the invention is directed to a method of
adjusting (e.g., controlling) a level of a stress hormone [e.g.,
cortisol (e.g., reducing a cortisol level); e.g., oxytocin (e.g.,
increasing an oxytocin level); e.g., serotonin (e.g., increasing a
serotonin level)] in a subject, the method comprising
transcutaneously delivering mechanical stimulation to the subject
using a mechanical wave having a vibrational waveform selected to
reduce the level of the stress hormone in the subject upon and/or
following the delivering of the mechanical wave to the subject.
[0093] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for reducing stress in a user as measured by a level of a
stress hormone [e.g., cortisol (e.g., reducing a cortisol level);
e.g., oxytocin (e.g., increasing an oxytocin level); e.g.,
serotonin (e.g., increasing a serotonin level)] for the
subject.
[0094] In another aspect, the invention is directed to a
transcutaneous neuromodulation device [e.g., a wearable device;
e.g., a non-invasive device (e.g., not comprising any components
that penetrate skin)] for treating a disorder in a subject (e.g.,
anxiety and/or an anxiety related disorder) by promoting nerve
stimulation through mechanical vibration, comprising: one or more
mechanical transducers, a battery, and a controller board, wherein
the transducer, battery and controller board are in communication
(e.g., through one or more connectors; e.g., wirelessly), and
wherein the controller board controls waveform output through the
transducer, thereby producing a mechanical vibration, and wherein
the disorder is a member selected from the group consisting of:
agoraphobia, body focused repetitive behaviors, generalized anxiety
disorder, health anxiety, hoarding disorder (HD),
obsessive-compulsive disorder, panic disorder, post-traumatic
stress disorder (PTSD), separation anxiety, social anxiety
disorder, a specific phobia (e.g., fear of heights, fear of public
speaking, social phobia, panic attack, fear of flying, germ phobia,
and the like), acute stress disorder, adjustment disorder with
anxious features, substance-induced anxiety disorder, selective
mutism in children, somatic symptom disorder, illness anxiety
disorder, attention deficit disorder (ADD), attention deficit
hyperactivity disorder, autism.
[0095] In another aspect, the invention is directed to a method of
treating a disorder in a human subject by promoting nerve
stimulation in the human subject through mechanical vibration using
a transcutaneous, neuromodulation device [e.g., a wearable device;
e.g., a non-invasive device (e.g., not comprising any components
that penetrate skin)], the device comprising one or more
transducers (e.g., mechanical transducers), a battery, connectors,
and a controller board, wherein the controller board controls
waveform output through the connectors and the transducers, and
wherein the transducers transcutaneously applied stimulates the one
or more nerves, the method comprising: contacting the one or more
transducers of the device to the human subject, generating the
waveform output signal, activating the transducers using the
waveform output signal (e.g., by applying the waveform output
signal to the transducers to generate a mechanical wave), and
promoting stimulation of the one or more nerves of the human
subject, wherein the disorder is a member selected from the group
consisting of: agoraphobia, body focused repetitive behaviors,
generalized anxiety disorder, health anxiety, hoarding disorder
(HD), obsessive-compulsive disorder, panic disorder, post-traumatic
stress disorder (PTSD), separation anxiety, social anxiety
disorder, a specific phobia (e.g., fear of heights, fear of public
speaking, social phobia, panic attack, fear of flying, germ phobia,
and the like), acute stress disorder, adjustment disorder with
anxious features, substance-induced anxiety disorder, selective
mutism in children, somatic symptom disorder, illness anxiety
disorder, attention deficit disorder (ADD), attention deficit
hyperactivity disorder, autism.
[0096] In another aspect, the invention is directed to a method of
a disorder in a subject by providing transcutaneous mechanical
stimulation (e.g., non-invasive mechanical stimulation) to the
subject via a stimulation device (e.g., a wearable device), the
method comprising: generating a mechanical wave by a mechanical
transducer of the stimulation device in response to an applied
electronic drive signal; controlling a waveform of the electronic
drive signal by a controller board (e.g., a controller board of the
stimulation device; e.g., a remote controller board); and
delivering the mechanical wave to a body location of the subject
via the stimulation device, thereby providing the transcutaneous
mechanical stimulation to the subject, wherein the disorder is a
member selected from the group consisting of: agoraphobia, body
focused repetitive behaviors, generalized anxiety disorder, health
anxiety, hoarding disorder (HD), obsessive-compulsive disorder,
panic disorder, post-traumatic stress disorder (PTSD), separation
anxiety, social anxiety disorder, a specific phobia (e.g., fear of
heights, fear of public speaking, social phobia, panic attack, fear
of flying, germ phobia, and the like), acute stress disorder,
adjustment disorder with anxious features, substance-induced
anxiety disorder, selective mutism in children, somatic symptom
disorder, illness anxiety disorder, attention deficit disorder
(ADD), attention deficit hyperactivity disorder, autism.
[0097] In one aspect, the invention is directed to a transcutaneous
neuromodulation device [e.g., a wearable device; e.g., a
non-invasive device (e.g., not comprising any components that
penetrate skin)] for promoting nerve stimulation through mechanical
vibration, comprising: one or more mechanical transducers, a
battery, and one or more controller boards, wherein the one or more
mechanical transducers, the battery and the one or more controller
boards are in communication (e.g., through one or more connectors;
e.g., wirelessly), and wherein the controller board controls
waveform output through the one or more mechanical transducers,
thereby producing mechanical vibration, and wherein the waveform
output comprises an isochronic wave.
[0098] In certain embodiments, the device promotes stimulation
(e.g., wherein the waveform is selected to promote stimulation) of
one or more nerves [e.g., a vagus nerve; e.g., a trigeminal nerve;
e.g., peripheral nerves; e.g., a greater auricular nerve; e.g., a
lesser occipital nerve; e.g., one or more cranial nerves (e.g.,
cranial nerve VII; e.g., cranial nerve IX; e.g., cranial nerve XI;
e.g., cranial nerve XII)]. In certain embodiments, the one or more
nerves comprises a vagus nerve and/or a trigeminal nerve. In
certain embodiments, the one or more nerves comprises a C-tactile
afferent.
[0099] In certain embodiments, the device promotes stimulation of
(e.g., wherein the waveform is selected to promote stimulation of)
one or more mechanoreceptors and/or cutaneous sensory receptors in
the skin (e.g., to stimulate an afferent sensory pathway and use
properties of receptive fields to propagate stimulation through
tissue and bone). In certain embodiments, the one or more
mechanoreceptors and/or cutaneous sensory receptors comprise Piezo2
protein and/or Merkel cells.
[0100] In certain embodiments, the one or more controller boards
modulate the waveform output to introduce particular signal that
include active or inactive pulse durations and frequencies
configured to accommodate particular mechanoreceptor recovery
periods, adaptation times, inactivation times, sensitization and
desensitization times, or latencies.
[0101] In certain embodiments, the one or more controller boards
modulate the waveform output to enhance or inhibit the expression
of presynaptic molecules essential for synaptic vesicle release in
neurons. In certain embodiments, the one or more controller boards
modulate the waveform output to enhance or inhibit the expression
of neuroactive substances that can act as fast excitatory
neurotransmitters or neuromodulators.
[0102] In certain embodiments, the one or more controller boards
modulates the waveform output to stimulate mechanoreceptor cells
associated with A.delta.-fibers and C-fibers (e.g., including C
tactile fibers) in order to stimulate nociceptive, thermoceptive,
interoceptive and/or other pathways modulated by these fibers.
[0103] In certain embodiments, the one or more controller boards
modulate the waveform output using dynamical systems methods to
produce a preferred response in neural network dynamics (e.g., via
modulation of signal timing). In certain embodiments, the one or
more controller boards modulates the waveform output using
dynamical systems measures to assess response signals (e.g.,
electronic) to detect particular network responses correlated with
changes in mechanical wave properties (e.g., and modulates the
waveform output to target/optimally enhance particular preferred
responses).
[0104] In certain embodiments, the device comprises an adhesive
(e.g., a biocompatible adhesive) for adhering at least one of the
one or more mechanical transducers (e.g., up to all) to a subject
[e.g., skin (e.g., on a neck of; e.g., overlaying at least one
mastoid process of; e.g., of an outer or posterior of at least one
ear of) a human subject](e.g., wherein the at least one mechanical
transducer is embedded within the adhesive; e.g., wherein the at
least one mechanical transducer is surrounded by the adhesive).
[0105] In certain embodiments, the device comprising one or more
ergonomic support components, wherein the one or more transducers
are supported by (e.g., housed within; e.g., mounted on) the one or
more ergonomic support component(s) (e.g., collectively) and the
one or more ergonomic support component(s) is/are formed (e.g.,
molded) to maintain the transducer in substantial proximity to one
or more mastoid regions of a human subject (e.g., by maintaining
substantial contact with skin overlaying the one or more mastoid
regions).
[0106] In certain embodiments, the device comprises a first
ergonomic support component, the first ergonomic support component
comprising: (a) a first housing comprising a casing (e.g., molded
casing) of sufficient size to at least partially house (i) a first
transducer set comprising at least a portion (e.g., half; e.g.,
all) of the one or more mechanical transducers and (ii) a first
controller board set comprising at least a portion (e.g., half;
e.g., all) of the one or more controller boards, wherein the first
transducer set is disposed adjacent to a window in the first
housing [e.g., an insulated region of the first housing that
contacts skin of the human subject in substantial proximity to a
first mastoid region (e.g., on a first (e.g., left; e.g., right)
side of head of the subject); e.g., wherein the window comprises
fabric, adhesive, etc. placed in between a surface of the
transducers of the first transducer set and skin of the subject so
as to prevent direct contact with skin]; and (b) a first
elastomeric arm comprising a resilient material and formed (e.g.,
molded) to engage an first ear of the subject and thereby support
(e.g., fully) the first housing (e.g., and first transducer set and
first controller board set housed therein), wherein the first
housing is coupled to a distal end of the first elastomeric arm,
wherein the distal end of the first elastomeric arm substantially
aligns the window of the first housing with a first body location
on the subject in substantial proximity to a first mastoid region
(e.g., on a first side of the subject's head; e.g., on a left side;
e.g., on a right side), and wherein the resilient material provides
a force to hold the first housing against the first body
location.
[0107] In certain embodiments, the device further comprises a
second ergonomic support component, the second ergonomic support
component comprising: (a) a second housing comprising a casing
(e.g., molded casing) of sufficient size to at least partially
house (i) a second transducer set comprising at least a portion
(e.g., half; e.g., all) of the one or more mechanical transducers
and (ii) a second controller board set comprising at least a
portion (e.g., half; e.g., all) of the one or more controller
boards, wherein the second transducer set is disposed adjacent to a
window in the second housing [e.g., an insulated region of the
second housing that contacts skin of the human subject in
substantial proximity to a second mastoid region (e.g., on a second
(e.g., left; e.g., right) side of head of the subject); e.g.,
wherein the window comprises fabric, adhesive, etc. placed in
between a surface of the transducers of the second transducer set
and skin of the subject so as to prevent direct contact with skin];
and (b) a second elastomeric arm comprising a resilient material
and formed (e.g., molded) to engage an ear of the subject and
thereby support (e.g., fully) the second housing (e.g., and second
transducer set and second controller board set housed therein),
wherein the second housing is coupled to a distal end of the second
elastomeric arm, wherein the distal end of the second elastomeric
arm substantially aligns the window of the second housing with a
second body location on the subject in substantial proximity to a
second mastoid region (e.g., on a second side of the subject's
head; e.g., on a right side; e.g., on a left side), and wherein the
resilient material provides a force to hold the second housing
against the second body location.
[0108] In certain embodiments, the first and second ergonomic
support components are in wireless communication with each other
(e.g., via near-field magnetic induction (NFMI) e.g., so as to
avoid/overcome interference from the subject's head) for
synchronizing delivery of the mechanical vibration to the first and
second mastoid regions of the subject (e.g., for synchronizing
delivery of a first mechanical vibration produced by the first
transducer set and delivery of a second mechanical vibration
produced by the second transducer set).
[0109] In certain embodiments, the one or more ergonomic support
components comprises: a linkage component formed to engage (e.g.,
wrap around a top of) a head of the subject; two housings disposed
at opposite ends of the linkage component so as to be positioned on
opposite sides of the head of the subject, wherein each housing
comprising a casing (e.g., a molded casing) of sufficient size to
at least partially house a corresponding transducer set comprising
at least a portion (e.g., one; e.g., half; e.g., all) of the one or
more mechanical transducers, wherein the mechanical transducers are
disposed adjacent to a window in each housing; and two elastomeric
hinges, each disposed at the opposite ends of the linkage component
and mounted to flexibly couple a housings to the linkage component,
wherein at least one of the elastomeric hinges is formed and
positioned to substantially align the window of each housing with
and against opposing mastoid regions on opposite sides of the head
of the subject.
[0110] In certain embodiments, the linkage component comprises an
adjustment mechanism comprising two partially overlaid,
interlocking, and sliding curved arms (e.g., curved elastomeric
arms), wherein said curved arms are maintained in alignment with
each other to form an arc (e.g., approximately matching an average
arc of a human head) and slide with respect to each other so as to
vary an amount of overlap, thereby varying a size of the arc (e.g.,
to match different size human heads), and wherein the two
elastomeric hinges are disposed on opposing ends of the arc formed
by the two sliding arms.
[0111] In certain embodiments, the device comprises at least one
transducer array comprising a plurality of (e.g., two or more)
mechanical transducers maintained in a fixed spatial arrangement in
relation to each other (e.g., in substantial proximity to each
other; e.g., spaced along a straight or curved line segment) and
wherein at least a portion of the one or more controller boards
(e.g., a single controller board; e.g., two or more controller
boards) are in communication with the mechanical transducers of the
transducer array to control output of the mechanical transducers of
the transducer array in relation to each other [e.g., wherein the
at least a portion of the one or more controller boards
synchronizes mechanical vibration produced by each mechanical
transducer of the transducer array (e.g., such that each mechanical
transducer begins and/or ends producing mechanical vibration at a
particular delay with respect to one or more other mechanical
transducers of the array; e.g., such that the mechanical
transducers are sequentially triggered, one after the other; e.g.,
wherein the mechanical transducers are spaced along a straight or
curved line segment and triggered sequentially along the line
segment, such that an apparent source of mechanical vibration moves
along the line segment to mimic a stroking motion)] [e.g., wherein
a first portion of the mechanical transducers outputs a different
frequency mechanical vibration from a second portion of the
mechanical transducers of the transducer array (e.g., wherein each
mechanical transducer of the transducer array outputs a different
frequency mechanical vibration)].
[0112] In certain embodiments, the device comprises a receiver in
communication with the one or more controller boards, wherein the
receiver is operable to receive a signal from and/or transmit a
signal (e.g., wirelessly; e.g., via a wired connection) to a
personal computing device (e.g., a smart phone; e.g., a personal
computer; e.g., a laptop computer; e.g., a tablet computer; e.g., a
smartwatch; e.g., a fitness tracker; e.g., a smart charger)(e.g.,
to upload new waveforms and/or settings for waveforms).
[0113] In certain embodiments, the one or more controller boards
is/are operable to modulate and/or select the waveform output in
response to (e.g., based on) the signal received from the personal
computing device by the receiver.
[0114] In certain embodiments, the device is non-invasive (e.g.,
does not comprise any components for penetrating skin).
[0115] In certain embodiments, the isochronic wave comprises a
frequency component ranging from 5 to 15 Hz (e.g., ranging from
approximately 7 to approximately 13 Hz; e.g., a frequency range
matching an alpha brain wave frequency range; e.g., approximately
10 Hz). In certain embodiments, the isochronic wave comprises a
frequency component ranging from 0 to 49 Hz (e.g., from 18 to 48
Hz; e.g., from 15 to 40 Hz; e.g. from 8 to 14 Hz).
[0116] In certain embodiments, one or more low-amplitude
sub-intervals of the isochronic wave have a duration of greater
than or approximately two seconds (e.g., wherein the one or more
low-amplitude sub-intervals have a duration of approximately two
seconds; e.g., wherein the one or more low-amplitude sub-intervals
have a duration ranging from approximately two seconds to
approximately 10 seconds; e.g., wherein the one or more low
amplitude sub-intervals have a duration ranging from approximately
two seconds to approximately 4 seconds).
[0117] In certain embodiments, the isochronic wave comprises a
carrier wave [e.g., a periodic wave having a substantially constant
frequency (e.g., ranging from 5 to 15 Hz; e.g., ranging from
approximately 7 to approximately 13 Hz; e.g., a frequency range
matching an alpha brain wave frequency range; e.g., approximately
10 Hz)] modulated by an envelope function having one or more
low-amplitude sub-intervals [e.g., a periodic envelope function
(e.g., a square wave; e.g., a 0.5 Hz square wave); e.g., the one or
more low-amplitude sub-intervals having a duration of greater than
or approximately equal to two seconds; e.g., the one or more
low-amplitude sub-intervals having a duration of approximately two
seconds].
[0118] In certain embodiments, the device comprises a receiver in
communication with the one or more controller boards, wherein the
receiver is operable to receive a signal from and/or transmit a
signal to a monitoring device (e.g., directly from and/or to the
monitoring device; e.g., via one or more intermediate server(s)
and/or computing device(s))(e.g., a wearable monitoring device;
e.g., a personal computing device; e.g., a fitness tracker; e.g., a
heart-rate monitor; e.g., an electrocardiograph (EKG) monitor;
e.g., an electroencephalography (EEG) monitor; e.g., an
accelerometer; e.g., a blood-pressure monitor; e.g., a galvanic
skin response (GSR) monitor) and wherein the one or more controller
boards is/are operable to modulate and/or select the waveform
output in response to (e.g., based on) the signal from the wearable
monitoring device received by the receiver.
[0119] In certain embodiments, the device is operable to record
usage data (e.g., parameters such as a record of when the device
was used, duration of use, etc.) and/or one or more biofeedback
signals for a human subject [e.g., wherein the device comprises one
or more sensors, each operable to measure and record one or more
biofeedback signals (e.g., a galvanic skin response (GSR) sensor;
e.g., a heart-rate monitor; e.g., an accelerometer)][e.g., wherein
the device is operable to store the recorded usage data and/or
biofeedback signals for further processing and/or transmission to
an external computing device, e.g., for computation (e.g., using a
machine learning algorithm that receives the one or more
biofeedback signals as input, along with, optionally, user reported
information) and display of one or more performance metrics (e.g.,
a stress index) to a subject using the device]. In certain
embodiments, the one or more controller boards is/are operable to
automatically modulate and/or select the waveform output in
response to (e.g., based on) the recorded usage data and/or
biofeedback signals (e.g., using a machine learning algorithm that
receives the one or more biofeedback signals as input, along with,
optionally, user reported information, to optimize the waveform
output).
[0120] In certain embodiments, a level [e.g., amplitude (e.g., a
force; e.g., a displacement)] of at least a portion of the
mechanical vibration is based on activation thresholds of one or
more target cells and/or proteins (e.g., mechanoreceptors (e.g., C
tactile afferents); e.g., nerves; e.g., sensory thresholds
corresponding to a level of tactile sensation) [e.g., wherein the
one or more controller boards modulate the waveform output based on
sub-activation thresholds (e.g., accounting for the response of the
mechanical transducers)].
[0121] In certain embodiments, an amplitude of the mechanical
vibration corresponds to a displacement ranging from 1 micron to 10
millimeters (e.g., approximately 25 microns)(e.g., wherein the
amplitude is adjustable over the displacement ranging from 1 micron
to 10 millimeters)[e.g., wherein the amplitude corresponds to a
force of approximately 0.4N][e.g., thereby matching the amplitude
to activation thresholds of C tactile afferents].
[0122] In certain embodiments, the isochronic wave comprises one or
more components (e.g., additive noise; e.g., stochastic resonance
signals) that, when transduced by the transducer to produce the
mechanical wave, correspond to sub-threshold signals that are below
an activation threshold of one or more target cells and/or proteins
(e.g., below a level of tactile sensation).
[0123] In certain embodiments, the isochronic wave comprises one or
more components (e.g., additive noise; e.g., stochastic resonance
signals) that, when transduced by the transducer to produce the
mechanical wave, correspond to supra-threshold signals that are
above an activation threshold of one or more target cells and/or
proteins (e.g., above a level of tactile sensation).
[0124] In another aspect, the invention is directed to a
transcutaneous neuromodulation device [e.g., a wearable device;
e.g., a non-invasive device (e.g., not comprising any components
that penetrate skin)] for promoting nerve stimulation through
mechanical vibration, comprising: one or more mechanical
transducers, a battery, and one or more controller boards, wherein
the one or more mechanical transducers, the battery and the one or
more controller boards are in communication (e.g., through one or
more connectors; e.g., wirelessly), and wherein the one or more
controller boards control waveform output through the one or more
mechanical transducers, and the one or more mechanical transducers
transcutaneously stimulate one or more nerves of a human subject
and wherein the waveform output comprises an isochronic wave.
[0125] In another aspect, the invention is directed to a
transcutaneous stimulation device [e.g., a wearable device; e.g., a
non-invasive device (e.g., not comprising any components that
penetrate skin)] for promoting mechanoreceptor stimulation through
mechanical vibration, comprising: one or more mechanical
transducers, a battery, and one or more controller boards, wherein
the one or more mechanical transducers, the battery and the one or
more controller boards are in communication (e.g., through one or
more connectors; e.g., wirelessly), and wherein the one or more
controller boards control waveform output through the transducer,
and the one or more mechanical transducers transcutaneously
stimulate one or more mechanoreceptors of a human subject and
wherein the waveform output comprises an isochronic wave.
[0126] In another aspect, the invention is directed to a method of
treating a subject by providing transcutaneous mechanical
stimulation (e.g., non-invasive mechanical stimulation) to the
subject via a stimulation device (e.g., a wearable device), the
method comprising: generating a mechanical wave by a mechanical
transducer of the stimulation device in response to an applied
electronic drive signal; controlling a waveform of the electronic
drive signal by a controller board (e.g., a controller board of the
stimulation device; e.g., a remote controller board), wherein the
waveform comprises an isochronic wave; and delivering the
mechanical wave to a body location of the subject via the
stimulation device, thereby providing the transcutaneous mechanical
stimulation to the subject.
[0127] In certain embodiments, the mechanical wave promotes
stimulation (e.g., wherein the waveform is selected to promote
stimulation) of one or more nerves [e.g., a vagus nerve; e.g., a
trigeminal nerve; e.g., peripheral nerves; e.g., a greater
auricular nerve; e.g., a lesser occipital nerve; e.g., one or more
cranial nerves (e.g., cranial nerve VII; e.g., cranial nerve IX;
e.g., cranial nerve XI; e.g., cranial nerve XII)]. In certain
embodiments, the one or more nerves comprises a vagus nerve and/or
a trigeminal nerve. In certain embodiments, the one or more nerves
comprises a C-tactile afferent.
[0128] In certain embodiments, the mechanical wave promotes
stimulation of (e.g., wherein the waveform is selected to promote
stimulation of) one or more mechanoreceptors and/or cutaneous
sensory receptors in the skin (e.g., to stimulate an afferent
sensory pathway and use properties of receptive fields to propagate
stimulation through tissue and bone). In certain embodiments, the
one or more mechanoreceptors and/or cutaneous sensory receptors
comprise Piezo2 protein and/or Merkel cells.
[0129] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform to
introduce particular signals that include active or inactive pulse
durations and frequencies configured to accommodate particular
mechanoreceptor recovery periods, adaptation times, inactivation
times, sensitization and desensitization times, or latencies.
[0130] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform to
enhance or inhibit the expression of presynaptic molecules
essential for synaptic vesicle release in neurons.
[0131] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform to
enhance or inhibit the expression of neuroactive substances that
can act as fast excitatory neurotransmitters or
neuromodulators.
[0132] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform to
stimulate mechanoreceptor cells associated with A.delta.-fibers and
C-fibers (e.g., including C tactile fibers) in order to stimulate
nociceptive, thermoceptive, interoceptive and/or other pathways
modulated by these fibers.
[0133] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform using
dynamical systems methods to produce a preferred response in neural
network dynamics (e.g., via modulation of signal timing).
[0134] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform using
dynamical systems measures to assess response signals (e.g.,
electronic) to detect particular network responses correlated with
changes in mechanical wave properties (e.g., and modulates the
waveform output to target/optimally enhance particular preferred
responses).
[0135] In certain embodiments, the delivering the mechanical wave
to the body location comprises contacting the mechanical transducer
to a surface (e.g., skin) of the subject at the body location.
[0136] In certain embodiments, the contacting the mechanical
transducer to the surface of the subject at the body location
comprises using an adhesive (e.g., a biocompatible adhesive) for
adhering at least one of the one or more mechanical transducers
(e.g., up to all) to a subject [e.g., skin (e.g., on a neck of;
e.g., overlaying at least one mastoid process of; e.g., of an outer
or posterior of at least one ear of) a human subject](e.g., wherein
the at least one mechanical transducer is embedded within the
adhesive; e.g., wherein the at least one mechanical transducer is
surrounded by the adhesive).
[0137] In certain embodiments, the contacting the mechanical
transducer to the surface of the subject at the body location
comprises using one or more ergonomic support components, wherein
the one or more transducers are supported by (e.g., housed within;
e.g., mounted on) the one or more ergonomic support component(s)
(e.g., collectively) and the one or more ergonomic support
component(s) is/are formed (e.g., molded) to maintain the
transducer in substantial proximity to one or more mastoid regions
of a human subject (e.g., by maintaining substantial contact with
skin overlaying the one or more mastoid regions).
[0138] In certain embodiments, the one or more ergonomic support
components comprise(s) a first ergonomic support component, the
first ergonomic support component comprising: (a) a first housing
comprising a casing (e.g., molded casing) of sufficient size to at
least partially house (i) a first transducer set comprising at
least a portion (e.g., half; e.g., all) of the one or more
mechanical transducers and (ii) a first controller board set
comprising at least a portion (e.g., half; e.g., all) of the one or
more controller boards, wherein the first transducer set is
disposed adjacent to a window in the first housing [e.g., an
insulated region of the first housing that contacts skin of the
human subject in substantial proximity to a first mastoid region
(e.g., on a first (e.g., left; e.g., right) side of head of the
subject); e.g., wherein the window comprises fabric, adhesive, etc.
placed in between a surface of the transducers of the first
transducer set and skin of the subject so as to prevent direct
contact with skin]; and (b) a first elastomeric arm comprising a
resilient material and formed (e.g., molded) to engage an first ear
of the subject and thereby support (e.g., fully) the first housing
(e.g., and first transducer set and first controller board set
housed therein), wherein the first housing is coupled to a distal
end of the first elastomeric arm, wherein the distal end of the
first elastomeric arm substantially aligns the window of the first
housing with a first body location on the subject in substantial
proximity to a first mastoid region (e.g., on a first side of the
subject's head; e.g., on a left side; e.g., on a right side), and
wherein the resilient material provides a force to hold the first
housing against the first body location.
[0139] In certain embodiments, the one or more ergonomic support
components further comprise(s) a second ergonomic support
component, the second ergonomic support component comprising: (a) a
second housing comprising a casing (e.g., molded casing) of
sufficient size to at least partially house (i) a second transducer
set comprising at least a portion (e.g., half; e.g., all) of the
one or more mechanical transducers and (ii) a second controller
board set comprising at least a portion (e.g., half; e.g., all) of
the one or more controller boards, wherein the second transducer
set is disposed adjacent to a window in the second housing [e.g.,
an insulated region of the second housing that contacts skin of the
human subject in substantial proximity to a second mastoid region
(e.g., on a second (e.g., left; e.g., right) side of head of the
subject); e.g., wherein the window comprises fabric, adhesive, etc.
placed in between a surface of the transducers of the second
transducer set and skin of the subject so as to prevent direct
contact with skin]; and (b) a second elastomeric arm comprising a
resilient material and formed (e.g., molded) to engage an ear of
the subject and thereby support (e.g., fully) the second housing
(e.g., and second transducer set and second controller board set
housed therein), wherein the second housing is coupled to a distal
end of the second elastomeric arm, wherein the distal end of the
second elastomeric arm substantially aligns the window of the
second housing with a second body location on the subject in
substantial proximity to a second mastoid region (e.g., on a second
side of the subject's head; e.g., on a right side; e.g., on a left
side), and wherein the resilient material provides a force to hold
the second housing against the second body location.
[0140] In certain embodiments, the first and second ergonomic
support components are in wireless communication with each other
(e.g., via near-field magnetic induction (NFMI) e.g., so as to
avoid/overcome interference from the subject's head) for
synchronizing delivery of the mechanical vibration to the first and
second mastoid regions of the subject (e.g., for synchronizing
delivery of a first mechanical vibration produced by the first
transducer set and delivery of a second mechanical vibration
produced by the second transducer set).
[0141] In certain embodiments, the one or more ergonomic support
components comprises: a linkage component formed to engage (e.g.,
wrap around a top of) a head of the subject two housings disposed
at opposite ends of the linkage component so as to be positioned on
opposite sides of the head of the subject, wherein each housing
comprising a casing (e.g., a molded casing) of sufficient size to
at least partially house a corresponding transducer set comprising
at least a portion (e.g., one; e.g., half; e.g., all) of the one or
more mechanical transducers, wherein the mechanical transducers are
disposed adjacent to a window in each housing; two elastomeric
hinges, each disposed at the opposite ends of the linkage component
and mounted to flexibly couple a housings to the linkage component;
wherein at least one of the elastomeric hinges is formed and
positioned to substantially align the window of each housing with
and against opposing mastoid regions on opposite sides of the head
of the subject.
[0142] In certain embodiments, the linkage component comprises an
adjustment mechanism comprising two partially overlaid,
interlocking, and sliding curved arms (e.g., curved elastomeric
arms), wherein said curved arms are maintained in alignment with
each other to form an arc (e.g., approximately matching an average
arc of a human head) and slide with respect to each other so as to
vary an amount of overlap, thereby varying a size of the arc (e.g.,
to match different size human heads), and wherein the two
elastomeric hinges are disposed on opposing ends of the arc formed
by the two sliding arms.
[0143] In certain embodiments, the mechanical transducer is a
member of a transducer array comprising a plurality of (e.g., two
or more) mechanical transducers maintained in a fixed spatial
arrangement in relation to each other (e.g., in substantial
proximity to each other; e.g., spaced along a straight or curved
line segment) and wherein the controller board controls output of
the mechanical transducer in relation to other mechanical
transducers of the array [e.g., so as to synchronize mechanical
vibration produced by each mechanical transducer of the transducer
array (e.g., such that each mechanical transducer begins and/or
ends producing mechanical vibration at a particular delay with
respect to one or more other mechanical transducers of the array;
e.g., such that the mechanical transducers are sequentially
triggered, one after the other; e.g., wherein the mechanical
transducers are spaced along a straight or curved line segment and
triggered sequentially along the line segment, such that an
apparent source of mechanical vibration moves along the line
segment to mimic a stroking motion)][e.g., wherein a first portion
of the mechanical transducers outputs a different frequency
mechanical vibration from a second portion of the mechanical
transducers of the transducer array (e.g., wherein each mechanical
transducer of the transducer array outputs a different frequency
mechanical vibration)].
[0144] In certain embodiments, the transducer is a linear
transducer (e.g., operable to produce mechanical vibration
comprising a longitudinal component (e.g., a longitudinal
vibration)).
[0145] In certain embodiments, the mechanical transducer is
incorporated into a headphone (e.g., an in-ear headphone; e.g., an
over-the-ear headphone).
[0146] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises receiving (e.g., by a receiver in
communication with the controller board) a signal from a personal
computing device (e.g., a smart phone; e.g., a personal computer;
e.g., a laptop computer; e.g., a tablet computer; e.g., a
smartwatch; e.g., a fitness tracker; e.g., a smart charger)(e.g.,
to upload new waveforms and/or settings for waveforms).
[0147] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating and/or selecting the
waveform in response to (e.g., based on) the signal received from
the personal computing device by the receiver.
[0148] In certain embodiments, the delivering the mechanical wave
to the body location is performed in a non-invasive fashion (e.g.,
without penetrating skin of the subject).
[0149] In certain embodiments, the method comprising providing, by
a secondary stimulation device, one or more external
stimulus/stimuli (e.g., visual stimulus; e.g., acoustic stimulus;
e.g., limbic priming; e.g., a secondary tactile signal).
[0150] In certain embodiments, the isochronic wave comprises a
frequency component ranging from 5 to 15 Hz (e.g., ranging from
approximately 7 to approximately 13 Hz; e.g., a frequency range
matching an alpha brain wave frequency range; e.g., approximately
10 Hz). In certain embodiments, the isochronic wave comprises a
frequency component ranging from 0 to 49 Hz (e.g., from 18 to 48
Hz; e.g., from 15 to 40 Hz; e.g. from 8 to 14 Hz).
[0151] In certain embodiments, one or more low-amplitude
sub-intervals of the isochronic wave have a duration of greater
than or approximately two seconds (e.g., wherein the one or more
low-amplitude sub-intervals have a duration of approximately two
seconds; e.g., wherein the one or more low-amplitude sub-intervals
have a duration ranging from approximately two seconds to
approximately 10 seconds; e.g., wherein the one or more low
amplitude sub-intervals have a duration ranging from approximately
two seconds to approximately 4 seconds).
[0152] In certain embodiments, the isochronic wave comprises a
carrier wave [e.g., a periodic wave having a substantially constant
frequency (e.g., ranging from 5 to 15 Hz; e.g., ranging from
approximately 7 to approximately 13 Hz; e.g., a frequency range
matching an alpha brain wave frequency range; e.g., approximately
10 Hz)] modulated by an envelope function having one or more
low-amplitude sub-intervals [e.g., a periodic envelope function
(e.g., a square wave; e.g., a 0.5 Hz square wave); e.g., the one or
more low-amplitude sub-intervals having a duration of greater than
or approximately equal to two seconds; e.g., the one or more
low-amplitude sub-intervals having a duration of approximately two
seconds].
[0153] In certain embodiments, the isochronic wave is also a
transformed time-varying wave. In certain embodiments, the
isochronic wave comprises a chirped wave. In certain embodiments,
the waveform of the electronic drive signal comprises a transformed
time-varying wave having a functional form corresponding to a
carrier wave within an envelope {e.g., wherein the transformed-time
varying wave is the carrier wave and is further modulated by an
envelope [e.g., wherein the envelope is a sinusoidal wave; e.g.,
wherein the envelope has a monotonically increasing (in time)
amplitude (e.g., wherein the envelope has a functional form
corresponding to an increasing (in time) exponential)]; e.g.,
wherein the transformed time-varying wave is the envelope that
modulates a carrier wave [e.g., wherein the carrier wave is a
periodic wave (e.g., a sinusoidal wave; e.g., a square wave; e.g.,
a sawtooth wave)(e.g., having a higher frequency than the
envelope)]}.
[0154] In certain embodiments, a functional form of the waveform of
the electronic drive signal is based on one or more recorded
natural sounds (e.g., running water; e.g., ocean waves; e.g.,
purring; e.g., breathing; e.g., chanting; e.g., gongs; e.g.,
bells).
[0155] In certain embodiments, the method comprises receiving an
electronic response signal from a monitoring device (e.g., directly
from and/or to the monitoring device; e.g., via one or more
intermediate server(s) and/or computing device(s))(e.g., a wearable
monitoring device; e.g., a personal computing device; e.g., a
fitness tracker; e.g., a heart-rate monitor; e.g., an
electrocardiograph (EKG) monitor; e.g., an electroencephalography
(EEG) monitor; e.g., an accelerometer; e.g., a blood-pressure
monitor; e.g., a galvanic skin response (GSR) monitor) and wherein
the controlling the waveform of the electronic drive signal
comprises adjusting and/or selecting the waveform in response to
(e.g., based on) the received electronic response signal.
[0156] In certain embodiments, the method comprises recording usage
data (e.g., parameters such as a record of when the device was
used, duration of use, etc.) and/or one or more biofeedback signals
for a human subject [e.g., using one or more sensors, each operable
to measure and record one or more biofeedback signals (e.g., a
galvanic skin response (GSR) sensor; e.g., a heart-rate monitor;
e.g., an accelerometer)][e.g., storing and/or providing the
recorded usage data and/or biofeedback signals for further
processing and/or transmission to an external computing device,
e.g., for computation (e.g., using a machine learning algorithm
that receives the one or more biofeedback signals as input, along
with, optionally, user reported information) and display of one or
more performance metrics (e.g., a stress index) to a subject].
[0157] In certain embodiments, the method comprises automatically
modulating and/or selecting the waveform of the electronic drive
signal in response to (e.g., based on) the recorded usage data
and/or biofeedback signals (e.g., using a machine learning
algorithm that receives the one or more biofeedback signals as
input, along with, optionally, user reported information, to
optimize the waveform output).
[0158] In certain embodiments, a level [e.g., amplitude (e.g., a
force; e.g., a displacement)] of at least a portion of the
mechanical wave is (e.g., modulated and/or selected) based on
activation thresholds of one or more target cells and/or proteins
(e.g., mechanoreceptors (e.g., C tactile afferents); e.g., nerves;
e.g., sensory thresholds corresponding to a level of tactile
sensation) [e.g., wherein the one or more controller boards
modulate the waveform output based on sub-activation thresholds
(e.g., accounting for the response of the mechanical
transducers)].
[0159] In certain embodiments, an amplitude of the mechanical wave
corresponds to a displacement ranging from 1 micron to 10
millimeters (e.g., approximately 25 microns)(e.g., wherein the
amplitude is adjustable over the displacement ranging from 1 micron
to 10 millimeters)[e.g., wherein the amplitude corresponds to a
force of approximately 0.4N][e.g., thereby matching the amplitude
to activation thresholds of C tactile afferents].
[0160] In another aspect, the invention is directed to a method of
treating a subject by providing transcutaneous mechanical
stimulation (e.g., non-invasive mechanical stimulation) to the
subject via a stimulation device (e.g., a wearable device), the
method comprising: generating a mechanical wave by a mechanical
transducer of the stimulation device in response to an applied
electronic drive signal; controlling a waveform of the electronic
drive signal by a controller board (e.g., a controller board of the
stimulation device; e.g., a remote controller board); and
delivering the mechanical wave to a body location of the subject
via the stimulation device, wherein the body location is in
proximity to a mastoid of the subject (e.g., wherein the mastoid
lies directly beneath the body location), thereby providing the
transcutaneous mechanical stimulation to the subject.
[0161] In another aspect, the invention is directed to a method of
treating a subject by providing transcutaneous mechanical
stimulation (e.g., non-invasive mechanical stimulation) to one or
more nerves of the subject via a stimulation device (e.g., a
wearable device), the method comprising: generating a mechanical
wave by a mechanical transducer of the stimulation device in
response to an applied electronic drive signal; controlling a
waveform of the electronic drive signal by a controller board
(e.g., of the stimulation device; e.g., a remote controller board);
and delivering the mechanical wave to a body location of the
subject via the wearable stimulation device, thereby stimulating
the one or more nerves, wherein the one or more nerves comprise(s)
a cranial nerve (e.g., vagus nerve; e.g., trigeminal nerve; e.g.,
facial nerve) of the subject.
[0162] In another aspect, the invention is directed to a method of
treating a subject by providing transcutaneous mechanical
stimulation (e.g., non-invasive mechanical stimulation) to one or
more nerves and/or mechanoreceptors of the subject via a
stimulation device (e.g., a wearable device), the method
comprising: generating a mechanical wave by a mechanical transducer
of the stimulation device in response to an applied electronic
drive signal; controlling a waveform of the electronic drive signal
by a controller board (e.g., a controller board of the wearable
stimulation device; e.g., a remote controller board), wherein the
waveform comprises a frequency component ranging from approximately
5 Hz to 15 Hz (e.g., approximately 10 Hz; e.g., ranging from
approximately 7 Hz to approximately 13 Hz; e.g., a frequency range
matching an alpha brain wave frequency); and delivering the
mechanical wave to a body location of the subject via the
stimulation device, thereby providing the transcutaneous mechanical
stimulation of the one or more nerves and/or mechanoreceptors of
the subject.
[0163] In another aspect, the invention is directed to a method of
treating a subject by providing transcutaneous mechanical
stimulation (e.g., non-invasive mechanical stimulation) to the
subject via a stimulation device (e.g., a wearable device), the
method comprising: generating a mechanical wave by a mechanical
transducer of the stimulation device in response to an applied
electronic drive signal; receiving an electronic response signal
from a monitoring device (e.g., a wearable monitoring device)
operable to monitor one or more physiological signals from the
subject and generate, in response to the one or more physiological
signals from the subject, the electronic response signal (e.g.,
wherein the electronic response signal is received directly from
the monitoring device; e.g., wherein the electronic response signal
is received from the wearable monitoring device via one or more
intermediate servers and/or processors); responsive to the
receiving the electronic response signal, controlling, via a
controller board (e.g., a controller board of the stimulation
device; e.g., a remote controller board), a waveform of the
electronic drive signal to adjust and/or select the waveform based
at least in part on the received electronic response signal; and
delivering the mechanical wave to a body location of the subject
via the stimulation device, thereby providing the transcutaneous
mechanical stimulation to the subject.
[0164] In another aspect, the invention is directed to a method of
treating a subject by providing transcutaneous mechanical
stimulation (e.g., non-invasive mechanical stimulation) to the
subject via a stimulation device (e.g., a wearable device), the
method comprising: (a) generating a mechanical wave by a mechanical
transducer of the stimulation device in response to an applied
electronic drive signal; (b) accessing and/or receiving [e.g., by a
processor of a computing device, of and/or in communication with
the stimulation device, e.g., an intermediate server and/or
processor (e.g., of a mobile computing device in communication with
the stimulation device)] subject response data (e.g., entered by
the subjects themselves or biofeedback data recorded via sensors)
and/or initialization setting data [e.g., physical characteristics
of the subject (e.g., age, height, weight, gender, body-mass index
(BMI), and the like); e.g., activity levels (e.g., physical
activity levels); e.g., biofeedback data recorded by one or more
sensors (e.g., included within the device and/or external to and in
communication with the device)(e.g., a heart rate; e.g., a galvanic
skin response; e.g., physical movement (e.g., recorded by an
accelerometer)); e.g., results of a preliminary survey (e.g.,
entered by the subject themselves, e.g., via a mobile computing
device, an app, and/or online portal; e.g., provided by a
therapist/physician treating the subject for a disorder)]; (c)
responsive to the accessed and/or received subject response data
and/or initialization setting data, controlling, via a controller
board (e.g., a controller board of the stimulation device; e.g., a
remote controller board), a waveform of the electronic drive signal
to adjust and/or select the waveform based at least in part on the
subject response data and/or initialization setting data (e.g.,
using a machine learning algorithm that receives one or more
biofeedback signals as input, along with, optionally, user reported
information, to optimize the waveform output); and (d) delivering
the mechanical wave to a body location of the subject via the
stimulation device, thereby providing the transcutaneous mechanical
stimulation to the subject.
[0165] In certain embodiments, step (b) comprises receiving and/or
accessing subject response data [e.g., results of a survey recorded
for the subject (e.g., entered by the subject themselves, e.g., via
a mobile computing device, an app, and/or online portal; e.g.,
provided by a therapist/physician treating the subject for a
disorder); e.g., biofeedback data recorded by one or more sensors
(e.g., included within the device and/or external to and in
communication with the device)(e.g., a heart rate; e.g., a galvanic
skin response; e.g., physical movement (e.g., recorded by an
accelerometer))] provided following their receipt of a round (e.g.,
a duration) of the transcutaneous mechanical stimulation provided
by the stimulation device; and step (c) comprises controlling the
waveform of the electronic drive signal based at least in part on
the subject feedback, thereby modifying the transcutaneous
mechanical stimulation provided to the subject based on subject
response data.
[0166] In another aspect, the invention is directed to a method of
treating a subject by providing transcutaneous mechanical
stimulation (e.g., non-invasive mechanical stimulation) to the
subject via a stimulation device (e.g., a wearable device), the
method comprising: generating a first mechanical wave by a first
mechanical transducer of the stimulation device in response to a
first applied electronic drive signal; controlling a first waveform
of the first electronic drive signal by a controller board (e.g., a
controller board of the stimulation device; e.g., a remote
controller board); and delivering the first mechanical wave to a
first body location (e.g., on a right side; e.g., a location behind
a right ear) of the subject via the stimulation device; generating
a second mechanical wave by a second mechanical transducer of the
stimulation device in response to a second applied electronic drive
signal; controlling a second waveform of the second electronic
drive signal by the controller board; and delivering the second
mechanical wave to a second body location (e.g., on a left side;
e.g., a location behind a left ear) of the subject via the
stimulation device, thereby providing the transcutaneous mechanical
stimulation to the subject.
[0167] In another aspect, the invention is directed to a method of
treating a subject by providing transcutaneous mechanical
stimulation (e.g., non-invasive mechanical stimulation) to the
subject via a stimulation device (e.g., a wearable device), the
method comprising: generating a first mechanical wave by a first
mechanical transducer of the stimulation device in response to an
applied electronic drive signal; controlling a waveform of the
first electronic drive signal by a controller board (e.g., a
controller board of the stimulation device; e.g., a remote
controller board); and delivering the first mechanical wave to a
first body location (e.g., on a right side; e.g., a location behind
a right ear) of the subject via the stimulation device; generating
a second mechanical wave by a second mechanical transducer of the
stimulation device in response to the applied electronic drive
signal; delivering the second mechanical wave to a second body
location (e.g., on a left side; e.g., a location behind a left ear)
of the subject via the stimulation device, thereby providing the
transcutaneous mechanical stimulation to the subject.
[0168] In another aspect, the invention is directed to a method of
stimulating one or more nerves and/or mechanoreceptors of a subject
(e.g., a human subject), the method comprising: using the device
method comprising using the device articulated in any of paragraphs
[096]-[124], for stimulation of the one or more nerves and/or
mechanoreceptors of the subject.
[0169] In another aspect, the invention is directed to a method of
stimulating one or more nerves of a human subject using a
transcutaneous, neuromodulation device [e.g., a wearable device;
e.g., a non-invasive device (e.g., not comprising any components
that penetrate skin)], the device comprising one or more
transducers (e.g., mechanical transducers), a battery, connectors,
and one or more controller boards, wherein the one or more
controller boards control waveform output through the connectors
and the one or more transducers, and wherein the transducers
transcutaneously applied stimulate the one or more nerves, the
method comprising: contacting the one or more transducers of the
device to the human subject, generating the waveform output signal,
activating the transducers using the waveform output signal (e.g.,
by applying the waveform output signal to the transducers to
generate a mechanical wave), and stimulating the one or more nerves
of the human subject, wherein the waveform output comprises an
isochronic wave.
[0170] In another aspect, the invention is directed to a method of
stimulating one or more mechanoreceptors of a human subject using
transcutaneous stimulation device [e.g., a wearable device; e.g., a
non-invasive device (e.g., not comprising any components that
penetrate skin)], the device comprising one or more mechanical
transducers, a battery, connectors, and one or more controller
boards, wherein the one or more controller boards control waveform
output through the connectors and the one or more mechanical
transducers, and wherein the one or more mechanical transducers
transcutaneously applied stimulate the one or more
mechanoreceptors, the method comprising: contacting the one or more
mechanical transducers of the device to the human subject,
generating the waveform output signal, activating the mechanical
transducers using the waveform output signal (e.g., by applying the
waveform output signal to the transducers to generate a mechanical
wave), and stimulating the one or more mechanoreceptors of the
human subject, wherein the waveform output comprises an isochronic
wave.
[0171] In another aspect, the invention is directed to a method of
improving interoception in a subject (e.g., a human subject)[e.g.,
improving and/or restoring mind-body connection (e.g., mindfulness)
in the subject; e.g., effortlessly to quiet mind of the subject;
e.g., to improve and/or restore mindfulness without meditation],
the method comprising transcutaneously delivering mechanical
stimulation to the subject using a mechanical wave having a
vibrational waveform selected to improve interoception in the
subject upon and/or following the delivering of the mechanical wave
to the subject.
[0172] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for improving interoception [e.g., improving and/or restoring
mind-body connection (e.g., mindfulness) in the subject; e.g.,
effortlessly to quiet mind of the subject; e.g., to improve and/or
restore mindfulness without meditation].
[0173] In another aspect, the invention is directed to a method of
promoting relaxation and/or reducing stress in a subject (e.g., a
human subject)[e.g., to promote calm and positive emotional states;
e.g., to promote and/or stimulate subject's body's own relaxation
response (e.g., to lead to greater calm, clarity, and/or focus in
the subject); e.g., to improve cognitive performance; e.g., to
support and maintain memory, concentration, and focus; e.g., to
provide long term drug free neurological benefits; e.g., to reduce
fatigue and/or irritability], the method comprising
transcutaneously delivering mechanical stimulation to the subject
using a mechanical wave having a vibrational waveform selected to
promote relaxation and/or reduce stress in the subject upon and/or
following the delivering of the mechanical wave to the subject.
[0174] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects or embodiments
described herein and a label indicating that the device is to be
used for promoting relaxation and/or managing stress [e.g., the
label indicating that the device to be used as a serenity device;
e.g., the label indicating that the device is to be used (e.g., as
a safe, easy, and/or effective way) to promote calm and positive
emotional states; e.g., to promote and/or stimulate subject's
body's own relaxation response (e.g., to lead to greater calm,
clarity, and/or focus in the subject); e.g., to improve cognitive
performance; e.g., to support and maintain memory, concentration,
and focus; e.g., to provide long term drug free neurological
benefits; e.g., to reduce fatigue and/or irritability].
[0175] In another aspect, the invention is directed to a method of
improving mental acuity and/or concentration in a subject (e.g., a
human subject)(e.g., improving clarity and/or focus; e.g.,
improving cognitive performance), the method comprising
transcutaneously delivering mechanical stimulation to the subject
using a mechanical wave having a vibrational waveform selected to
improve mental acuity and/or concentration in the subject upon
and/or following the delivering of the mechanical wave to the
subject.
[0176] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for improving mental acuity and/or concentration (e.g.,
improving clarity and/or focus; e.g. improving cognitive
performance).
[0177] In another aspect, the invention is directed to a method of
enhancing learning capacity and/or memory (e.g., supporting and
maintaining memory, concentration, and focus) in a subject (e.g., a
human subject), the method comprising transcutaneously delivering
mechanical stimulation to the subject using a mechanical wave
having a vibrational waveform selected to enhance learning capacity
and/or memory in the subject upon and/or following the delivering
of the mechanical wave to the subject.
[0178] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for enhancing learning capacity and/or memory e.g., supporting
and maintaining memory, concentration, and focus).
[0179] In another aspect, the invention is directed to a method of
managing (e.g., reducing negative effects of; e.g., provide relief
from) a social phobia in a subject (e.g., a human subject), the
method comprising transcutaneously delivering mechanical
stimulation to the subject using a mechanical wave having a
vibrational waveform selected to manage the social phobia in the
subject upon and/or following the delivering of the mechanical wave
to the subject.
[0180] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for managing (e.g., reducing negative effects of; e.g.,
provide relief from) a social phobia.
[0181] In another aspect, the invention is directed to a method of
reducing performance anxiety in a subject, the method comprising
transcutaneously delivering mechanical stimulation to the subject
using a mechanical wave having a vibrational waveform selected to
reduce performance anxiety in the subject upon and/or following the
delivering of the mechanical wave to the subject.
[0182] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects or embodiments
described herein and a label indicating that the device is to be
used for reducing performance anxiety.
[0183] In another aspect, the invention is directed to a method of
improving quality of life in a subject (e.g., a human subject) when
the subject has a condition (e.g., high blood pressure; e.g.,
tinnitus; e.g., anxiety)(e.g., to help living well with anxiety),
the method comprising transcutaneously delivering mechanical
stimulation to the subject using a mechanical wave having a
vibrational waveform selected to improve quality of life in the
subject having the condition upon and/or following the delivering
of the mechanical wave to the subject.
[0184] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects or embodiments
described herein and a label indicating that the device is to be
used for improving quality of life in a subject (e.g., a human
subject) when the subject has a condition (e.g., high blood
pressure; e.g., tinnitus; e.g., anxiety)(e.g., to help living well
with anxiety).
[0185] In another aspect, the invention is directed to a method of
reducing (e.g., frequency of; e.g., intensity of; e.g., risk of)
stress-induced headaches and/or stress headaches in a subject
(e.g., a human subject), the method comprising transcutaneously
delivering mechanical stimulation to the subject using a mechanical
wave having a vibrational waveform selected to reduce stress
induced headaches in the subject upon and/or following the
delivering of the mechanical wave to the subject.
[0186] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects or embodiments
described herein and a label indicating that the device is to be
used for reducing (e.g., frequency of; e.g., intensity of; e.g.,
risk of) stress induced headaches and/or stress headaches.
[0187] In another aspect, the invention is directed to a method of
reducing stress-induced infertility in a subject, the method
comprising transcutaneously delivering mechanical stimulation to
the subject using a mechanical wave having a vibrational waveform
selected to stress-induced infertility in the subject upon and/or
following the delivering of the mechanical wave to the subject.
[0188] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for reducing stress-induced infertility.
[0189] In another aspect, the invention is directed to a method of
managing stress-induced blood pressure conditions (e.g., high-blood
pressure; e.g., hypertension; e.g., hypotension) in a subject, the
method comprising transcutaneously delivering mechanical
stimulation to the subject using a mechanical wave having a
vibrational waveform selected to manage stress-induced high blood
pressure in the subject upon and/or following the delivering of the
mechanical wave to the subject.
[0190] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects or embodiments
described herein and a label indicating that the device is to be
used for managing stress-induced blood pressure conditions (e.g.,
high-blood pressure; e.g., hypertension; e.g., hypotension).
[0191] In another aspect, the invention is directed to a method of
reducing (e.g., frequency of; e.g., intensity of; e.g., risk of)
stress-induced diseases in a subject (e.g., a human subject), the
method comprising transcutaneously delivering mechanical
stimulation to the subject using a mechanical wave having a
vibrational waveform selected to reduce stress induced headaches in
the subject upon and/or following the delivering of the mechanical
wave to the subject.
[0192] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for reducing (e.g., frequency of; e.g., intensity of; e.g.,
risk of) stress induced diseases.
[0193] In another aspect, the invention is directed to a method of
improving peripheral nerve sensitivity in a subject, the method
comprising transcutaneously delivering mechanical stimulation to
the subject using a mechanical wave having a vibrational waveform
selected to improve peripheral nerve sensitivity in the subject
upon and/or following the delivering of the mechanical wave to the
subject.
[0194] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for improving peripheral nerve sensitivity.
[0195] In another aspect, the invention is directed to a method of
supporting immune system function in a subject, the method
comprising transcutaneously delivering mechanical stimulation to
the subject using a mechanical wave having a vibrational waveform
selected to support immune system function in the subject upon
and/or following the delivering of the mechanical wave to the
subject.
[0196] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for supporting immune system function.
[0197] In another aspect, the invention is directed to a method of
managing stress-induced anger and/or mood problems (e.g., reduce
fatigue and/or irritability) in a subject, the method comprising
transcutaneously delivering mechanical stimulation to the subject
using a mechanical wave having a vibrational waveform selected to
manage stress induced anger and/or mood problems in the subject
upon and/or following the delivering of the mechanical wave to the
subject.
[0198] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for managing stress induced anger and mood problems (e.g., to
reduce fatigue and/or irritability).
[0199] In another aspect, the invention is directed to a method of
managing stress-induced sleep problems in a subject, the method
comprising transcutaneously delivering mechanical stimulation to
the subject using a mechanical wave having a vibrational waveform
selected to manage stress-induced sleep problems in the subject
(e.g., to improve sleep quality; e.g., to provide for drug-free
promotion of longer and more restful sleep) upon and/or following
the delivering of the mechanical wave to the subject.
[0200] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects or embodiments
described herein and a label indicating that the device is to be
used for managing stress-induced sleep problems (e.g., improve
sleep quality; e.g., to provide for drug-free promotion of longer
and more restful sleep).
[0201] In another aspect, the invention is directed to a method of
reducing stress-induced menstrual cramping in a subject, the method
comprising transcutaneously delivering mechanical stimulation to
the subject using a mechanical wave having a vibrational waveform
selected to reduce stress-induced menstrual cramping in the subject
upon and/or following the delivering of the mechanical wave to the
subject.
[0202] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for reducing stress-induced menstrual cramping.
[0203] In another aspect, the invention is directed to a method of
improving appetite and/or salivation in a subject, the method
comprising transcutaneously delivering mechanical stimulation to
the subject using a mechanical wave having a vibrational waveform
selected to improve appetite and/or salivation in the subject upon
and/or following the delivering of the mechanical wave to the
subject.
[0204] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for improving appetite and/or salivation.
[0205] In another aspect, the invention is directed to a method of
improving balance in a subject, the method comprising
transcutaneously delivering mechanical stimulation to the subject
using a mechanical wave having a vibrational waveform selected to
improve balance in the subject upon and/or following the delivering
of the mechanical wave to the subject.
[0206] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for improving balance.
[0207] In another aspect, the invention is directed to a method of
improving immune function in a subject, the method comprising
transcutaneously delivering mechanical stimulation to the subject
using a mechanical wave having a vibrational waveform selected to
improving immune function in the subject upon and/or following the
delivering of the mechanical wave to the subject.
[0208] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for improving immune function.
[0209] In another aspect, the invention is directed to a method of
increasing (e.g., an amplitude of) alpha brain waves in a subject,
the method comprising transcutaneously delivering mechanical
stimulation to the subject using a mechanical wave having a
vibrational waveform selected to increase alpha brain waves in the
subject upon and/or following the delivering of the mechanical wave
to the subject.
[0210] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for improving alpha brain waves.
[0211] In another aspect, the invention is directed to a method of
enhancing (e.g., increasing) heart rate variability in a subject
(e.g., a human subject), the method comprising transcutaneously
delivering mechanical stimulation to the subject using a mechanical
wave having a vibrational waveform selected to enhance (e.g.,
increase) heart rate variability in the subject upon and/or
following the delivering of the mechanical wave to the subject.
[0212] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for enhancing (e.g., increasing) heart rate variability.
[0213] In another aspect, the invention is directed to a method of
improving vagal tone in a subject, the method comprising
transcutaneously delivering mechanical stimulation to the subject
using a mechanical wave having a vibrational waveform selected to
improve vagal tone in the subject upon and/or following the
delivering of the mechanical wave to the subject.
[0214] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for improving vagal tone.
[0215] In another aspect, the invention is directed to a method of
promoting sleep management in a subject, the method comprising
transcutaneously delivering mechanical stimulation to the subject
using a mechanical wave having a vibrational waveform selected to
promote sleep management (e.g., to provide drug-free promotion of
longer and more restful sleep) in the subject upon and/or following
the delivering of the mechanical wave to the subject.
[0216] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects or embodiments
described herein and a label indicating that the device is to be
used for promoting sleep management (e.g., to provide drug-free
promotion of longer and more restful sleep).
[0217] In one aspect, the invention is directed to a method of
reducing stress induced ringing in ears of a subject, the method
comprising transcutaneously delivering mechanical stimulation to
the subject using a mechanical wave having a vibrational waveform
selected to reduce stress induced ringing in the ears of the
subject upon and/or following the delivering of the mechanical wave
to the subject.
[0218] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for reducing stress induced ringing in ears.
[0219] In another aspect, the invention is directed to a method of
enhancing sexual function in a subject, the method comprising
transcutaneously delivering mechanical stimulation to the subject
using a mechanical wave having a vibrational waveform selected to
enhance sexual function in the subject upon and/or following the
delivering of the mechanical wave to the subject.
[0220] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for enhancing sexual function.
[0221] In another aspect, the invention is directed to a method of
enhancing libido, sexual arousal, and/or orgasm in a subject, the
method comprising transcutaneously delivering mechanical
stimulation to the subject using a mechanical wave having a
vibrational waveform selected to enhance libido, sexual arousal,
and/or orgasm in the subject upon and/or following the delivering
of the mechanical wave to the subject.
[0222] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for enhancing libido, sexual arousal, and/or orgasm.
[0223] In another aspect, the invention is directed to a method of
reducing blushing in a subject, the method comprising
transcutaneously delivering mechanical stimulation to the subject
using a mechanical wave having a vibrational waveform selected to
reduce blushing in the subject upon and/or following the delivering
of the mechanical wave to the subject.
[0224] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for reducing blushing.
[0225] In another aspect, the invention is directed to a method of
adjusting (e.g., controlling) a level of a stress hormone [e.g.,
cortisol (e.g., reducing a cortisol level); e.g., oxytocin (e.g.,
increasing an oxytocin level); e.g., serotonin (e.g., increasing a
serotonin level] in a subject, the method comprising
transcutaneously delivering mechanical stimulation to the subject
using a mechanical wave having a vibrational waveform selected to
reduce the level of the stress hormone in the subject upon and/or
following the delivering of the mechanical wave to the subject.
[0226] In another aspect, the invention is directed to a kit
comprising the device of any one of the aspects and embodiments
described herein and a label indicating that the device is to be
used for reducing stress in a user as measured by a level of a
stress hormone [e.g., cortisol (e.g., reducing a cortisol level);
e.g., oxytocin (e.g., increasing an oxytocin level); e.g.,
serotonin (e.g., increasing a serotonin level)] for the
subject.
[0227] In another aspect, the invention is directed to a method of
a subject by providing transcutaneous mechanical stimulation (e.g.,
non-invasive mechanical stimulation) to one or more nerves and/or
mechanoreceptors of the subject via a stimulation device (e.g., a
wearable device), in combination with one or more rounds of a
therapy [e.g., psychotherapy; e.g., exposure therapy (e.g., for
treatment of various phobias such as fear of heights, fear of
public speaking, social phobia, panic attack, fear of flying, germ
phobia, and the like); e.g., cognitive behavioral therapy (CBT);
e.g., acceptance and commitment therapy (ACT)] the method
comprising: generating a mechanical wave by a mechanical transducer
of the stimulation device in response to an applied electronic
drive signal; controlling a waveform of the electronic drive signal
by a controller board (e.g., a controller board of the wearable
stimulation device; e.g., a remote controller board); and
delivering the mechanical wave to a body location of the subject
via the stimulation device at one or more times each in proximity
to and/or during a round of the therapy received by the subject
[e.g., prior to the round of therapy (e.g., such that the subject
is in a more relaxed state prior to the round of the therapy; e.g.,
such that the subject is in a more responsive state prior to the
round of the therapy; e.g., such that the subject is more open to
an exposure; e.g., such that the subject is in a state of improved
receptiveness and/or readiness to change); e.g., during the round
of the therapy; e.g., following (e.g., immediately following) the
round of the therapy; e.g., in between two or more rounds of
therapy], thereby providing the transcutaneous mechanical
stimulation of the one or more nerves and/or mechanoreceptors of
the subject in combination with one or more rounds of the
therapy.
[0228] In another aspect, the invention is directed to a
transcutaneous neuromodulation device [e.g., a wearable device;
e.g., a non-invasive device (e.g., not comprising any components
that penetrate skin)] for promoting nerve stimulation through
mechanical vibration, comprising: one or more mechanical
transducers, a battery, and one or more controller boards, wherein
the one or more mechanical transducers, the battery and the one or
more controller boards are in communication (e.g., through one or
more connectors; e.g., wirelessly), and wherein the controller
board controls waveform output through the one or more mechanical
transducers, thereby producing mechanical vibration, and wherein
the waveform output comprises an transformed time-varying wave.
[0229] In certain embodiments, the device promotes stimulation
(e.g., wherein the waveform is selected to promote stimulation) of
one or more nerves [e.g., a vagus nerve; e.g., a trigeminal nerve;
e.g., peripheral nerves; e.g., a greater auricular nerve; e.g., a
lesser occipital nerve; e.g., one or more cranial nerves (e.g.,
cranial nerve VII; e.g., cranial nerve IX; e.g., cranial nerve XI;
e.g., cranial nerve XII)]. In certain embodiments, the one or more
nerves comprises a vagus nerve and/or a trigeminal nerve. In
certain embodiments, the one or more nerves comprises a C-tactile
afferent.
[0230] In certain embodiments, the device promotes stimulation of
(e.g., wherein the waveform is selected to promote stimulation of)
one or more mechanoreceptors and/or cutaneous sensory receptors in
the skin (e.g., to stimulate an afferent sensory pathway and use
properties of receptive fields to propagate stimulation through
tissue and bone). In certain embodiments, the one or more
mechanoreceptors and/or cutaneous sensory receptors comprise Piezo2
protein and/or Merkel cells.
[0231] In certain embodiments, the one or more controller boards
modulate the waveform output to introduce particular signal that
include active or inactive pulse durations and frequencies
configured to accommodate particular mechanoreceptor recovery
periods, adaptation times, inactivation times, sensitization and
desensitization times, or latencies.
[0232] In certain embodiments, the one or more controller boards
modulate the waveform output to enhance or inhibit the expression
of presynaptic molecules essential for synaptic vesicle release in
neurons.
[0233] In certain embodiments, the one or more controller boards
modulate the waveform output to enhance or inhibit the expression
of neuroactive substances that can act as fast excitatory
neurotransmitters or neuromodulators.
[0234] In certain embodiments, the one or more controller boards
modulates the waveform output to stimulate mechanoreceptor cells
associated with A.delta.-fibers and C-fibers (e.g., including C
tactile fibers) in order to stimulate nociceptive, thermoceptive,
interoceptive and/or other pathways modulated by these fibers.
[0235] In certain embodiments, the one or more controller boards
modulate the waveform output using dynamical systems methods to
produce a preferred response in neural network dynamics (e.g., via
modulation of signal timing).
[0236] In certain embodiments, the one or more controller boards
modulates the waveform output using dynamical systems measures to
assess response signals (e.g., electronic) to detect particular
network responses correlated with changes in mechanical wave
properties (e.g., and modulates the waveform output to
target/optimally enhance particular preferred responses).
[0237] In certain embodiments, the device comprises an adhesive
(e.g., a biocompatible adhesive) for adhering at least one of the
one or more mechanical transducers (e.g., up to all) to a subject
[e.g., skin (e.g., on a neck of; e.g., overlaying at least one
mastoid process of; e.g., of an outer or posterior of at least one
ear of) a human subject](e.g., wherein the at least one mechanical
transducer is embedded within the adhesive; e.g., wherein the at
least one mechanical transducer is surrounded by the adhesive).
[0238] In certain embodiments, the device comprising one or more
ergonomic support components, wherein the one or more transducers
are supported by (e.g., housed within; e.g., mounted on) the one or
more ergonomic support component(s) (e.g., collectively) and the
one or more ergonomic support component(s) is/are formed (e.g.,
molded) to maintain the transducer in substantial proximity to one
or more mastoid regions of a human subject (e.g., by maintaining
substantial contact with skin overlaying the one or more mastoid
regions).
[0239] In certain embodiments, the device comprises a first
ergonomic support component, the first ergonomic support component
comprising: (a) a first housing comprising a casing (e.g., molded
casing) of sufficient size to at least partially house (i) a first
transducer set comprising at least a portion (e.g., half; e.g.,
all) of the one or more mechanical transducers and (ii) a first
controller board set comprising at least a portion (e.g., half;
e.g., all) of the one or more controller boards, wherein the first
transducer set is disposed adjacent to a window in the first
housing [e.g., an insulated region of the first housing that
contacts skin of the human subject in substantial proximity to a
first mastoid region (e.g., on a first (e.g., left; e.g., right)
side of head of the subject); e.g., wherein the window comprises
fabric, adhesive, etc. placed in between a surface of the
transducers of the first transducer set and skin of the subject so
as to prevent direct contact with skin]; and (b) a first
elastomeric arm comprising a resilient material and formed (e.g.,
molded) to engage an first ear of the subject and thereby support
(e.g., fully) the first housing (e.g., and first transducer set and
first controller board set housed therein), wherein the first
housing is coupled to a distal end of the first elastomeric arm,
wherein the distal end of the first elastomeric arm substantially
aligns the window of the first housing with a first body location
on the subject in substantial proximity to a first mastoid region
(e.g., on a first side of the subject's head; e.g., on a left side;
e.g., on a right side), and wherein the resilient material provides
a force to hold the first housing against the first body
location.
[0240] In certain embodiments, the device further comprises a
second ergonomic support component, the second ergonomic support
component comprising: (a) a second housing comprising a casing
(e.g., molded casing) of sufficient size to at least partially
house (i) a second transducer set comprising at least a portion
(e.g., half; e.g., all) of the one or more mechanical transducers
and (ii) a second controller board set comprising at least a
portion (e.g., half; e.g., all) of the one or more controller
boards, wherein the second transducer set is disposed adjacent to a
window in the second housing [e.g., an insulated region of the
second housing that contacts skin of the human subject in
substantial proximity to a second mastoid region (e.g., on a second
(e.g., left; e.g., right) side of head of the subject); e.g.,
wherein the window comprises fabric, adhesive, etc. placed in
between a surface of the transducers of the second transducer set
and skin of the subject so as to prevent direct contact with skin];
and (b) a second elastomeric arm comprising a resilient material
and formed (e.g., molded) to engage an ear of the subject and
thereby support (e.g., fully) the second housing (e.g., and second
transducer set and second controller board set housed therein),
wherein the second housing is coupled to a distal end of the second
elastomeric arm, wherein the distal end of the second elastomeric
arm substantially aligns the window of the second housing with a
second body location on the subject in substantial proximity to a
second mastoid region (e.g., on a second side of the subject's
head; e.g., on a right side; e.g., on a left side), and wherein the
resilient material provides a force to hold the second housing
against the second body location.
[0241] In certain embodiments, the first and second ergonomic
support components are in wireless communication with each other
(e.g., via near-field magnetic induction (NFMI) e.g., so as to
avoid/overcome interference from the subject's head) for
synchronizing delivery of the mechanical vibration to the first and
second mastoid regions of the subject (e.g., for synchronizing
delivery of a first mechanical vibration produced by the first
transducer set and delivery of a second mechanical vibration
produced by the second transducer set).
[0242] In certain embodiments, the one or more ergonomic support
components comprises: a linkage component formed to engage (e.g.,
wrap around a top of) a head of the subject; two housings disposed
at opposite ends of the linkage component so as to be positioned on
opposite sides of the head of the subject, wherein each housing
comprising a casing (e.g., a molded casing) of sufficient size to
at least partially house a corresponding transducer set comprising
at least a portion (e.g., one; e.g., half; e.g., all) of the one or
more mechanical transducers, wherein the mechanical transducers are
disposed adjacent to a window in each housing; two elastomeric
hinges, each disposed at the opposite ends of the linkage component
and mounted to flexibly couple a housings to the linkage component;
wherein at least one of the elastomeric hinges is formed and
positioned to substantially align the window of each housing with
and against opposing mastoid regions on opposite sides of the head
of the subject.
[0243] In certain embodiments, the linkage component comprises an
adjustment mechanism comprising two partially overlaid,
interlocking, and sliding curved arms (e.g., curved elastomeric
arms), wherein said curved arms are maintained in alignment with
each other to form an arc (e.g., approximately matching an average
arc of a human head) and slide with respect to each other so as to
vary an amount of overlap, thereby varying a size of the arc (e.g.,
to match different size human heads), and wherein the two
elastomeric hinges are disposed on opposing ends of the arc formed
by the two sliding arms.
[0244] In certain embodiments, the device comprises at least one
transducer array comprising a plurality of (e.g., two or more)
mechanical transducers maintained in a fixed spatial arrangement in
relation to each other (e.g., in substantial proximity to each
other; e.g., spaced along a straight or curved line segment) and
wherein at least a portion of the one or more controller boards
(e.g., a single controller board; e.g., two or more controller
boards) are in communication with the mechanical transducers of the
transducer array to control output of the mechanical transducers of
the transducer array in relation to each other [e.g., wherein the
at least a portion of the one or more controller boards
synchronizes mechanical vibration produced by each mechanical
transducer of the transducer array (e.g., such that each mechanical
transducer begins and/or ends producing mechanical vibration at a
particular delay with respect to one or more other mechanical
transducers of the array; e.g., such that the mechanical
transducers are sequentially triggered, one after the other; e.g.,
wherein the mechanical transducers are spaced along a straight or
curved line segment and triggered sequentially along the line
segment, such that an apparent source of mechanical vibration moves
along the line segment to mimic a stroking motion)] [e.g., wherein
a first portion of the mechanical transducers outputs a different
frequency mechanical vibration from a second portion of the
mechanical transducers of the transducer array (e.g., wherein each
mechanical transducer of the transducer array outputs a different
frequency mechanical vibration)].
[0245] In certain embodiments, the transducer is a linear
transducer (e.g., operable to produce mechanical vibration
comprising a longitudinal component (e.g., a longitudinal
vibration)).
[0246] In certain embodiments, the device is incorporated into a
headphone (e.g., an in-ear headphone; e.g., an over-the-ear
headphone).
[0247] In certain embodiments, the device comprising a receiver in
communication with the one or more controller boards, wherein the
receiver is operable to receive a signal from and/or transmit a
signal (e.g., wirelessly; e.g., via a wired connection) to a
personal computing device (e.g., a smart phone; e.g., a personal
computer; e.g., a laptop computer; e.g., a tablet computer; e.g., a
smartwatch; e.g., a fitness tracker; e.g., a smart charger)(e.g.,
to upload new waveforms and/or settings for waveforms).
[0248] In certain embodiments, the one or more controller boards
is/are operable to modulate and/or select the waveform output in
response to (e.g., based on) the signal received from the personal
computing device by the receiver.
[0249] In certain embodiments, the device is non-invasive (e.g.,
does not comprise any components for penetrating skin).
[0250] In certain embodiments, the device comprises a secondary
stimulation device for providing one or more external
stimulus/stimuli (e.g., visual stimulus; e.g., acoustic stimulus;
e.g., limbic priming; e.g., a secondary tactile signal).
[0251] In certain embodiments, the transformed time-varying wave
comprises a frequency component ranging from 5 to 15 Hz (e.g.,
ranging from approximately 7 to approximately 13 Hz; e.g., a
frequency range matching an alpha brain wave frequency range; e.g.,
approximately 10 Hz).
[0252] In certain embodiments, the transformed time-varying wave
comprises a frequency component ranging from 0 to 49 Hz (e.g., from
18 to 48 Hz; e.g., from 15 to 40 Hz; e.g. from 8 to 14 Hz).
[0253] In certain embodiments, the transformed time-varying wave
comprises a carrier wave [e.g., a periodic wave having a
substantially constant frequency (e.g., ranging from 5 to 15 Hz;
e.g., ranging from approximately 7 to approximately 13 Hz; e.g., a
frequency range matching an alpha brain wave frequency range; e.g.,
approximately 10 Hz)] modulated by an envelope function having one
or more low-amplitude sub-intervals [e.g., a periodic envelope
function (e.g., a square wave; e.g., a 0.5 Hz square wave); e.g.,
the one or more low-amplitude sub-intervals having a duration of
greater than or approximately equal to two seconds; e.g., the one
or more low-amplitude sub-intervals having a duration of
approximately two seconds].
[0254] In certain embodiments, the transformed time varying wave
comprises an isochronic wave. In certain embodiments, the
transformed time-varying wave comprises a chirped wave. In certain
embodiments, a functional form of the waveform output is based on
one or more recorded natural sounds (e.g., running water; e.g.,
ocean waves; e.g., purring; e.g., breathing; e.g., chanting; e.g.,
gongs; e.g., bells).
[0255] In certain embodiments, the device comprises a receiver in
communication with the one or more controller boards, wherein the
receiver is operable to receive a signal from and/or transmit a
signal to a monitoring device (e.g., directly from and/or to the
monitoring device; e.g., via one or more intermediate server(s)
and/or computing device(s))(e.g., a wearable monitoring device;
e.g., a personal computing device; e.g., a fitness tracker; e.g., a
heart-rate monitor; e.g., an electrocardiograph (EKG) monitor;
e.g., an electroencephalography (EEG) monitor; e.g., an
accelerometer; e.g., a blood-pressure monitor; e.g., a galvanic
skin response (GSR) monitor) and wherein the one or more controller
boards is/are operable to modulate and/or select the waveform
output in response to (e.g., based on) the signal from the wearable
monitoring device received by the receiver.
[0256] In certain embodiments, the device is operable to record
usage data (e.g., parameters such as a record of when the device
was used, duration of use, etc.) and/or one or more biofeedback
signals for a human subject [e.g., wherein the device comprises one
or more sensors, each operable to measure and record one or more
biofeedback signals (e.g., a galvanic skin response (GSR) sensor;
e.g., a heart-rate monitor; e.g., an accelerometer)][e.g., wherein
the device is operable to store the recorded usage data and/or
biofeedback signals for further processing and/or transmission to
an external computing device, e.g., for computation (e.g., using a
machine learning algorithm that receives the one or more
biofeedback signals as input, along with, optionally, user reported
information) and display of one or more performance metrics (e.g.,
a stress index) to a subject using the device].
[0257] In certain embodiments, the one or more controller boards
is/are operable to automatically modulate and/or select the
waveform output in response to (e.g., based on) the recorded usage
data and/or biofeedback signals (e.g., using a machine learning
algorithm that receives the one or more biofeedback signals as
input, along with, optionally, user reported information, to
optimize the waveform output).
[0258] In certain embodiments, a level [e.g., amplitude (e.g., a
force; e.g., a displacement)] of at least a portion of the
mechanical vibration is based on activation thresholds of one or
more target cells and/or proteins (e.g., mechanoreceptors (e.g., C
tactile afferents); e.g., nerves; e.g., sensory thresholds
corresponding to a level of tactile sensation) [e.g., wherein the
one or more controller boards modulate the waveform output based on
sub-activation thresholds (e.g., accounting for the response of the
mechanical transducers)].
[0259] In certain embodiments, an amplitude of the mechanical
vibration corresponds to a displacement ranging from 1 micron to 10
millimeters (e.g., approximately 25 microns)(e.g., wherein the
amplitude is adjustable over the displacement ranging from 1 micron
to 10 millimeters)[e.g., wherein the amplitude corresponds to a
force of approximately 0.4N][e.g., thereby matching the amplitude
to activation thresholds of C tactile afferents].
[0260] In certain embodiments, the transformed time-varying wave
comprises one or more components (e.g., additive noise; e.g.,
stochastic resonance signals) that, when transduced by the
transducer to produce the mechanical wave, correspond to
sub-threshold signals that are below an activation threshold of one
or more target cells and/or proteins (e.g., below a level of
tactile sensation).
[0261] In certain embodiments, the transformed time-varying wave
comprises one or more components (e.g., additive noise; e.g.,
stochastic resonance signals) that, when transduced by the
transducer to produce the mechanical wave, correspond to
supra-threshold signals that are above an activation threshold of
one or more target cells and/or proteins (e.g., above a level of
tactile sensation).
[0262] In another aspect, the invention is directed to a
transcutaneous neuromodulation device [e.g., a wearable device;
e.g., a non-invasive device (e.g., not comprising any components
that penetrate skin)] for promoting nerve stimulation through
mechanical vibration, comprising: one or more mechanical
transducers, a battery, and one or more controller boards, wherein
the one or more mechanical transducers, the battery and the one or
more controller boards are in communication (e.g., through one or
more connectors; e.g., wirelessly), and wherein the one or more
controller boards control waveform output through the one or more
mechanical transducers, and the one or more mechanical transducers
transcutaneously stimulate one or more nerves of a human subject
and wherein the waveform output comprises an transformed
time-varying wave.
[0263] In another aspect, the invention is directed to a
transcutaneous stimulation device [e.g., a wearable device; e.g., a
non-invasive device (e.g., not comprising any components that
penetrate skin)] for promoting mechanoreceptor stimulation through
mechanical vibration, comprising: one or more mechanical
transducers, a battery, and one or more controller boards, wherein
the one or more mechanical transducers, the battery and the one or
more controller boards are in communication (e.g., through one or
more connectors; e.g., wirelessly), and wherein the one or more
controller boards control waveform output through the transducer,
and the one or more mechanical transducers transcutaneously
stimulate one or more mechanoreceptors of a human subject and
wherein the waveform output comprises an transformed time-varying
wave.
[0264] In another aspect, the invention is directed to a method of
treating a subject by providing transcutaneous mechanical
stimulation (e.g., non-invasive mechanical stimulation) to the
subject via a stimulation device (e.g., a wearable device), the
method comprising: generating a mechanical wave by a mechanical
transducer of the stimulation device in response to an applied
electronic drive signal; controlling a waveform of the electronic
drive signal by a controller board (e.g., a controller board of the
stimulation device; e.g., a remote controller board), wherein the
waveform comprises an transformed time-varying wave; and delivering
the mechanical wave to a body location of the subject via the
stimulation device, thereby providing the transcutaneous mechanical
stimulation to the subject.
[0265] In certain embodiments, the mechanical wave promotes
stimulation (e.g., wherein the waveform is selected to promote
stimulation) of one or more nerves [e.g., a vagus nerve; e.g., a
trigeminal nerve; e.g., peripheral nerves; e.g., a greater
auricular nerve; e.g., a lesser occipital nerve; e.g., one or more
cranial nerves (e.g., cranial nerve VII; e.g., cranial nerve IX;
e.g., cranial nerve XI; e.g., cranial nerve XII)]. In certain
embodiments, the one or more nerves comprises a vagus nerve and/or
a trigeminal nerve. In certain embodiments, the one or more nerves
comprises a C-tactile afferent.
[0266] In certain embodiments, the mechanical wave promotes
stimulation of (e.g., wherein the waveform is selected to promote
stimulation of) one or more mechanoreceptors and/or cutaneous
sensory receptors in the skin (e.g., to stimulate an afferent
sensory pathway and use properties of receptive fields to propagate
stimulation through tissue and bone). In certain embodiments, the
one or more mechanoreceptors and/or cutaneous sensory receptors
comprise Piezo2 protein and/or Merkel cells. In certain
embodiments, the controlling the waveform of the electronic drive
signal comprises modulating the waveform to introduce particular
signals that include active or inactive pulse durations and
frequencies configured to accommodate particular mechanoreceptor
recovery periods, adaptation times, inactivation times,
sensitization and desensitization times, or latencies.
[0267] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform to
enhance or inhibit the expression of presynaptic molecules
essential for synaptic vesicle release in neurons.
[0268] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform to
enhance or inhibit the expression of neuroactive substances that
can act as fast excitatory neurotransmitters or
neuromodulators.
[0269] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform to
stimulate mechanoreceptor cells associated with A.delta.-fibers and
C-fibers (e.g., including C tactile fibers) in order to stimulate
nociceptive, thermoceptive, interoceptive and/or other pathways
modulated by these fibers.
[0270] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform using
dynamical systems methods to produce a preferred response in neural
network dynamics (e.g., via modulation of signal timing).
[0271] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating the waveform using
dynamical systems measures to assess response signals (e.g.,
electronic) to detect particular network responses correlated with
changes in mechanical wave properties (e.g., and modulates the
waveform output to target/optimally enhance particular preferred
responses).
[0272] In certain embodiments, the delivering the mechanical wave
to the body location comprises contacting the mechanical transducer
to a surface (e.g., skin) of the subject at the body location.
[0273] In certain embodiments, the contacting the mechanical
transducer to the surface of the subject at the body location
comprises using an adhesive (e.g., a biocompatible adhesive) for
adhering at least one of the one or more mechanical transducers
(e.g., up to all) to a subject [e.g., skin (e.g., on a neck of;
e.g., overlaying at least one mastoid process of; e.g., of an outer
or posterior of at least one ear of) a human subject](e.g., wherein
the at least one mechanical transducer is embedded within the
adhesive; e.g., wherein the at least one mechanical transducer is
surrounded by the adhesive).
[0274] In certain embodiments, the contacting the mechanical
transducer to the surface of the subject at the body location
comprises using one or more ergonomic support components, wherein
the one or more transducers are supported by (e.g., housed within;
e.g., mounted on) the one or more ergonomic support component(s)
(e.g., collectively) and the one or more ergonomic support
component(s) is/are formed (e.g., molded) to maintain the
transducer in substantial proximity to one or more mastoid regions
of a human subject (e.g., by maintaining substantial contact with
skin overlaying the one or more mastoid regions).
[0275] In certain embodiments, the one or more ergonomic support
components comprise(s) a first ergonomic support component, the
first ergonomic support component comprising: (a) a first housing
comprising a casing (e.g., molded casing) of sufficient size to at
least partially house (i) a first transducer set comprising at
least a portion (e.g., half; e.g., all) of the one or more
mechanical transducers and (ii) a first controller board set
comprising at least a portion (e.g., half; e.g., all) of the one or
more controller boards, wherein the first transducer set is
disposed adjacent to a window in the first housing [e.g., an
insulated region of the first housing that contacts skin of the
human subject in substantial proximity to a first mastoid region
(e.g., on a first (e.g., left; e.g., right) side of head of the
subject); e.g., wherein the window comprises fabric, adhesive, etc.
placed in between a surface of the transducers of the first
transducer set and skin of the subject so as to prevent direct
contact with skin]; and (b) a first elastomeric arm comprising a
resilient material and formed (e.g., molded) to engage an first ear
of the subject and thereby support (e.g., fully) the first housing
(e.g., and first transducer set and first controller board set
housed therein), wherein the first housing is coupled to a distal
end of the first elastomeric arm, wherein the distal end of the
first elastomeric arm substantially aligns the window of the first
housing with a first body location on the subject in substantial
proximity to a first mastoid region (e.g., on a first side of the
subject's head; e.g., on a left side; e.g., on a right side), and
wherein the resilient material provides a force to hold the first
housing against the first body location.
[0276] In certain embodiments, the one or more ergonomic support
components further comprise(s) a second ergonomic support
component, the second ergonomic support component comprising: (a) a
second housing comprising a casing (e.g., molded casing) of
sufficient size to at least partially house (i) a second transducer
set comprising at least a portion (e.g., half; e.g., all) of the
one or more mechanical transducers and (ii) a second controller
board set comprising at least a portion (e.g., half; e.g., all) of
the one or more controller boards, wherein the second transducer
set is disposed adjacent to a window in the second housing [e.g.,
an insulated region of the second housing that contacts skin of the
human subject in substantial proximity to a second mastoid region
(e.g., on a second (e.g., left; e.g., right) side of head of the
subject); e.g., wherein the window comprises fabric, adhesive, etc.
placed in between a surface of the transducers of the second
transducer set and skin of the subject so as to prevent direct
contact with skin]; and (b) a second elastomeric arm comprising a
resilient material and formed (e.g., molded) to engage an ear of
the subject and thereby support (e.g., fully) the second housing
(e.g., and second transducer set and second controller board set
housed therein), wherein the second housing is coupled to a distal
end of the second elastomeric arm, wherein the distal end of the
second elastomeric arm substantially aligns the window of the
second housing with a second body location on the subject in
substantial proximity to a second mastoid region (e.g., on a second
side of the subject's head; e.g., on a right side; e.g., on a left
side), and wherein the resilient material provides a force to hold
the second housing against the second body location.
[0277] In certain embodiments, the first and second ergonomic
support components are in wireless communication with each other
(e.g., via near-field magnetic induction (NFMI) e.g., so as to
avoid/overcome interference from the subject's head) for
synchronizing delivery of the mechanical vibration to the first and
second mastoid regions of the subject (e.g., for synchronizing
delivery of a first mechanical vibration produced by the first
transducer set and delivery of a second mechanical vibration
produced by the second transducer set).
[0278] In certain embodiments, the one or more ergonomic support
components comprises: a linkage component formed to engage (e.g.,
wrap around a top of) a head of the subject two housings disposed
at opposite ends of the linkage component so as to be positioned on
opposite sides of the head of the subject, wherein each housing
comprising a casing (e.g., a molded casing) of sufficient size to
at least partially house a corresponding transducer set comprising
at least a portion (e.g., one; e.g., half; e.g., all) of the one or
more mechanical transducers, wherein the mechanical transducers are
disposed adjacent to a window in each housing; two elastomeric
hinges, each disposed at the opposite ends of the linkage component
and mounted to flexibly couple a housings to the linkage component;
wherein at least one of the elastomeric hinges is formed and
positioned to substantially align the window of each housing with
and against opposing mastoid regions on opposite sides of the head
of the subject.
[0279] In certain embodiments, the linkage component comprises an
adjustment mechanism comprising two partially overlaid,
interlocking, and sliding curved arms (e.g., curved elastomeric
arms), wherein said curved arms are maintained in alignment with
each other to form an arc (e.g., approximately matching an average
arc of a human head) and slide with respect to each other so as to
vary an amount of overlap, thereby varying a size of the arc (e.g.,
to match different size human heads), and wherein the two
elastomeric hinges are disposed on opposing ends of the arc formed
by the two sliding arms.
[0280] In certain embodiments, the mechanical transducer is a
member of a transducer array comprising a plurality of (e.g., two
or more) mechanical transducers maintained in a fixed spatial
arrangement in relation to each other (e.g., in substantial
proximity to each other; e.g., spaced along a straight or curved
line segment) and wherein the controller board controls output of
the mechanical transducer in relation to other mechanical
transducers of the array [e.g., so as to synchronize mechanical
vibration produced by each mechanical transducer of the transducer
array (e.g., such that each mechanical transducer begins and/or
ends producing mechanical vibration at a particular delay with
respect to one or more other mechanical transducers of the array;
e.g., such that the mechanical transducers are sequentially
triggered, one after the other; e.g., wherein the mechanical
transducers are spaced along a straight or curved line segment and
triggered sequentially along the line segment, such that an
apparent source of mechanical vibration moves along the line
segment to mimic a stroking motion)][e.g., wherein a first portion
of the mechanical transducers outputs a different frequency
mechanical vibration from a second portion of the mechanical
transducers of the transducer array (e.g., wherein each mechanical
transducer of the transducer array outputs a different frequency
mechanical vibration)].
[0281] In certain embodiments, the transducer is a linear
transducer (e.g., operable to produce mechanical vibration
comprising a longitudinal component (e.g., a longitudinal
vibration)).
[0282] In certain embodiments, the mechanical transducer is
incorporated into a headphone (e.g., an in-ear headphone; e.g., an
over-the-ear headphone).
[0283] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises receiving (e.g., by a receiver in
communication with the controller board) a signal from a personal
computing device (e.g., a smart phone; e.g., a personal computer;
e.g., a laptop computer; e.g., a tablet computer; e.g., a
smartwatch; e.g., a fitness tracker; e.g., a smart charger)(e.g.,
to upload new waveforms and/or settings for waveforms).
[0284] In certain embodiments, the controlling the waveform of the
electronic drive signal comprises modulating and/or selecting the
waveform in response to (e.g., based on) the signal received from
the personal computing device by the receiver.
[0285] In certain embodiments, the delivering the mechanical wave
to the body location is performed in a non-invasive fashion (e.g.,
without penetrating skin of the subject).
[0286] In certain embodiments, the method comprising providing, by
a secondary stimulation device, one or more external
stimulus/stimuli (e.g., visual stimulus; e.g., acoustic stimulus;
e.g., limbic priming; e.g., a secondary tactile signal).
[0287] In certain embodiments, the transformed time-varying wave
comprises a frequency component ranging from 5 to 15 Hz (e.g.,
ranging from approximately 7 to approximately 13 Hz; e.g., a
frequency range matching an alpha brain wave frequency range; e.g.,
approximately 10 Hz).
[0288] In certain embodiments, the transformed time-varying wave
comprises a frequency component ranging from 0 to 49 Hz (e.g., from
18 to 48 Hz; e.g., from 15 to 40 Hz; e.g. from 8 to 14 Hz).
[0289] In certain embodiments, the transformed time-varying wave
comprises a carrier wave [e.g., a periodic wave having a
substantially constant frequency (e.g., ranging from 5 to 15 Hz;
e.g., ranging from approximately 7 to approximately 13 Hz; e.g., a
frequency range matching an alpha brain wave frequency range; e.g.,
approximately 10 Hz)] modulated by an envelope function having one
or more low-amplitude sub-intervals [e.g., a periodic envelope
function (e.g., a square wave; e.g., a 0.5 Hz square wave); e.g.,
the one or more low-amplitude sub-intervals having a duration of
greater than or approximately equal to two seconds; e.g., the one
or more low-amplitude sub-intervals having a duration of
approximately two seconds].
[0290] In certain embodiments, the transformed time varying wave
comprises an isochronic wave. In certain embodiments, the
transformed time-varying wave comprises a chirped wave. In certain
embodiments, the waveform of the electronic drive signal comprises
a transformed time-varying wave having a functional form
corresponding to a carrier wave within an envelope {e.g., wherein
the transformed-time varying wave is the carrier wave and is
further modulated by an envelope [e.g., wherein the envelope is a
sinusoidal wave; e.g., wherein the envelope has a monotonically
increasing (in time) amplitude (e.g., wherein the envelope has a
functional form corresponding to an increasing (in time)
exponential)]; e.g., wherein the transformed time-varying wave is
the envelope that modulates a carrier wave [e.g., wherein the
carrier wave is a periodic wave (e.g., a sinusoidal wave; e.g., a
square wave; e.g., a sawtooth wave)(e.g., having a higher frequency
than the envelope)]}.
[0291] In certain embodiments, a functional form of the waveform of
the electronic drive signal is based on one or more recorded
natural sounds (e.g., running water; e.g., ocean waves; e.g.,
purring; e.g., breathing; e.g., chanting; e.g., gongs; e.g.,
bells).
[0292] In certain embodiments, the method comprises receiving an
electronic response signal from a monitoring device (e.g., directly
from and/or to the monitoring device; e.g., via one or more
intermediate server(s) and/or computing device(s))(e.g., a wearable
monitoring device; e.g., a personal computing device; e.g., a
fitness tracker; e.g., a heart-rate monitor; e.g., an
electrocardiograph (EKG) monitor; e.g., an electroencephalography
(EEG) monitor; e.g., an accelerometer; e.g., a blood-pressure
monitor; e.g., a galvanic skin response (GSR) monitor), and wherein
the controlling the waveform of the electronic drive signal
comprises adjusting and/or selecting the waveform in response to
(e.g., based on) the received electronic response signal.
[0293] In certain embodiments, the method comprises recording usage
data (e.g., parameters such as a record of when the device was
used, duration of use, etc.) and/or one or more biofeedback signals
for a human subject [e.g., using one or more sensors, each operable
to measure and record one or more biofeedback signals (e.g., a
galvanic skin response (GSR) sensor; e.g., a heart-rate monitor;
e.g., an accelerometer)][e.g., storing and/or providing the
recorded usage data and/or biofeedback signals for further
processing and/or transmission to an external computing device,
e.g., for computation (e.g., using a machine learning algorithm
that receives the one or more biofeedback signals as input, along
with, optionally, user reported information) and display of one or
more performance metrics (e.g., a stress index) to a subject].
[0294] In certain embodiments, the method comprises automatically
modulating and/or selecting the waveform of the electronic drive
signal in response to (e.g., based on) the recorded usage data
and/or biofeedback signals (e.g., using a machine learning
algorithm that receives the one or more biofeedback signals as
input, along with, optionally, user reported information, to
optimize the waveform output).
[0295] In certain embodiments, a level [e.g., amplitude (e.g., a
force; e.g., a displacement)] of at least a portion of the
mechanical wave is (e.g., modulated and/or selected) based on
activation thresholds of one or more target cells and/or proteins
(e.g., mechanoreceptors (e.g., C tactile afferents); e.g., nerves;
e.g., sensory thresholds corresponding to a level of tactile
sensation) [e.g., wherein the one or more controller boards
modulate the waveform output based on sub-activation thresholds
(e.g., accounting for the response of the mechanical
transducers)].
[0296] In certain embodiments, an amplitude of the mechanical wave
corresponds to a displacement ranging from 1 micron to 10
millimeters (e.g., approximately 25 microns)(e.g., wherein the
amplitude is adjustable over the displacement ranging from 1 micron
to 10 millimeters)[e.g., wherein the amplitude corresponds to a
force of approximately 0.4N][e.g., thereby matching the amplitude
to activation thresholds of C tactile afferents].
[0297] In another aspect, the invention is directed to a method of
stimulating one or more nerves and/or mechanoreceptors of a subject
(e.g., a human subject), the method comprising: using the device
articulated in any of paragraphs [227] to [295] for stimulation of
the one or more nerves and/or mechanoreceptors of the subject.
[0298] In another aspect, the invention is directed to a method of
stimulating one or more nerves of a human subject using a
transcutaneous, neuromodulation device [e.g., a wearable device;
e.g., a non-invasive device (e.g., not comprising any components
that penetrate skin)], the device comprising one or more
transducers (e.g., mechanical transducers), a battery, connectors,
and one or more controller boards, wherein the one or more
controller boards control waveform output through the connectors
and the one or more transducers, and wherein the transducers
transcutaneously applied stimulate the one or more nerves, the
method comprising: contacting the one or more transducers of the
device to the human subject, generating the waveform output signal,
activating the transducers using the waveform output signal (e.g.,
by applying the waveform output signal to the transducers to
generate a mechanical wave), and stimulating the one or more nerves
of the human subject, wherein the waveform output comprises an
transformed time-varying wave.
[0299] In another aspect, the invention is directed to a method of
stimulating one or more mechanoreceptors of a human subject using
transcutaneous stimulation device [e.g., a wearable device; e.g., a
non-invasive device (e.g., not comprising any components that
penetrate skin)], the device comprising one or more mechanical
transducers, a battery, connectors, and one or more controller
boards, wherein the one or more controller boards control waveform
output through the connectors and the one or more mechanical
transducers, and wherein the one or more mechanical transducers
transcutaneously applied stimulate the one or more
mechanoreceptors, the method comprising: contacting the one or more
mechanical transducers of the device to the human subject,
generating the waveform output signal, activating the mechanical
transducers using the waveform output signal (e.g., by applying the
waveform output signal to the transducers to generate a mechanical
wave), and stimulating the one or more mechanoreceptors of the
human subject, wherein the waveform output comprises an transformed
time-varying wave.
[0300] Elements of embodiments involving one aspect of the
invention (e.g., compositions, e.g., systems, e.g., methods) can be
applied in embodiments involving other aspects of the invention,
and vice versa.
BRIEF DESCRIPTION OF THE DRAWINGS
[0301] The foregoing and other objects, aspects, features, and
advantages of the present disclosure will become more apparent and
better understood by referring to the following description taken
in conjunction with the accompanying drawings, in which:
[0302] FIG. 1A is a schematic showing Piezo1 mechanical triggered
cell surface protein channels, which modulate nerves, vascular
endothelial, and other cell types; (from Murthy, 2017);
[0303] FIG. 1B is a schematic showing a Piezo2 mechanically
triggered cell surface protein, which modulate nerves, vascular
endothelial, and other cell types; (from Qiu, 2018)
[0304] FIG. 2A is a schematic showing the vagal pathway; from (He,
2012);
[0305] FIG. 2B is a schematic showing vagal innervation and sensory
distribution of the ear; from (Riviello, 2016);
[0306] FIG. 3 is a table showing biological targets of the devices
and methods, in certain embodiments.
[0307] FIG. 4 is a graph showing an example isochronic wave,
according to an illustrative embodiment.
[0308] FIG. 5 is a schematic of a stimulation device, according to
an illustrative embodiment;
[0309] FIG. 6A is a schematic showing multiple transducers
connected to a controller board in series, according to an
illustrative embodiment.
[0310] FIG. 6B is a schematic showing multiple transducers of
differing sizes connected to a controller board in series,
according to an illustrative embodiment.
[0311] FIG. 6C is a schematic showing multiple transducers, each
connected to a dedicated controller board, along with a master
controller board, according to an illustrative embodiment.
[0312] FIG. 6D is a schematic showing multiple transducers of
differing sizes, each connected to a dedicated controller board,
along with a master controller board, according to an illustrative
embodiment.
[0313] FIG. 7 is a block flow diagram of a process for stimulating
one or more nerves and/or one or more mechanoreceptors, according
to an illustrative embodiment.
[0314] FIG. 8A is a block flow diagram of a process for treating a
subject via mechanical stimulation using a transformed time varying
wave, according to an illustrative embodiment.
[0315] FIG. 8B is a block flow diagram of a process for treating a
subject by delivering mechanical stimulation to a mastoid location,
according to an illustrative embodiment;
[0316] FIG. 8C is a block flow diagram of a process for treating a
subject via mechanical stimulation by stimulating a cranial nerve
of the subject, according to an illustrative embodiment;
[0317] FIG. 8D is a block flow diagram of a process for treating a
subject via mechanical stimulation of one or more nerves and/or
mechanoreceptors, wherein the mechanical stimulation is generated
using a waveform comprising a frequency component ranging from
approximately 5 to 15 Hz, according to an illustrative
embodiment;
[0318] FIG. 9 is a block flow diagram of a process for treating a
subject via mechanical stimulation generated and/or modulated in
response to feedback from a monitoring device, according to an
illustrative embodiment;
[0319] FIG. 10 is a block flow diagram of a process for treating a
subject via mechanical stimulation generated and/or modulated based
on subject feedback and/or initialization setting data, according
to an illustrative embodiment.
[0320] FIG. 11 is a block flow diagram showing a processes for
treating anxiety and/or an anxiety related disorder by providing
transcutaneous mechanical stimulation in combination with one or
more rounds of therapy, according to an illustrative
embodiment.
[0321] FIG. 12 is a block flow diagram of a process for treating a
subject via mechanical stimulation delivered to the subject in a
binaural fashion, according to an illustrative embodiment;
[0322] FIG. 13 is a block flow diagram of a process for treating a
subject via mechanical stimulation delivered to the subject in a
monaural fashion, according to an illustrative embodiment;
[0323] FIG. 14A is a block flow diagram of a process for treating a
subject via mechanical stimulation using a transformed time varying
wave, according to an illustrative embodiment;
[0324] FIG. 14B is a block flow diagram of a process for treating a
subject via mechanical stimulation of one or more nerves and/or
mechanoreceptors, wherein the mechanical stimulation is generated
using a waveform comprising a frequency component ranging from
approximately 8 to 48 Hz, according to an illustrative
embodiment;
[0325] FIG. 14C is a block flow diagram of a process for
controlling a waveform using dynamical systems methods, according
to an illustrative embodiment;
[0326] FIG. 15A is a graph of an example waveform comprising a
transformed time-varying wave (TTVW), according to an illustrative
embodiment;
[0327] FIG. 15B is a graph of an example waveform comprising a
transformed time-varying wave (TTVW), according to an illustrative
embodiment;
[0328] FIG. 15C is a graph of an example waveform comprising a
transformed time-varying wave (TTVW), according to an illustrative
embodiment;
[0329] FIG. 15D is a graph of an example waveform comprising a
transformed time-varying wave (TTVW), according to an illustrative
embodiment;
[0330] FIG. 15E is a graph of an example waveform comprising a
transformed time-varying wave (TTVW), according to an illustrative
embodiment;
[0331] FIG. 16A is a graph of an example waveform comprising a sine
wave inside a pulse, according to an illustrative embodiment.
[0332] FIG. 16B is a graph of an example waveform comprising a
modulated sine wave, according to an illustrative embodiment.
[0333] FIG. 17A is a schematic illustrating a waveform comprising
additive subthreshold noise; modified from (Moss, 2004);
[0334] FIG. 17B is a graph showing a waveform comprising a sine
wave with added stochastic resonance noise, according to an
illustrative embodiment.
[0335] FIG. 18A is a graph showing a waveform comprising a chirped
wave, according to an illustrative embodiment.
[0336] FIG. 18B is a graph of an example aperiodic waveform,
according to an illustrative embodiment;
[0337] FIG. 18C is a graph of an example waveform, according to an
illustrative embodiment;
[0338] FIG. 18D is a graph of an example waveform, according to an
illustrative embodiment;
[0339] FIG. 18E is a graph of an example waveform, according to an
illustrative embodiment;
[0340] FIG. 18F is a graph of an example waveform, according to an
illustrative embodiment;
[0341] FIG. 18G is a graph of an example waveform, according to an
illustrative embodiment;
[0342] FIG. 18H is a graph of an example sawtooth waveform,
according to an illustrative embodiment;
[0343] FIG. 19 is a chart showing approaches for producing various
waveforms according to illustrative embodiments used with the
systems, methods, and devices described herein;
[0344] FIG. 20 is a schematic illustrating an approach for
generating and updating a personalized waveform tailored to an
individual user, according to an illustrative embodiment.
[0345] FIG. 21 is a graph showing characteristics of various
physiological signals associated with relaxation and focused states
of a subject, according to an illustrative embodiment.
[0346] FIG. 22 is a schematic illustrating a label to be included
in a kit comprising the devices described herein, according to an
illustrative embodiment.
[0347] FIG. 23 is a schematic illustrating how, in certain
embodiments, different stimuli types can elicit different responses
in a subject.
[0348] FIG. 24 is a schematic of an example mechanotransduction
pathway for stimulating afferent nerves.
[0349] FIG. 25 is a diagram illustrating example characteristics of
mechanical stimulation that can be tailored to elicit a particular
response in a subject, according to an illustrative embodiment.
[0350] FIG. 26 is a series of schematics illustrating a proposed
use of the devices and methods described herein for treating a
subject, according to an illustrative embodiment.
[0351] FIG. 27 is a set of two images and a schematic illustrating
collection of electroencephalogram (EEG) data, according to an
illustrative embodiment.
[0352] FIG. 28A is a schematic showing different brain regions from
which EEG sensors collect signal, according to an illustrative
embodiment.
[0353] FIG. 28B is a set of three graphs showing changes in
absolute power measured by EEG sensors in different brain
regions.
[0354] FIG. 29 is a set of graphs illustrating coherence analysis
in EEG measurements, according to an illustrative embodiment.
[0355] FIG. 30 is a set of graphs showing coherence analysis in EEG
data performed for a subject receiving mechanical stimulation in
accordance with the devices, systems, and methods described
herein.
[0356] FIG. 31 is a graph comparing heart rate variability (HRV)
results for two different types of stimulation used for treatment
of anxiety with a control (sham stimulation).
[0357] FIG. 32A is a schematic plan view of a transcutaneous
neuromodulation device in accordance with one or more embodiments
of the invention.
[0358] FIG. 32B is a schematic perspective view of the
transcutaneous neuromodulation device of FIG. 32A in accordance
with one or more embodiments of the invention.
[0359] FIG. 32C is a schematic side view of a portion of an
ergonomic support device for use with a transcutaneous
neuromodulation device depicting a series of control maneuvers for
operating the device in accordance with one or more embodiments of
the invention.
[0360] FIG. 32D is a schematic side view of a transcutaneous
neuromodulation device positioned on a human subject in accordance
with one or more embodiments of the invention.
[0361] FIG. 32E is a schematic plan view of a transcutaneous
neuromodulation device positioned in a storage/charging case in
accordance with one or more embodiments of the invention.
[0362] FIG. 33A is a schematic perspective view of an alternative
transcutaneous neuromodulation device in accordance with one or
more embodiments of the invention.
[0363] FIG. 33B is a schematic perspective view of the
transcutaneous neuromodulation device of FIG. 33A rotated 180
degrees.
[0364] FIG. 33C is a schematic showing a view of a portion of the
transcutaneous neuromodulation device of FIG. 33A showing an
interior of an adjustment mechanism, according to an illustrative
embodiment.
[0365] FIG. 33D is a 3D rendered version of the view shown in FIG.
33C.
[0366] FIG. 33E is schematic showing a sectional view of an
adjustment mechanism according to an illustrative embodiment.
[0367] FIG. 33F is a 3D rendered version of the sectional view
shown in FIG. 33E.
[0368] FIG. 33G is schematic showing an underside of a portion of
an adjustment mechanism with grooves, according to an illustrative
embodiment.
[0369] FIG. 33H is a 3D rendered version of the view shown in FIG.
33G.
[0370] FIG. 33I is an enlarged perspective view of a portion of a
transcutaneous neuromodulation device in accordance with one or
more embodiments of the invention.
[0371] FIG. 33J is an enlarged perspective view of another portion
of a transcutaneous neuromodulation device in accordance with one
or more embodiments of the invention.
[0372] FIG. 33K is a schematic side view of a transcutaneous
neuromodulation device positioned on a human subject in accordance
with one or more embodiments of the invention.
[0373] FIG. 34A and FIG. 34B are schematic perspective views of an
interface portion of a transcutaneous neuromodulation device in
accordance with one or more embodiments of the invention.
[0374] FIG. 35 is a block diagram of an exemplary cloud computing
environment, used in certain embodiments.
[0375] FIG. 36 is a block diagram of an example computing device
and an example mobile computing device used in certain
embodiments.
[0376] FIG. 37 is a schematic showing an approach for processing
qEEG data, used in certain embodiments.
[0377] FIG. 38A is visualization of qEEG data for a subject showing
a qEEG map for the subject prior to performing an intervention
using the mechanical stimulation approaches described herein.
[0378] FIG. 38B is visualization of qEEG data for a subject showing
a qEEG map for the subject after performing an intervention using
the mechanical stimulation approaches described herein.
[0379] FIG. 39A is a visualization of qEEG data for a subject
comparing a pre-intervention and post-intervention qEEG map.
[0380] FIG. 39B is a visualization of qEEG data for a subject
comparing a pre-intervention and post-intervention qEEG map.
[0381] FIG. 40A is a histogram showing age distributions for
participants in a pilot study assessing efficacy of embodiments of
the devices and methods described herein for treatment of
anxiety.
[0382] FIG. 40B is an infographic showing gender distribution for
participants in a pilot study assessing efficacy of embodiments of
the devices and methods described herein for treatment of
anxiety.
[0383] FIG. 41 is a histogram showing feedback regarding ease of
use from participants in in a pilot study assessing efficacy of
embodiments of the devices and methods described herein for
treatment of anxiety.
[0384] FIG. 42 is a picture of a device used for providing
mechanical stimulation to subjects in a pilot study assessing
efficacy of embodiments of the devices and methods described herein
for treatment of anxiety.
[0385] FIG. 43A is a set of graphs showing individual results from
a first participant in a pilot study assessing efficacy of
embodiments of the devices and methods described herein for
treatment of anxiety.
[0386] FIG. 43B is a set of graphs showing individual results from
a second participant in a pilot study assessing efficacy of
embodiments of the devices and methods described herein for
treatment of anxiety.
[0387] FIG. 43C is a set of graphs showing individual results from
a third participant in a pilot study assessing efficacy of
embodiments of the devices and methods described herein for
treatment of anxiety.
[0388] FIG. 43D is a set of graphs showing individual results from
a fourth participant in a pilot study assessing efficacy of
embodiments of the devices and methods described herein for
treatment of anxiety.
[0389] FIG. 43E is a set of graphs showing individual results from
a fifth participant in a pilot study assessing efficacy of
embodiments of the devices and methods described herein for
treatment of anxiety.
[0390] FIG. 44A is a histogram showing GAD-7 scores at enrollment,
interim, and exit for participants in a pilot study assessing
efficacy of embodiments of the devices and methods described herein
for treatment of anxiety.
[0391] FIG. 44B is a histogram showing VAS scores at enrollment,
interim, and exit for participants in a pilot study assessing
efficacy of embodiments of the devices and methods described herein
for treatment of anxiety.
[0392] FIG. 44C is a histogram showing STAI-STATE scores at
enrollment, interim, and exit for participants in a pilot study
assessing efficacy of embodiments of the devices and methods
described herein for treatment of anxiety.
[0393] FIG. 44D is a histogram showing STAI-TRAIT scores at
enrollment, interim, and exit for participants in a pilot study
assessing efficacy of embodiments of the devices and methods
described herein for treatment of anxiety.
[0394] The features and advantages of the present disclosure will
become more apparent from the detailed description set forth below
when taken in conjunction with the drawings, in which like
reference characters identify corresponding elements throughout. In
the drawings, like reference numbers generally indicate identical,
functionally similar, and/or structurally similar elements.
Definitions
[0395] Nerve stimulation: As used herein, the terms "stimulate" and
"stimulating", when used in reference to nerves, such as in
"stimulating one or more nerves" refer to any action that causes a
change in the behavior of one or more nerves including, but not
limited to, causing of firing one or more action potentials along
the nerve. For example, changes in nerve behavior resulting from
nerve stimulation may include, without limitation, changes in
firing threshold, response to network activity, action potential
amplitude, and timing of firing.
[0396] Nerves may be stimulated through a variety of mechanisms.
For example, nerves may be stimulated by a signal, such as a
mechanical vibration, through the interaction of a variety of
proteins and cells. In particular, sensory proteins and cells may
form a mechanosensory network through which a mechanical signal
initiates a process, or modifies an ongoing process, resulting in a
series of biological signals (e.g., chemical signals) within the
network, ultimately causing stimulation of a nerve. Nerves may also
be stimulated directly, without necessarily involving additional
biomolecules, cells, and the like. For example, when free ends of
nerves are subjected to mechanical force (e.g., as delivered via a
mechanical vibration), a change in behavior may be generated within
the nerve, such that the nerve is stimulated.
[0397] Isochronic wave: As used herein, the term "isochronic wave"
refers to a time-varying signal (e.g., an electronic signal)
comprising one or more low-amplitude sub-intervals within which an
amplitude of the signal is substantially reduced in comparison with
its amplitude at other sub-intervals.
[0398] In certain embodiments, the amplitude of the isochronic wave
within the one or more low-amplitude sub intervals is approximately
zero.
[0399] In certain embodiments, a duration of the one or more
low-amplitude sub-intervals corresponds to (e.g., is approximately
equal to; e.g., is greater than or approximately equal to) a
refractory period of a mechanoreceptor and/or nerve target, such as
a Piezo2 protein, a Merkel Cell, a Vagus nerve, a C-tactile
afferent, and the like. In certain embodiments, a duration of the
one or more low-amplitude sub-intervals corresponds to a refractory
period of a Piezo2 protein (e.g., approximately two seconds; e.g.,
greater than or approximately equal to two seconds).
[0400] In certain embodiments, a functional form of the isochronic
wave corresponds to a carrier wave modulated by an envelope
function, the envelope function comprising one or more
low-amplitude sub-intervals within which its amplitude is
substantially reduced in comparison with its amplitude at other
times. The one or more low-amplitude sub-intervals of such an
isochronic wave thus correspond to those of the envelope
function.
[0401] As used herein, the term "modulated" refers to the
functional form of the isochronic wave, and is not intended to
limit the manner in which the isochronic wave is produced.
[0402] In certain embodiments, the carrier wave is a periodic wave.
In certain embodiments, a frequency of the periodic carrier wave is
selected for stimulation of a particular nerve and/or
mechanoreceptor target, such as a Piezo2 protein (e.g., less than
or approximately equal to 100 Hz), a Merkel Cell (e.g., ranging
from approximately 5 to 15 Hz), a vagus nerve (e.g., ranging from
approximately 20 to 200 Hz; e.g., 50 to 200 Hz; e.g., 100 to 200
Hz; e.g., 130 to 180 Hz), e.g., a C-Tactile Afferent (e.g., less
than or approximately equal to 50 Hz). In certain embodiments, a
frequency of the carrier wave corresponds to a frequency of a
particular type of brain wave (e.g., for entrainment of brain
waves). For example, theta, alpha, beta, gamma brain waves have
frequencies ranging from 4-8 Hz, 8-16 Hz, 16-30 Hz, and 30-60 Hz,
respectively.
[0403] In certain embodiments, the envelope function is periodic,
such that the one or more low-amplitude sub intervals repeat, in
periodic fashion. In certain embodiments, the envelope function is
a square wave. In certain embodiments, a frequency of the periodic
envelope function corresponds to a breathing rate of a subject
(e.g., corresponding to 6 to 10 breaths per minute; e.g.,
approximately 0.1 Hz)
[0404] In certain embodiments, an isochronic wave is also a
transformed time-varying wave.
[0405] Transformed time-varying wave: As used herein, the term
"transformed time varying wave" refers to a signal (e.g., an
electronic signal) whose functional form is a modified base
time-varying wave, such that variation in the amplitude of the base
time-varying wave is transformed over one or more sub-intervals of
the base time-varying wave. In certain embodiments one or more of
the sub-intervals each span a peak of the base-time varying
wave.
[0406] As used herein, the terms "transformed" and "modified" refer
to the functional form of the transformed periodic wave, and are
not intended to limit the manner in which the transformed
time-varying wave is produced.
[0407] In certain embodiments, the amplitude of transformed
time-varying wave is substantially flat within one or more of the
one or more sub-intervals. In certain embodiments, the amplitude of
the transformed time-varying wave varies as a linear or near-linear
ramp within one or more of the one or more sub-intervals. The
linear ramp may have a positive or negative slope with respect to
time. In certain embodiments, the amplitude of the transformed
time-varying wave has a sinusoidal functional form within one or
more of the one or more sub-intervals. In certain embodiments, a
functional form of the transformed time-varying wave is the same
for each sub-interval. In certain embodiments, the transformed
time-varying wave has a first functional form within a first
sub-interval and a second functional form within a second
sub-interval.
[0408] In certain embodiments, the base time-varying wave is a
periodic wave (a base periodic wave). In certain embodiments, the
base periodic wave is a sinusoidal wave. In certain embodiments,
the base periodic wave is a square wave. In certain embodiments,
the base periodic wave is a periodic pulse train. The base periodic
wave may have a substantially constant frequency. For example, the
base periodic wave may have a frequency ranging from approximately
18 and 48 Hz. In certain embodiments, the base periodic wave has a
time-varying frequency. In certain embodiments, the base periodic
wave is chirped. In certain embodiments, the base time-varying wave
is aperiodic. In certain embodiments, the base time-varying wave is
a random signal.
[0409] In certain embodiments, a transformed time-varying wave has
a mathematical form described as follows. If the total duration of
a signal is T, and if the time interval [0; T] is divided in N
subintervals [t.sub.i, t.sub.i+1]0<=i<=N-1, where t.sub.0=0
and t.sub.N=T, a transformed time-varying wave refers to a signal
which is defined on each subinterval [t.sub.i, t.sub.i+1] as either
a portion of a base-time varying wave as defined above, or a curved
or linear segment with a net negative, positive or null derivative
over each subinterval [t.sub.i, t.sub.i-1].
[0410] A particular example of a transformed time-varying wave is a
polygonal pulse train wherein the signal on each subinterval
[t.sub.i, t.sub.i+1]0<=i<=N-1 is a linear segment.
[0411] Polygonal pulse train: As used herein, the term "polygonal
pulse train" refers to a signal that is composed of a succession of
polygonal pulse shapes. A polygonal pulse shape has a functional
form P(t) where t is the time variable on an interval [0; T] such
that and P(t+T(t))=P(t) where T(t)=1/f(t) is the period of the
pulse shape and f(t) is a constant or time-varying waveform
frequency. The time interval [0; T] may be divided into
subintervals [t.sub.i: t.sub.i+1], such that for any time t such
that t.sub.i<t<t.sub.i+1, the signal amplitude P(t) is equal
to a.sub.it+b.sub.i, where a.sub.i and b.sub.i are constants
determining the slope and height of the linear polygon edge on the
time interval [t.sub.i: t.sub.i+1]. The resulting series of linear
ramps are concatenated into a polygonal pulse of duration T, such
that the time index t.sub.i takes values between 0 and T.
Accordingly, P(t) is composed of between 1 and less than or equal
to T*Fs-1 (where Fs is the signal sampling rate) linear ramps
defining the polygonal pulse shape repeating with period T(t). The
polygonal pulse train may be composed of a single polygonal pulse
shape or a concatenation of 2 or more polygonal pulse shapes.
[0412] Aperiodic time-varying wave: As used herein, the term
"aperiodic time-varying wave" refers to a signal, A(t), such as
there is no possible value T where A(t+T)=A(t) for each time tin
the time interval on which A is defined. An example of an aperiodic
time-varying wave is a signal having a functional form
corresponding to a sum of two sine waveforms of respective
frequencies f and f, wherein f divided by f is an irrational
number.
[0413] Contact, contacting: As used herein, the terms "contact" and
"contacting" as used in reference to a transducer refer to placing
the transducer in sufficient proximity to a body (e.g., a surface
of a subject) so as to deliver a mechanical wave generated by the
mechanical transducer to the body (e.g., to a tissue of interest at
and/or beneath a surface of the subject). In certain embodiments, a
surface of the mechanical transducer is placed in physical contact
(e.g., touching) a surface of the body. In certain embodiments,
there may be a small gap between the surface of the mechanical
transducer and the surface of the body. In certain embodiments, the
gap is an air gap, filled with air. In certain embodiments, another
material, such as an adhesive, insulating material, etc., is in
between the surface of the mechanical transducer and the surface of
the body.
[0414] Dynamical system, dynamical systems methods, dynamical
systems measures: As used herein, the term "dynamical system",
refers to a state space S, a set of times T and a rule R for
evolution, R: S.times.T.fwdarw.S that gives the consequent(s) to a
state s.di-elect cons.S. A dynamical system can be considered to be
a model describing the temporal evolution of a system. The state
space S may be a discrete or continuous collection of coordinates
that describe the state of the system. The state space S and/or set
of times T may also be discrete or continuous. In certain
embodiments, the state space S and/or set of times T may be
represented by a topological group. Given the current state of the
system, the evolution rule R predicts the next state or states. The
evolution rule R provides a prediction of a next state and/or
states that follow from the current state space value.
[0415] As used herein, the term "dynamical systems methods" refers
to formal or mathematical descriptions of dynamical systems. As
used herein, the term "dynamical systems measures" refers to
techniques used to evaluate and identify particular dynamical
systems states S and rules for evolution R.
[0416] Tissue: As used herein, the term "tissue" refers to bone
(osseous tissue) as well as soft-tissue.
DETAILED DESCRIPTION OF THE INVENTION
[0417] It is contemplated that systems, devices, methods, and
processes of the claimed invention encompass variations and
adaptations developed using information from the embodiments
described herein. Adaptation and/or modification of the systems,
architectures, devices, methods, and processes described herein may
be performed, as contemplated by this description.
[0418] Throughout the description, where articles, devices, and
systems are described as having, including, or comprising specific
components, or where processes and methods are described as having,
including, or comprising specific steps, it is contemplated that,
additionally, there are articles, devices, and systems of the
present invention that consist essentially of, or consist of, the
recited components, and that there are processes and methods
according to the present invention that consist essentially of, or
consist of, the recited processing steps.
[0419] It should be understood that the order of steps or order for
performing certain action is immaterial so long as the invention
remains operable. Moreover, two or more steps or actions may be
conducted simultaneously.
[0420] The mention herein of any publication, for example, in the
Background section, is not an admission that the publication serves
as prior art with respect to any of the claims presented herein.
The Background section is presented for purposes of clarity and is
not meant as a description of prior art with respect to any
claim.
[0421] Documents are incorporated herein by reference as noted.
Where there is any discrepancy in the meaning of a particular term,
the meaning provided in the Definition section above is
controlling.
[0422] Headers are provided for the convenience of the reader--the
presence and/or placement of a header is not intended to limit the
scope of the subject matter described herein.
A. Nerve Stimulation and Health Benefits
[0423] Since the Egyptians, Greeks, and Romans first used electric
eels to treat disease and injury, treatment stimulation of nerves
has primarily involved electrical stimulation of the nerve and
connected tissues. The modern era of electrical neurostimulation
began in 1780 when Luigi Galvani showed that a leg of a dead frog
could be moved by applying a voltage to nerves and tissues.
[0424] However, while nerves conduct instructions between the brain
and tissues and organs via electrical current, the application of
electric currents is almost never the manner by which sensory
nerves are stimulated in nature. For example, somatosensory nerves
have evolved specific responses to a wide variety of stimuli: skin
receptors (exteroceptors) close to the skin surface detect touch,
pressure, vibration, temperature, pain; muscle and joint receptors
(proprioceptors) in tendons, muscles and joints detect body
position and movement; and visceral receptors (interoceptors)
through the body monitor internal organ states and detect critical
parameters such as heart rate and blood pressure. Different types
of sensory nerves in the skin are triggered by specific types of
inputs to afferent neurons: mechanoreceptors triggered by touch,
stretch, pressure, hair vibrations; mechanoreceptors triggered by
low frequency acoustic stimuli; tactile corpuscles that respond to
touch and low frequency vibrations around 50 Hz; lamellar
corpuscles that detect rapid vibrations in the range of 200-300 Hz;
Ruffini endings that detect tension in the skin and fascia; Merkel
endings that detect sustained pressure and inflammation;
baroreceptors that are excited through stretching blood vessels;
hair follicles that transmit vibrations and acoustic stimuli all
over the body, including hearing in the cochlea by transducing
sound; ligaments composed of multiple types of mechanoreceptors to
help proprioception and balance; nociceptors triggered by trauma
results in pain signals to local tissues and the brain; and
thermoreceptors are portions of sensory neurons that sense
temperature and heat.
[0425] Mechanoreceptors in the skin allow for the detection of
diverse stimuli, conveying sensory information for pain,
temperature, itch, and a broad spectrum of touch information to the
central nervous system. In mammals, cutaneous low-threshold
mechanoreceptors (LTMRs) constitute a diverse group of primary
somatosensory neurons that function to sense external mechanical
force (Olson, 2016). LTMRs are a subpopulation of dorsal root
ganglion (DRG) and trigeminal ganglion (TG) neurons that elaborate
a single axonal process that bifurcates into a peripheral branch
innervating the skin/hair and a central branch innervating the
spinal cord or brainstem (Olson, 2016). Innocuous (non-painful)
touch sensations are conveyed from LTMRs innervating a wide variety
of combinations of mechanosensory end organs adapted for the
detection of diverse stimuli (Zimmerman, 2014). LTMRs occur in a
variety of subtypes capable of mediating unique functional
responses or aspects of touch through different structures and
functions, diverse peripheral innervation patterns, and
physiological responses to stimulation. The different types of
mammalian LTMRS are traditionally categorized according to their
action potential conduction velocity and cell morphology, and
include A.beta.-LTMRs (rapid-conducting), A.delta.-LTMRs (medium
conduction velocity), and C-LTMRs (slow-conducting), which exhibit
great diversity in their physiological, molecular, anatomical, and
functional properties (Olson, 2016). These can be further
classified by the type of response to sustained mechanical stimuli,
including rapidly adapting (RA--burst firing at stimulus
onset/offset), slowly adapting (SA--sustained firing throughout the
stimulus), and intermediate adapting (IA--burst at stimulus onset
followed by sustained firing throughout stimulus at a rate lower
than SA-LTMRs) (Olson, 2016). A.beta.-LTMRs are the principal type
of primary sensory neurons that mediate discriminative touch and
tactile perception in mammals, and particular types of LTMRs
innervate the different types of mechanoreceptors complexes,
including: A.beta. SA1-LTMRs, which innervate Merkel cells in the
basal epidermis and convey information on sustained touch stimuli;
A.beta. SA2-LTMRs, hypothesized to terminate in Ruffini corpuscles
in the dermis and exhibit high sensitivity to skin stretch; A.beta.
RA1-LTMRs, which innervate Meissner's corpuscles in dermal
papillae, and respond to movement across the skin; and A.beta.
RA2-LTMRs, which terminate in Pacinian corpuscles in the deep
dermis and exhibit sensitivity to high-frequency vibration
(Zimmerman, 2014).
[0426] At the molecular level, the processes underlying translation
of mechanical forces into biological signals involve the activation
of ion channels in the cell membrane. Mechanosensitive ion channels
are relevant for a wide range of physiological processes, and have
been shown to mediate touch, pain, proprioception, hearing,
regulation of vascular tone and muscle and tendon stretch. For
example, Merkel cells, excitatory cells capable of firing Ca.sup.+2
action potentials, have been identified as the primary sites of
tactile transduction (Ma, 2014). Each of these Merkel-neurite
complexes, known as a `touch spot` in glabrous skin and a `touch
dome` in hairy skin, consists of an A.beta. neuronal fiber forming
a receptor network with a cluster of approximately 5-150 Merkel
cells (Olson, 2016). The LTMRs that innervate touch domes exhibit
exquisite sensitivity to gentle touch stimulation.
[0427] Merkel cells are unique among epithelial cells; they are the
only known neuron-like cells in vertebrate skin, forming close
synaptic-like contacts with A.beta. SA1-LTMRs at the
epidermal-dermal junction (Maksimovic, 2013), and clustered
complexes composed of Merkel cells and afferent AP nerve fibers
directly transduce tactile information into afferent AP signaling.
In a manner similar to that of the gustatory system and hair cells
of the auditory system, where non-neuronal cells participate in
stimulus-specific transduction, in Merkel-A.beta. SA1-LTMR
complexes, non-neuronal components of cutaneous touch complexes
detect stimuli and potentiate LTMR responses: both Merkel cells
themselves and AP SA1-LTMRs respond directly to cutaneous
mechanical stimulation, and Merkel cells signal to AP SA1-LTMRs to
achieve optimal activation of the LTMR (Zimmerman, 2015). Thus,
both Merkel cells and AP SA1-LTMRs function as mechanoreceptors,
with Merkel cells in touch dome complexes mediating sustained
firing to static touch. Moreover, Merkel cells express numerous
types of presynaptic molecules involved in synaptic vesicle release
in neurons, and also produce a large number of neuroactive
substances, including classical neurotransmitters and neuropeptides
that can act as fast excitatory neurotransmitters or
neuromodulators (Maksimovic et al., 2013). These multiple spike
encoders may send reciprocal messages such that a spike generated
at any spike encoder antidromically propagates to all other spike
encoders, initiating absolute refractory periods and restarting the
process of spike initiation, a mechanism to maintain a stable
overall response to sustained stimulus observed in Merkel cell
complexes (Lesniak, 2015).
[0428] Piezo proteins are a class of mechanically activated ion
channels that are believed to play roles in a variety of sensory
modalities (Xu, 2016). Piezo proteins, including Piezo1 and Piezo2,
convert mechanical forces into biological signals via ion channel
activation, and can induce mechanically activated cationic currents
in numerous eukaryotic cell types. Piezo proteins are relevant to
touch perception, proprioception, pulmonary respiration, red blood
cell volume regulation, vascular physiology, and various human
genetic disorders (Murthy, 2017). FIGS. 1A and 1B show schematics
of piezo proteins Piezo1 and Piezo2, respectively.
[0429] In particular, Piezo2, as found in primary sensory neurons
and specialized touch receptors located in the skin, mediates
gentle touch sensation and proprioception (Xu, 2016), and is found
in sensory tissues such as the dorsal root ganglia sensory neurons
and Merkel cells that respond to touch (Wu, 2017). In Merkel cells,
the Piezo2 mechanosensitive ion channel has recently been shown to
be involved in driving direct mechano-afferent coupling AP nerve
fibers (Ma, 2014; Woo, 2014). Piezo2 channels exhibit extremely
short response latency (0.2 ms), producing signals in afferent
A.beta.-fibers capable of one-on-one responses to high-frequency
stimuli (up to 1,200-1,500 Hz) for long periods of time
(Gottschaldt and VahleHinz, 1981). These two features may offer a
direct mechanosensitive pathway between Piezo2 ion channel activity
and afferent AP-afferent nerve sites (Ma, 2014). Further, in
addition to tactile A.beta.-fibers, Merkel cell complexes in the
dermis are also innervated by a minority of noci- and
thermo-ceptive A.delta.-fibers, and nociceptive C-fibers.
Piezo2-driven complexes of dermal Merkel cells may play in these
other sensory pathways.
[0430] Neural Signaling Dynamics
[0431] The nervous system is a complex nonlinear network composed
of elements (neurons) which themselves exhibit nonlinear behaviors
(Rulkov, 2002). As a result, the output of the nonlinear dynamical
nervous system, is not a linear weight average of the input it
receives, but rather, neural signaling arises from the interplay of
dynamic processes across multiple scales of interaction within the
network (Nanni, 2017). These dynamic interactions give rise to
emergent properties that are not deducible from the properties of
individual neurons in isolation. The dynamic interactions result
from the dynamic relationships and dependencies formed when these
are linked together in a network. For example, the transposition
from microscopic pulse frequencies at the receptor level (sensory
microscopic signal) to mesoscopic pulse and wave densities at the
microcircuit and network level (perceptual mesoscopic signal)
results from multiple interactions between large numbers of
otherwise autonomously active nonlinear neurons, producing
mesoscopic dynamics that cannot be predicted from the behavior of
individual neurons only (Freeman, 2009).
[0432] Dynamical systems formalisms describe the processes by which
the interactions of large numbers of network components give rise
to the emergence of dynamic mesoscopic processes such as these.
Models for describing nonlinear dynamical processes have applied
methods from a wide range of mathematical techniques, including
time series analyses, chaoticity, entropy, nonlinearity, fractality
analysis (Nanni, 2017), phase space reconstruction, recurrence
quantification analysis, fractal and multifractal analysis,
detrended fluctuation analysis, power spectral density analysis,
wavelet analysis (Ivanov, 1996), complexity matching (West, 2008),
autocorrelation analysis (Sokunbi, 2014), independent component
analysis, and artificial intelligence modeling.
[0433] Dynamical systems methods predict the emergence of
mesoscopic masses, ensembles, and populations observed in biology
including changes in state (Freeman, 2009), bifurcations (Cessac,
2009), intermittency (Kwok, 2005), bursting (Cessac, 2009),
bistability, multistability, phase transitions, hysteresis,
nonlinear oscillations, limit cycles, phase-resetting, entrainment,
pacemaker annihilation, scale-invariance, fractal and multifractal
scaling, long-range correlations, soft assembly (Wiltshire, 2017),
power-law scaling, self-similarity, and self-organized criticality
(Werner, 2010), self-organized criticality, diffusion limited
aggregation, cardiac alternans phenomena, nonlinear waves (e.g.,
spirals, scrolls, solitons), complex periodic cycles and
quasiperiodicities, stochastic resonance and related
noise-modulated mechanisms (Levin, 1996; Gammaitoni, 1998;
Allegrini, 2009; Rigoli, 2014), time irreversibility, complex
responses, and chaos.
[0434] Biological signals such as EEG, MEG, or heart rate
variability (HRV) contain information about dynamical changes in
the activity of different parts of the nervous system (Di Leva,
2015). Dynamical systems methods may be applied to a wide range of
electrophysiological recordings, including microelectrode (ME)
recordings, electroencephalograms (EEG), magnetoencephalograms
(MEG), electrocardiograms (ECG), functional magnetic resonance
imaging (fMRT) data, electromyograms (EMG), electrocorticograms
(ECoG), electro-oculograms (EOG), galvanic skin response (GSR), and
pupillary response (PR) (Nanni 2017). For example, following from
seminal work in the study of complexity in neural signaling
(Linkenkaer-Hansen et al., 2001), a number of EEG studies
(Linkenkaer-Hansen et al., 2004) and work in other
neurophysiological modalities have now linked either fractal
scaling relations or the correlation dimension to various
functional states or clinical disorders (Hardstone et al., 2012).
Further, nonlinear dynamical measures of EEG and fMRI complexity
exhibit specific features in health, disease, different states of
consciousness, self-esteem (Delignieres, 2004), and a variety of
neurologic and neuropsychiatric conditions (Yang, 2013), including
sleep disorders (Bianchi, 2013), mood disorders, anxiety
(Srinivasan, 2002), depression (Mendez, 2012), post-traumatic
stress disorder (Chae, 2004), attention-deficit/hyperactivity
disorder (Fernandez, 2009), obsessive/compulsive disorder
(Fernandez, 2010), autism spectrum disorder (Ahmadlou, 2010),
attention deficit hyperactivity disorder (Li, 2007), dyslexia
(Sandu, 2008), epilepsy (Onias, 2014; Weng, 2015), stroke
(Yperzeele, 2015), Alzheimer's disease (Mizuno, 2010), multiple
sclerosis (Esteban, 2009), schizophrenia (Fernandez, 2014), and
Creutzfeldt-Jakob Disease (Morabito, 2017). Nonlinear dynamical
measures derived using dynamical systems methods applied to
biological signaling, including measures of psychophysiological
time series, such as respiration, galvanic skin response, blood
volume pulse, ECG and EEG, have been shown to be predictive of
affective states such as relaxation, engagement, stress, and anger
(Onorati, 2013). Further, analysis of ECG signals provides
information about autonomic nervous system activity relevant
diagnostics of atrial fibrillation and many disease conditions
which are not easily detectable using other diagnostic methods
(Pierzchalski, 2011).
[0435] Relatedly, measures of scaling relationships and fractality
in biological systems are often interpreted as an indicator of
healthy and efficient functioning (Goldberger, 1987), in organ
systems (Bassingthwaighte, 1994), cardiac risk and forecasting
sudden cardiac death (Pen, 1995), overall health and well-being
(Van Orden, 2007), and both task-oriented and resting-state fMRI
time series data (Ciuciu, 2012). Further, recent studies on heart
rate variability (HRV) have confirmed the presence of
state-specific nonlinear dynamical structures in these time series,
with demonstrated ability to separate normal subjects from patients
suffering from cardiovascular diseases (Cerutti, 2012) and
accurately characterize affective haptic perception (Valenza, 2016;
Triscoli 2017). Compared to conventional linear measures, nonlinear
dynamical HRV indices explain a greater percentage of the variance
in attention, memory, reaction times and mood (Young, 2015).
Dynamical systems methods can be used to produce appropriate
measures such as these for the detection of changes in health,
wellbeing, cognitive function and disease states (Cheng, 2013).
[0436] For example, measures of complexity and fractal dimension
(FD) allow for the assessment of the variability or roughness of a
quantity or object across an interval of time, over a region of
space, or with respect to other mathematical measures or data. A
variety of techniques for assessing complexity and FD have been
employed, including Katz's method, Higuchi's method, rescaled range
method, Hausdorff-Besicovitch dimension, Hurst exponent (Balocchi,
2011), Feigenbaum number (Gisiger, 2001), correlation dimension
(Guclu, 2011), temporal structure function analysis (Nanni, 2017)
phase portrait analysis, Poincare section analysis, correlation
dimension analysis, Lyapunov exponent, and Kolmogorov entropy
(Voss, 2009). A wide variety of neurological time series signals
neurosciences have been shown to possess fractal structure (DiLeva,
2013, 2015), and fractal analyses have been used to objectively
quantify complex patterns found in neuroscience and neurology and
make predictions about clinical outcomes, categorize pathological
states, and generate diagnoses (John, 2015). For example, fractals
in heart beat dynamics have been a useful differentiator between
physiological states such as sleep and wakefulness, as well as
different states of pathology and aging (Ivanov et al., 1996,
1999a,b; Amaral et al., 1998), and fractal analysis of EEG signals
using Higuchi's method has shown predictive power for medical
issues such as monitoring the depth of anesthesia and sedation,
sleep staging, bright light therapy and seasonal affective
disorder, analysis of posturography signals, and evoked EEG
(Klonowski, 2007, 2016). Improved signals of the devices and
methods described herein, e.g., to encourage a suboptimal or
pathological system towards a more optimal or healthy dynamic may
be based upon dynamical systems measures such as complexity and
FD.
[0437] Vagus Nerve Stimulation
[0438] The vagus nerve, also known as cranial nerve X, is an
interwebbing nerve bundle connecting almost every organ's sensory
receptors to the brain. The vagus nerve interacts and regulates the
parasympathetic nervous system or "rest and digest" control. The
vagus nerve complex forms a bi-directional neural connection
between the immune and nervous systems (Tracey, 2002; 2007) which
acts to regulate inflammation and innate immune responses during
tissue injury and pathogen invasion (FIG. 2A). As shown in FIG. 2A,
the vagal pathway includes the heart, lungs, stomach, cervix, and
many other organs and/or regions of the body (e.g., not pictured in
FIG. 2A). Various organs and/or regions of the body in the vagal
pathway can be accessed through the ear and project to the solitary
nucleus (NTS), dorsal motor nucleus (DMN), area postrema (AP),
rostral ventrolateral medulla (RVM), and the locus coeruleus (LC).
FIG. 2B shows further detail regarding vagal innervation and
sensory distribution of the ear.
[0439] Efferent vagal signalling plays roles in cardiac control
(Thayer, 2006) and can inhibit cytokine production via
acetylcholine receptor signalling in the spleen (Tracey, 2007). The
interrelatedness of afferent and efferent signalling is highlighted
in the manner by which afferent signals carried in the vagus nerve
can activate an efferent response that inhibits cytokine release,
or "cholinergic inflammatory reflex" (Tracey, 2007). Depressed
vagus nerve activity is associated with increased morbidity and
mortality in sepsis, rheumatoid arthritis, lupus, sarcoidosis,
inflammatory bowel diseases, trauma (Tracey, 2007), depression, and
stress (Porges, 1995). Enhanced vagal tone is associated with a
variety of benefits, including increased social and psychological
well-being (Kok, 2010; Oke, 2009) and yoga (Field, 2011).
[0440] Vagus nerve stimulation (VNS) using implantable devices has
received FDA approvals for epilepsy, depression, and obesity, and
the first approval for a noninvasive transcutaneous treatment was
granted to the Gammacore device (Electrocore, USA) in 2017.
Transcutaneous VNS methods are currently being investigated (and
found to be effective and safe) for a variety of conditions,
including atrial fibrillation (Stavrakis, 2015; Yu, 2013),
depression (Hein, 2013; Aaronson, 2013), diabetes (Huan, 2014),
endotoxemia (Huston, 2007), memory (Jacobs, 2015), myocardial
infarction (Wang, 2016), tinnitus (Kreuzer, 2014), and stroke (Cai,
2014).
[0441] Transcutaneous access is found through the auricular branch
of the vagus nerve (ABVN). The ABVN, which is the only peripheral
branch of the vagus nerve, mainly supplies the auricular concha and
most of the area around the auditory meatus. Vagal nerve
stimulation has been investigated using electrical stimulation
(Hei, 2013; Yakunina, 2017), acupuncture (He, 2012) and magnetic
resonance imaging (Frangos, 2015).
[0442] Vagal Tone and Wellbeing
[0443] Enhanced vagal tone (VT) is associated with numerous indices
of psychological well-being, including trait positive emotionality,
pro-social behavior, sympathy and decreased maladaptive coping,
including working memory, directed attention, fewer negative
responses to environmental stressors, greater self-regulatory
capacity, and better ability to regulate negative facial
expressions. Individuals higher in VT appear to be more cheerful
and kind and deal better with stress (Kok, 2010). Enhanced VT is
also associated with the benefits of many of mind-body therapies
(MBTs) and yoga (Kok, 2010; Oke, 2009; Field, 2011; Muehsam,
2016).
[0444] Enhanced VT could also be used to improve symptoms of common
stress-related disorders such as insomnia and reduced libido or
sexual function. In both men and women, sexual arousal and orgasm
are mediated by afferent vagal signaling to specific brain centers
(Stoleru, 2012): observations that women with complete spinal cord
injury were able to perceive genital stimulation and respond,
including to orgasm, showed that vagus nerves provide a direct
sensory pathway between the vagina, cervix, uterus, and the brain
(Whipple, 2002). Accordingly, as described herein, present device
and method may be used for priming of sexual arousal or desire,
priming of the limbic system, enhanced pleasure, climax and
orgasm.
[0445] Enhanced VT may play a role in our ability to cope with
stressors through increased ability to resolve stress-related
signaling in the vagally mediated hypothalamic-pituitary-adrenal
(HPA) axis (Kok, 2010; Muehsam, 2016). VT modulates the ability of
the HPA axis to resolve stress responses that mediate the
production of cortisol. For example, chronic cortisol elevations
due to physical, psychological and psychosocial stress contribute
to inflammation and can cause the immune system to become less
sensitive to cortisol, resulting in compromised immune responses.
Conversely, interventions such as VNS can improve health outcomes
and wellbeing by lessening allostatic load and the associated
neuroendocrine signaling that results in downstream immunologic and
nervous system consequences (Muehsam, 2016). More plainly put, VNS
can produce benefits by removing or ameliorating the harmful
effects of chronic stressors, thus allowing the body's innate
healing responses to be more fully expressed.
[0446] Interoception
[0447] Interoceptive signaling is a process that sends neural
information from the body to the brain. Early views on
interoception described it as "the sense of the physiological
condition of the entire body," beginning with the senses of
temperature, pain, and itching (Craig, 2002). Interoception is
believed to regulate many life processes at the most basic levels,
and plays roles in modulating emotional experience and subjective
awareness at "the most complex levels" (Duquette, 2017).
Interoception is how we perceive the inner landscape of our bodies,
thoughts and feelings. In a sense, interoception is how we perceive
ourselves.
[0448] Interoceptive stimuli send direct messages to the brain,
providing information about many vital activities, including
thirst, itch, dyspnea, `air hunger`, the Valsalva maneuver, sensual
touch, penile stimulation, sexual arousal, coolness, warmth,
exercise, heartbeat, wine-tasting (in sommeliers), and distension
of the bladder, stomach, rectum or esophagus (Craig, 2009).
[0449] Interoception emerges when afferent information is
processed, such as from C-tactile nerves or the vagus nerve and its
branches, including the auricular branch of the vagus nerve. There
are specialized areas of the CNS, for example, the nucleus tractus
solitarii, that receive afferent signals from the periphery and/or
the insula and/or the anterior cingulate cortex and/or related
regions that have specialize structures where information from
afferent nerve projections is processed. In addition to generating
conscious feelings of the visceral state, further specialization in
these structures in social mammals (humans, higher apes, elephants,
and cetaceans at least) where specialized neurons may be associated
with empathy or the visceral apprehension of another's emotional
state. The ability in these social mammals to sense the
interoceptive state of other members may serve to enhance social
cohesion and reduce negative interactions.
[0450] Interoceptive signalling can be tested in a variety of ways,
the most common of which is heartbeat detection: studies have found
that higher scores on heartbeat detection predict superior
performance on some laboratory gambling tasks, for stock market
traders as compared to non-traders, and that heartbeat detection
scores were predictive of the traders' profit and loss statements
(Kandasamy, 2016).
[0451] Enhanced interoception through nerve stimulation may provide
for improving resilience and symptoms of common stress-related
disorders such as insomnia, reduced anxieties including,
performance anxiety, social anxiety, fear, PTSD, and ADHD. Other
benefits of the present device and method include enhanced
attention and engagement, lower blood pressure, and reduced blood
cortisol levels. Enhanced interoception also offers a means for
ameliorating reduced libido or sexual function. In both men and
women, sexual arousal and orgasm are mediated by afferent vagal
signaling to specific brain centers (Stoleru, 2012): observations
that women with complete spinal cord injury were able to perceive
genital stimulation and respond, including to orgasm, showed that
vagus nerve fibers provide a direct sensory pathway from the
vagina, cervix, and uterus to the brain (Whipple, 2002). Benefits
of present device and method thus also include priming of sexual
arousal or desire, priming of the limbic system, enhanced pleasure,
climax and orgasm.
[0452] While electrical stimulation has been utilized for nerve
stimulation, mechanical stimulation approaches are relatively
uncommon. Ultrasound (>20 KHz) has been shown to activate
peripheral nerves (Legon 2012, Gavrilov 1976) and low frequency
acoustic vibrations (<20 KHz) targeted at activating
somatosensory mechanoreceptors have demonstrated success in
enhancing proprioception (Harry 2012, U.S. Pat. No. 8,308,665).
While mechanical stimulation has demonstrated ability to activate
nerves, the mechanisms have not yet been fully elucidated, nor has
the gamut of potential downstream effects been fully explored, such
as the ability to modulate psychophysiological arousal, produce
benefits through neural plasticity, or develop treatments for
disease conditions and symptoms.
[0453] Mechanical stimulation approaches, however, offer a number
of advantages in comparison with electrical stimulation. Notably,
mechanical stimulation offers a substantially more robust safety
profile than electrical stimulation. Notably, electrical
stimulation side effects include: 1) skin irritation resulting from
the gels needed for good skin contact, 2) the possibility of burns
or rashes, and 3) pain or irritation at the stimulation site. In
contrast, mechanical stimulation results in soft buzzing and/or
gentle warming sensation on the skin underneath the device, does
not require as precise placement, and does not require
skin-irritating gels or pose the same risk of burns or rashes.
[0454] Development of appropriate mechanical stimulation approaches
and devices is non-trivial. Mechanical and electrical stimulation
rely on different mechanisms of action to activate nerves.
Accordingly, because the approaches for delivering electricity are
inherently different than those used for delivering mechanical
stimulation, it is effective parameters used in transcutaneous
electric stimulation are not directly applicable to mechanical
stimulation approaches.
[0455] In certain embodiments, mechanical stimulation uses
displacement of mechanoreceptors and cutaneous sensory receptors in
the skin to stimulate the afferent sensory pathway and uses the
properties of receptive fields to propagate stimulation through
tissues and bone. Mechanical stimulation by mechanical transducers
can stimulate peripheral nerves to benefit sensation, peripheral
neuropathy, balance, and proprioception.
[0456] The approaches described herein include mechanical
stimulation of nerves beyond peripheral nerves, such as cranial
nerves and other nerve types. Stimulation of nerves other than
peripheral nerves can produce changes in both well-accepted
biometric measures--such as heart rate, heart rate variability,
blood pressure, electroencephalography, and blood levels of
neurotransmitters and proteins--and clinically-validated subjective
assessments of mood and cognitive state.
[0457] Moreover, in certain embodiments, the systems, methods, and
devices described herein are directed to a new family of waveforms
and treatment protocols delivered by vibratory devices for
non-invasively stimulating nerves, tissues and vasculature,
resulting in different and unique modulation of these peripheral
nerves and tissues, along with the sensory and motor nerve
processes they govern. As described herein, in certain embodiments,
the waveforms differ from traditional sinusoidal and square waves
through the introduction of particular transformed time-varying
waves, modulation frequencies, waveshapes, aperiodic waveforms,
polygonal pulse trains, or transformed periodic signals, including
sinusoids, square waves, triangle waves, or sawtooth waves and
other configurations. Because these waveforms result in biometric
and mood responses that are different than those achieved using
traditional neurostimulation waveforms, a health professional or
patient can stimulate a particular response or produce an enhanced
effect using a single device.
[0458] These new non-invasive neurostimulation protocols with
resulting unique and improved physiological responses provide major
advantages over using multiple different devices, different body
placement designs, and/or surgical implantation to achieve
different neuromodulation goals. Different neuromodulation goals
include: increasing or decreasing alertness versus fatigue and
sleepiness; decreasing tension and stress more quickly and to a
greater degree; enhancing resilience and recovery from stress
events; vibrating tissues and interrelated nerve systems in a
particular body location; affecting emotional states such as
arousal, enjoyment, hunger, anger, mood, depression, and alertness;
and resulting body states of fight/flight versus
calm/rest/digest.
B. Stimulation Targets
[0459] The devices and methods described herein may be used for
providing mechanical stimulation that elicits a response from a
variety of nerve, mechanoreceptor, and protein targets, as well as
for entrainment of brain waves. In particular, characteristics of
mechanical waves produced via the devices and methods described
herein can be tailored to target particular components (e.g.,
nerves, mechanoreceptors, proteins) of biological pathways, or
brain waves types. For example, FIG. 3 shows a table of various
protein, cell, and nerve targets, and associated frequency ranges
to which they respond. Also shown in the table of FIG. 3 are
frequencies associated with different types (theta, alpha, beta,
and gamma) of brain waves. Mechanical stimulation having
frequencies corresponding to these different types of brain waves
can be used to entrain brain waves of a subject.
[0460] i. Nerve Stimulation
[0461] In certain embodiments the systems, methods, and devices
described herein provide for mechanical stimulation of one or more
specific nerves. In certain embodiments, the one or more nerves
include a C-tactile afferent nerve, a vagus nerve and/or a
trigeminal nerve. The one or more nerves may include one or more
of: a peripheral nerve, a vestibular nerve, baroreceptors, a
greater auricular nerve, a lesser occipital nerve, cranial nerve
VII, cranial nerve IX, cranial nerve XI, and cranial nerve XII.
[0462] Nerves may be stimulated via mechanical waves generated by
the systems, methods, and devices described herein in a variety of
manners. For example, in certain cases, mechanical waves applied to
a subject's skin stimulate mechanoreceptors, which, as described
herein, in turn lead to stimulation of one or more nerves. Nerves
may also be stimulated directly via mechanical waves without
necessarily involving mechanoreceptors. In particular, subjecting
free ends of nerves to mechanical stress can stimulate nerves
directly.
[0463] In certain embodiments, the mechanical waves produced by the
systems, methods, and devices described herein are tailored
depending on the particular nerves to be stimulated. For example,
certain mechanical wave signals may be well suited to, and,
accordingly, used for the stimulation of certain nerves, such as a
vagus nerve, and different signals may be used for stimulation of
other nerves. In certain embodiments, the mechanical wave used for
nerve stimulation may also be controlled and tailored based on a
particular mechanisms of nerve stimulation. For example, one type
of mechanical wave may be used for stimulation of nerves using
mechanoreceptors, while another type may selectively target and/or
be optimized for direct stimulation of nerve free ends.
[0464] In certain embodiments, as shown in the table of FIG. 3,
different nerves may respond to different frequency ranges. For
example, the Vagus nerve may be targeted via stimulation having a
frequency ranging from approximately 20 to 200 Hz (e.g., 50 to 200
Hz; e.g., 100 to 200 Hz; e.g., 130 to 180 Hz), while a C-tactile
afferent may be targeted via stimulation having a frequency less
than or approximately equal to 50 Hz.
[0465] ii. Mechanoreceptor Stimulation
[0466] In certain embodiments, the systems, methods, and devices
described herein provide for stimulation of non-nerve targets such
as mechanoreceptors (e.g., Merkel cells; e.g., baroreceptors),
tissue regions, and vascular targets (e.g., a carotid artery).
Stimulation of mechanoreceptors, tissue regions, and vascular
targets may provide health benefits without necessarily requiring
nerve stimulation (although nerves may still be stimulated). In
certain embodiments, as with various different nerves, the systems,
methods, and devices described herein utilize mechanical waves that
are selectively tailored depending on the particular non-nerve
target to be stimulated.
[0467] For example, as shown in the table of FIG. 3, Merkel cells
respond to frequencies ranging from 5 to 15 Hz. Accordingly, in
certain embodiments, mechanical stimulation having a frequency
ranging from 5 to 15 Hz may be used for stimulation of Merkel
cells.
[0468] iii. Piezo Protein Stimulation
[0469] In certain embodiments, the systems, methods, and devices
described herein provide for stimulation of piezo proteins.
Specific mechanical waves may be produced by the systems, methods,
and devices described herein to target/optimally stimulate various
piezo proteins (e.g., Piezo1; e.g., Piezo2).
[0470] For example, constant stimulus of sensory receptors can
produce desensitization, and Piezo1 and Piezo2 desensitize, ceasing
to promote cation current, with different voltage-dependent time
constants (Wu, 2017). Following complete desensitization, an
inactivation mechanism operates such that the ion channel cannot be
efficiently opened without first returning the initial stimulus to
baseline for a recovery period (Gottlieb, 2012). For both Piezo1
and Piezo2, the recovery period required before fully responding to
a new stimulus is on the order of hundreds of milliseconds to
seconds (Coste, 2012). Accordingly, in certain embodiments, the
devices, systems, and methods described herein may generate and
deliver mechanical waves that are tailored (e.g., having particular
frequency components) to couple with these sensitization and
inactivation time constants, thereby producing preferred modes of
stimulation.
[0471] For example, as shown in the table of FIG. 3, Piezo2
proteins respond to frequencies below 100 Hz and have a refractory
range of approximately 2 seconds. Accordingly, mechanical waves
having frequency components below 100 Hz may be used for
stimulation of Piezo2 proteins. Mechanical waves, such as
isochronic signals as described herein, may also be tailored to
accommodate the refractory range (e.g., recovery period) of Piezo2
proteins. In particular, isochronic signals have one or more
low-amplitude sub-intervals, the duration of which can be selected
to accommodate the recovery period Piezo2 proteins. For example,
the isochronic signal shown in FIG. 4 is a periodic signal having
low-amplitude sub-intervals lasting 2 seconds, during which the
signal has substantially zero amplitude (e.g., it is effectively
`turned off`). Accordingly, such a signal allows for recovery of
the Piezo2 proteins before amplitude of the signal is increased
(e.g., `turned on`) and stimulus is again applied. Other isochronic
signals incorporating low-amplitude sub-intervals that accommodate
recovery periods of Piezo2 proteins may also be used. Low-amplitude
sub-intervals of isochronic signals may be analogously tailored for
recovery periods of other biological targets, such as Piezo1
proteins and other biological targets.
[0472] iv. Dynamical Systems Approaches
[0473] In certain embodiments, the mechanical waves produced by the
systems, methods, and devices described herein are controlled using
dynamical systems methods. Dynamical systems measures may be used
to assess electronic response signals (e.g., electronic) to detect
particular network responses correlated with changes in mechanical
wave properties. Particular waveforms of the electronic drive
signal are controlled based on the dynamical properties of the
electronic response signal such that the mechanical waves delivered
to the body location of the subject are modulated to
target/optimally enhance particular preferred responses. A block
flow diagram of an example process for using a dynamical systems
method for tailoring mechanical waves generated and delivered by
the approaches described herein is shown in FIG. 14C.
[0474] v. Brain Wave Entrainment
[0475] In certain embodiments, the mechanical waves produced by the
systems, methods, and devices described herein are tailored for
entrainment of brain waves. The table in FIG. 3 lists four types of
brain waves and their corresponding frequencies. As shown in the
table of FIG. 3, theta waves are associated with frequencies
ranging from approximately 4 to 8 Hz, alpha waves are associated
with frequencies ranging from approximately 8 to 16 Hz, beta waves
are associated with frequencies ranging from approximately 16 to 30
Hz, and gamma waves are associated with frequencies ranging from
approximately 30 to 60 Hz. Frequencies of the mechanical
stimulation provided by the devices, systems, and methods described
herein can be selected to fall within a range associated with a
particular type of brain wave. In certain embodiments, by providing
mechanical stimulation corresponding to a particular brainwave type
in this manner, the particular brainwave type corresponding to the
provided mechanical stimulation is induced in the subject.
C. Stimulation Device
[0476] As described herein, a stimulation (e.g., a
neurostimulation) device may be used to generate a mechanical wave
and deliver it to a subject in order to stimulate nerves and/or
targets such as mechanoreceptors, mechanosensitive proteins, tissue
regions, and vascular targets. FIG. 5 shows a schematic of an
example stimulation device 500. The stimulation device comprises
one or more mechanical transducers 504, one or more controller
boards 502, and a battery 506. The controller board(s) 502,
mechanical transducer(s) 504, and battery 506 are in communication
(e.g., through one or more connectors; e.g., wirelessly). The
controller board(s) 502 control(s) a waveform output that is
applied to the transducer(s) 504 in order to generate a mechanical
wave. The waveform output is an electronic signal that drives the
transducer(s), which, in response, generate a mechanical wave. The
mechanical wave can then be delivered to the subject, for example
by placing the transducers in contact with the subject's skin at
various body locations, in order to stimulate various nerves and/or
other targets via mechanical vibration. In certain embodiments, the
stimulation device is a wearable stimulation device. As shown in
FIGS. 6A-6D, in various embodiments of the neuromodulation devices
described herein, multiple mechanical transducers may be used and
controlled via one or more controller boards. Approaches and device
designs utilizing multiple mechanical transducers are described in
further detail below (in section C.iii).
[0477] In certain embodiments, the controller board(s) is/are in
communication with an external computing device, such as a personal
computing device (e.g., a personal computer; e.g.; a smartphone;
e.g., a laptop computer; e.g., a tablet computer; e.g., a
smartwatch; e.g., a fitness tracker), such that the waveform output
may be controlled via the external device. For example, a user may
use a smartphone to control the waveform output by sending a
wireless signal from the smartphone to the controller board(s) of
the stimulation device. In certain embodiments, the device
comprises various buttons, dials, and the like that are connected
to and/or in communication with the controller board(s) and which
may be adjusted to control the waveform output.
[0478] FIG. 7 shows an example process 700 for providing mechanical
stimulation to a subject (e.g., for treatment) using the devices
described herein. In process 700, transducers of the device are
contacted to the subject 702, a waveform output signal is generated
704 and used to activate the transducers 706 in order to deliver
mechanical stimulation to the subject. The delivered mechanical
stimulation may stimulate one or more nerves 708a and/or one or
more mechanoreceptors 708b of the subject.
[0479] FIGS. 8A-8D, 9-13 and 14A-14C also show example processes
for providing mechanical stimulation to a subject (e.g., for
treatment) based on various waveform types, target regions of a
subject's body, stimulation protocols, and the like. For example,
FIG. 8A shows an example process 800a for providing mechanical
stimulation to a subject using an isochronic waveform. FIG. 8B
shows an example process for providing mechanical stimulation to a
body location of a subject in proximity to a mastoid region. FIG.
8C shows an example process for delivering mechanical stimulation
to stimulate a cranial nerve of a subject. FIG. 8D shows an example
process 800d for stimulating one or more nerves and/or
mechanoreceptors of a subject using a waveform comprising a
frequency component ranging from approximately 5 to 15 Hz. FIGS. 9
and 10 show an example processes 900 and 1000, respectively, for
controlling a waveform of an electronic drive signal used to drive
a mechanical transducer in an interactive fashion (e.g., based on a
response signal providing biofeedback data for a subject,
initialization data, user feedback, and the like). FIG. 11 shows an
example process 1100 for providing mechanical stimulation in via
the devices and methods described herein in combination with
therapy. FIGS. 12 and 13 show example processes, 1200 and 1300,
respectively, for providing mechanical stimulation in the form of
binaural and monaural beats. FIG. 14A shows an example process
1400a for providing mechanical stimulation using a transformed time
varying wave. FIG. 14B shows an example process for providing
mechanical stimulation via a waveform comprising a frequency
component ranging from approximately 18 Hz to approximately 48 Hz.
Further details of these example processes are described herein.
FIG. 14C shows an example process using dynamical systems
approaches. Elements and features of any of the processes shown
these Figures, or others, and described herein can be combined with
other processes shown in the Figures and/or described herein, as
well as other approaches.
[0480] As described herein (e.g., above), the mechanical vibration
delivered to the subject can be tailored depending on the
particular target. In certain embodiments, the controller board
controls the waveform output in order to adjust the waveform output
and, in turn the generated mechanical wave accordingly. The manner
in which the waveform output is adjusted may account for a
particular response function of the transducers such that the
mechanical wave has a desired form.
[0481] i. Mechanical Transducers
[0482] Various transducers can be used to generate a mechanical
wave in response to an electronic drive signal, and deliver it to a
subject. Examples of such mechanical transducers include, without
limitation, piezoelectric, magnetic, and mechanoelectric
transducers. Transducer size may be varied, along with amplitude of
the mechanical wave, as well as the direction of the mechanical
force of the wave. For example, longitudinal (e.g., compression)
waves may be generated or transverse (e.g., shear) waves may be
generated.
[0483] Various other transducers may also be used. Different
transducers have different characteristics, such as operational
principle, frequency range, voltage, and area. A particular
transducer may be advantageous for a particular treatment
application based on its particular characteristics, and
accordingly be selected for use in a device for that particular
treatment application. For example, a linear transducer (e.g., a
linear resonance transducer) that operates over a wide frequency
range may be used. Movement of a vibrating element used to produce
a mechanical wave in a linear transducer, and, accordingly,
produces a longitudinal (e.g., compression) wave when placed in
contact with a body location on the subject. It has been discovered
that such linear motion is advantageous for stimulating certain
mechanoreceptors, such as Merkel cells.
[0484] The transducers can include adhesives for contacting to the
skin. The adhesives may be biocompatible adhesives. The transducers
may be embedded within an adhesive or surrounded by the
adhesive.
[0485] The device may also include ergonomic support components
within which and/or on which the transducers are housed and/or
mounted, respectively.
[0486] Such adhesives and/or ergonomic support components allow the
transducers to be placed in contact with a variety of body
locations on the subject, such that mechanical waves can be
delivered to desired locations accordingly.
[0487] For example, in certain embodiments, the transducers are
placed in proximity to a mastoid region. Transcutaneous
mechanostimulation in the mastoid region presents three primary
nervous system targets: the great auricular nerve, composed of
branches of spinal nerves C2 and C3, the trigeminal nerve, and the
auricular branch of the vagus nerve. The innervation of the mastoid
region is closely linked with that of the outer ear, which offers
another region for stimulation. The innervation of the auricle is
characterized by a great deal of overlap between multiple cranial
and spinal nerves. Innervations of at least four nerves supply the
anterior auricle: the auriculotemporal nerve, the ABVN, the lesser
occipital nerve, and the greater auricular nerve (He, 2012). All of
these nerves and their associated networks can be affected by
auricular mechanostimulation. Thus, due to the physical properties
of mechanical vibration, stimulation is able to propagate beyond
the target location the ABVN and trigeminal nerve but potentially
the greater auricular nerve as well as cranial nerves VII, IX, XI,
and XII, and the lesser occipital nerve.
[0488] For example, FIG. 8B shows an example process 800b for
providing mechanical stimulation by placing transducers in
proximity to a mastoid of a subject. As shown, an electronic drive
signal may be applied to a mechanical transducer to generate a
mechanical wave 802. As described herein, a waveform of the
electronic drive signal may be controlled, for example to produce a
desired response, and based on the particular location target
(e.g., the mastoid) 804. The mechanical wave is delivered to a body
location of a subject that is in proximity to (e.g., directly
above) a mastoid of the subject 806b, thereby providing mechanical
stimulation to the subject.
[0489] FIG. 8C shows an example process 800c for stimulating
cranial nerves of a subject 808c. Cranial nerves of a subject may
be stimulated by delivering a mechanical wave to a body location of
the subject in proximity to a mastoid, as in process 800b. Cranial
nerves of a subject may also be stimulated by delivering a
mechanical wave to other body locations of the subject.
[0490] ii. Coordinating Multiple Transducers in Transducer
Arrays
[0491] In certain embodiments, the devices and methods described
herein may utilize multiple mechanical transducers, arranged in one
or more transducer arrays. Combining multiple transducers in a
transducer array, and controlling their output in a synchronized
fashion provides an additional mechanism for tailoring delivery of
mechanical stimulation to a subject in order to produce a desired
response. In certain embodiments, various tactile sensations can be
mimicked by combining multiple transducers in transducer arrays.
For example in order to mimic a stroking motion, transducers can be
spaced along a straight or curved line segment and triggered in a
sequential fashion. Producing mechanical vibration that mimics a
stroking motion can be particularly useful for simulating affective
touch and producing a relaxed feeling in a subject and/or managing
anxiety and related disorders.
[0492] The transducers in a transducer array may be triggered in a
synchronized fashion such that each mechanical transducer begins
and/or ends producing mechanical vibration at a particular delay
with respect to each other. The transducers in a transducer array
may also be controlled so as to deliver different frequencies of
mechanical vibration (e.g., by controlling electric drive signal
waveforms used to drive each transducer).
[0493] Multiple transducers in a transducer array can be connected
and controlled via one or more controller boards in a number of
different manners, several embodiments of which are shown in FIGS.
6A-6D.
[0494] For example, if the waveform and frequency used to drive
each transducer in the transducer array is the same, then the
transducers can be connected in series and the waveform sent to
them at the same time by a single controller board. FIG. 6A
illustrates such an embodiment, wherein an array of multiple
transducers is connected to a single controller board. The
particular arrangement and connection path may be varied and
optimized to reduce/minimize noise, particularly when transducers
of different sizes are used in a single transducer array, as shown
in FIG. 6B. If the waveform and frequency of the electronic signal
used to drive each transducer is the same, transducers of an array
may be connected in series.
[0495] In embodiments wherein different transducers are driven by
different waveforms and/or frequencies, multiple controller boards
may be used (e.g., a particular controller board for each
waveform/frequency, the particular controller board connected to
one or more transducers), for example as shown in FIG. 6C. The
controller boards can be connected to a master controller board
that manages synchronization of the timing at which the various
different waveforms are delivered to the mechanical transducers of
the transducer array. For example, the master controller board may
comprise a timer to ensure that waveforms are sent at an
appropriate time. The timer can be built in or external.
[0496] In certain embodiments, just as the connection path for
transducers of different sizes driven by a single
waveform/frequency can be optimized to reduce/minimize noise (e.g.,
as described above with regard to FIG. 6B), the connection path
used to connect multiple controller boards to a master controller
can also be optimized to reduce/minimize signal noise when driving
different transducers with different waveforms and/or frequencies
(see FIG. 6D).
[0497] iii. Additional Components
[0498] The device can be stand-alone, combined with a mobile device
or computer app, employ headphones (e.g., over-the-ear headphones;
e.g., in-ear headphones) or a device which can modulate the
pressure of the transducer contact on the skin surface, thus
allowing for control of the transmission of the mechanical
stimulation into the body.
[0499] The device may coordinate with an external signal (e.g.,
from a wearable fitness or biometric monitor etc.).
[0500] The device may coordinate with external stimuli, and or
coaching (e.g., via an app) without the use of a control signal. In
this case, for example, a pre-set stimulation routine may deliver
stimulation in synchronization with external stimuli and/or
coaching. For example, a breath coaching app may be used so that
the user controls their breathing to breath at a specific cadence,
and the device may deliver synchronized mechanical stimulation.
D. Waveforms for Mechanical Stimulation
[0501] A variety of waveforms may be used to generate the
mechanical stimulation used in the approaches and in the devices
described herein. In certain embodiments, various waveforms may be
tailored to produce a particular desired response in a subject. For
example, as described above, and in further detail below, an
isochronic waveform, such as the waveform shown in FIG. 4, may be
used to reduce stress and/or treat anxiety and related disorders in
a subject. Examples of various waveforms are also shown in FIGS.
15A-15E, FIGS. 16A and 16B, FIGS. 17A and 17B, and FIGS.
18A-18H.
[0502] FIGS. 15A-15E show examples of transformed time-varying
waves (TTVWs), including examples of carrier and envelope
waveforms, wherein a TTVW may be used as a carrier and/or an
envelope, described further herein. FIGS. 16A and 16B show examples
of sine waves modulated by an envelope function. FIGS. 17A and 17B
show examples of stochastic resonance signals. Various additional
examples of waveforms are shown in FIGS. 18A-18H.
[0503] FIG. 19 shows a block flow diagram illustrating a general
approach for building different waveforms, and how various
characteristics of waveforms can be mixed and/or combined.
[0504] i. Isochronic Signals
[0505] In certain embodiments, an isochronic wave is used for
mechanical stimulation of a subject. As described herein,
isochronic waves include one or more low-amplitude sub-intervals,
over which an amplitude of the isochronic wave is substantially
less than its amplitude at other times. The low-amplitude
sub-intervals can be used to accommodate recovery periods of
particular biological targets, for example as described herein with
regard to Piezo2 proteins. FIG. 4 shows an example isochronic wave
used for targeting Piezo2 proteins and Merkel Cells. The example
isochronic wave shown in FIG. 4 corresponds to a periodic carrier
wave that is modulated by a square wave envelope. The periodic
carrier wave is a sine wave, having a frequency of 10 Hz. The 10 Hz
frequency is selected to fall within the 5-15 Hz range to which
Merkel cells respond, as shown in FIG. 3. The square wave envelope
has a 0.5 Hz frequency, which produces periodic low-amplitude
sub-intervals lasting two seconds, which correspond to a recovery
period of Piezo2 proteins. Such an isochronic wave can be used as
an electronic drive signal that, when applied to a mechanical
transducer, generates a substantially similar mechanical wave that
includes frequency components tailored to the response frequencies
of Merkel cells, as well low-amplitude sub-intervals--periods where
little to no stimulation is applied that accommodate recovery
periods of Piezo2 proteins. In this manner, stimulation can be
designed to account for various biological targets that are part of
a particular stimulation pathway.
[0506] Other isochronic signals may also be used. For example,
other types of periodic and non-periodic carrier waves and
envelopes described herein may be used. In certain embodiments, an
isochronic signal also comprising a TTVW is used. The TTVW may be
the carrier wave and/or the envelope.
[0507] FIG. 8A shows an example process 800a for providing
mechanical stimulation using an isochronic wave. As shown in FIG.
8A, a waveform of an electronic drive signal is controlled 804,
such that the electronic drive signal's waveform is an isochronic
wave 804a. The mechanical wave generated by applying the electronic
drive signal is delivered to a body location (not necessarily a
mastoid) of the subject 806, thereby providing mechanical
stimulation.
[0508] FIG. 8D shows an example process 800d for providing
mechanical stimulation using electronic drive signals having
waveforms comprising frequency components ranging from 5 to 15 Hz
(804d) in accordance with the frequency range to which Piezo
proteins are believed to respond, as described herein. In certain
embodiments, frequency ranges within this interval, such as
frequencies between 7 and 13 Hz, may be used so provide mechanical
stimulation having a frequency matching that of alpha brain waves.
Mechanical waves produced in this manner and delivered to a body
location of a subject can be used to stimulate nerves and/or
mechanoreceptors of the subject 808d.
[0509] ii. Interactive Stimulation
[0510] As described herein, in certain embodiments, waveforms may
be varied and controlled in an interactive fashion, for example by
a user (e.g., through an app in communication with the devices
described herein) or in response to received feedback and
physiological signals from the user.
[0511] FIG. 9 shows an example process 900 for providing
interactive mechanical stimulation to a subject in response to
received feedback in the form of an electronic response signal. In
process 900, a mechanical wave is generated by a mechanical
transducer using an electronic drive signal 902. An electronic
response signal from a monitoring device (e.g., a wearable
monitoring device; e.g., a personal computing device; e.g., a
fitness tracker; e.g., a heart-rate monitor; e.g., an
electrocardiograph (EKG) monitor; e.g., an electroencephalography
(EEG) monitor) operable to monitor one or more physiological
signals from the subject is received (e.g., directly from and/or to
the monitoring device; e.g., via one or more intermediate server(s)
and/or computing device(s)) 903. A waveform of the electronic drive
signal is controlled based on the electronic response signal 904
such that the mechanical wave delivered to the body location of the
subject 906 is modulated accordingly, reflecting the received
feedback. Accordingly, the systems, methods, and devices described
herein provide for adjustment and/or selection of a particular
waveform, tailored to a particular subject, based on received
feedback corresponding to subject biometrics such as blood-pressure
(BP), heart rate variability (HRV), galvanic skin response (GSR),
EEG signal, and the like.
[0512] FIG. 20 shows flow diagram for personalization of a
waveform. As shown in FIG. 20, physiological signals (e.g., subject
biometrics) such as accelerometer data (e.g., to measure activity
levels), HRV, and GSR can be used to adjust and/or select a
particular waveform, tailoring to a user. As shown in the Figure,
such physiological signals can be measured during and/or after
providing mechanical stimulation to a subject, for example to
evaluate the subject's response to the mechanical stimulation.
Based on the measured physiological signals, the waveform can be
adjusted (e.g. to improve efficacy and/or produce a particular
response in the subject). Other physiological signals may be
recorded via sensors such as a blood pressure (BP) monitor and EEG
monitor.
[0513] For example, FIG. 21 shows characteristics of various
physiological signals associated with relaxation and focused states
of a subject. As shown in FIG. 21, in a state of relaxation EEG
measurements indicate decreased theta and beta waves and increased
alpha waves in a subject. BP and HRV measurements show decreases in
BP and increases in HRV, respectively. Accordingly, to produce a
relaxation state in a subject undergoing mechanical stimulation,
physiological signals, such as various brain waves (e.g., as
measured via EEG), BP, and HRV, can be monitored for the subject,
and waveform characteristics can be modified to produce brain wave,
BP, and HRV characteristics that are associated with the relaxation
state, such as those shown in FIG. 21.
[0514] Other states in a subject can be produced by modifying a
waveform to produce that state. For example, as shown in FIG. 21, a
focused state is associated with decreased theta waves, neutral
alpha waves, increased beta waves, increased BP, and increased
HRV.
[0515] One or more of the characteristics, such as those shown in
FIG. 21, can be targeted in this manner, via monitoring of one or
more corresponding physiological signals, to produce a desired
state in a subject.
[0516] Feedback regarding the effects of mechanical stimulation may
also be obtained, and used for modification and tailoring of
waveforms, via other approaches. For example, as illustrated in
FIG. 20, subject feedback in a form of written or entered data may
be obtained and used to update a waveform used for providing
mechanical stimulation. For example, following receipt of a round
of mechanical stimulation, a subject may take a survey to assess
their response to the round of mechanical stimulation. The subject
may enter their survey responses themselves, for example via a
mobile computing device, an app, an online portal, and the like.
Subject feedback data may also be provided by a therapist/physician
treating the subject. Such feedback may then be evaluated, for
example processed via a mobile computing device or intermediate
server in communication with the stimulation device, and used to
update waveform characteristics. This approach, of subjecting a
subject to a round of stimulation, receiving and assessing
feedback, and updating a waveform accordingly, may be repeated for
multiple rounds of treatment using the stimulation.
[0517] Waveform characteristics may also be tailored prior to
providing stimulation to a subject, using initialization setting
data. For example, a subject may provide data relating to their
age, height, weight, gender, body-mass index (BMI), and the like,
activity levels, such as physical activity levels, or results of a
preliminary survey (e.g., entered by the subject themselves, e.g.,
via a mobile computing device, an app, and/or online portal; e.g.,
provided by a therapist/physician treating the subject for a
disorder). Based on such initialization settings data, an initial
waveform may be selected and/or tailored for the subject.
[0518] FIG. 10 shows an example process 1000 for treating a subject
using feedback and/or initialization settings data. In the example
process 1000, a mechanical wave is generated via a mechanical
transducer 1002, subject feedback and/or initialization data is
received and/or accessed 1003, and a waveform of an electronic
drive signal used to drive the mechanical transducer and generate
the mechanical waves is controlled based on the received and/or
accessed subject feedback and/or initialization data 1004. The
generated mechanical wave is delivered to a body location of the
subject to provide transcutaneous mechanical stimulation 1006.
[0519] iii. Transformed Time-Varying Waveforms (TTVWs)
[0520] In certain embodiments, a transformed time-varying waveform
(TTVW) is used. FIG. 15A shows an example of a TTVW. The example
TTVW shown in FIG. 15A is a modified version of a sine wave (e.g.,
the base time-varying wave is a sine wave), wherein the peaks of
the sine wave are `clipped` via a linear ramp. Various other
embodiments of TTVWs, as described herein, can be used.
[0521] FIG. 14A shows an example process 1400a for providing
mechanical stimulation using a transformed time varying wave. As
shown in FIG. 14A, a waveform of an electronic drive signal is
controlled 1404, such that the electronic drive signal's waveform
is a transformed time varying wave 1404a. The mechanical wave
generated by applying the electronic drive signal is delivered to a
body location (not necessarily a mastoid) of the subject 1406,
thereby providing mechanical stimulation.
[0522] iv. Frequency Ranges from 18-48 Hz
[0523] In certain embodiments, the waveforms used herein comprise a
frequency component in another frequency range (e.g., not
necessarily the 5-15 Hz range described above for stimulating
affective touch sensations). For example, a frequency component
ranging from 18-48 Hz. Frequency components in this range are also
desirable for stimulation. Notably, brain waves such as beta waves
include components in this frequency range and, accordingly,
waveforms with such frequency components serve as biomimetic
signals. Such frequency components may be used for stimulating
other sensations, either instead of or in addition to the affective
touch sensations described herein.
[0524] FIG. 14B shows an example process 1400b for providing
mechanical stimulation using electronic drive signals having
waveforms comprising frequency components ranging from 18 to 48 Hz
(1404b). Mechanical waves produced in this manner and delivered to
a body location of a subject can be used to stimulate nerves and/or
mechanoreceptors of the subject 1408b.
[0525] v. Carrier and Envelope Waveforms
[0526] In certain embodiments, the waveforms used herein have forms
of a carrier wave modulated by an envelope. FIGS. 16A and 16B show
two examples of such waveforms ("Waveform inside a Pulse", FIG.
16A, and "Modulated Sine Wave", FIG. 16B). Notably, a waveform may
include a TTVW (e.g., such as the modified sine wave of FIG. 15A)
that is a carrier signal, which is modulated by an envelope (e.g.,
a more slowly varying signal) and/or may comprise a TTVW that is an
envelope that modules a more rapidly varying signal. FIG. 15B and
FIG. 15C show examples of a TTVW that is a carrier signal modulated
by an envelope. In particular, FIG. 15B shows an expanded view of a
portion of the waveform such that the linear ramp portions of the
TTVW are visible, and FIG. 15C shows a graph of the same waveform
over a greater time range illustrating the periodic nature of the
example signal. FIG. 15D and FIG. 15E are example waveforms wherein
a TTVW is an envelope that modulates a more rapidly varying
signal.
[0527] In certain embodiments, a frequency of the envelope
corresponds to a breathing rate of a subject (e.g., corresponding
to 6 to 10 breaths per minute; e.g., approximately 0.1 Hz).
[0528] vi. Sub-threshold and Supra-threshold Stimulation
[0529] In certain embodiments, the approaches described herein may
utilize activation thresholds of target cells and/or proteins, such
as mechanoreceptors and/or nerves to set stimulation levels (e.g.,
amplitudes). In particular, stimuli that are of insufficient
magnitude to activate a particular target cell and/or protein and
initiate signaling are referred to as subthreshold, while stimuli
that are above such an activation threshold and, accordingly, are
of sufficient magnitude to activate a particular cell and/or
protein and initiate signaling are referred to as suprathreshold.
In certain embodiments, such activation thresholds correspond to
sensory thresholds, such that suprathreshold stimuli cause a
tactile sensation in the subject, while subthreshold stimuli do
not.
[0530] In certain embodiments, subthreshold and suprathreshold
signals can provide a source of acoustic frequency-range white
noise, pink noise, or noise spectra mimetic of biological noise
sources such as 1/f or shot noise. In certain embodiments,
subthreshold stimuli can be used to elicit stochastic resonance
effects in particular cells and signaling pathways that comprise
them.
[0531] FIGS. 17A and 17B show examples of stochastic resonance
signals. Stochastic noise is the counter-intuitive fact that adding
noise into a modulating system, such as a biological system does
not necessarily mask endoengous signals, but can enhance the signal
so it may be better detected at some threshold (Hanggi 2002). FIG.
17A illustrates addition of stochastic resonance noise, which can
increase signal detection above sensory thresholds and action
potential firing. FIG. 17B shows a sine wave with stochastic
resonance noise added. In certain embodiments, such waveforms
incorporating stochastic resonance signals are used to for
providing mechanical stimulation to a subject.
[0532] vii. Multiple Signals--Binaural and Monaural Beats
[0533] Mechanical stimulation may be provided in a variety of
manners, including in a binaural and/or a monaural fashion. For
example, FIG. 12 shows an example process 1200 for providing
mechanical stimulation in a binaural manner. As shown in FIG. 12, a
first and second electronic drive signal 1201a and 1201b are used
to generate a first 1202a and second 1202b mechanical wave,
respectively. The first mechanical wave is delivered to a first
body location 1206a and the second mechanical wave is delivered to
a second body location 1206b. Waveforms of the first and second
electronic drive signals may be controlled (e.g., separately)
(1204a and 1204b) to produce a desired response. The second
electronic drive signal may be a delayed version of the first
electronic drive signal, or may be a different signal.
[0534] FIG. 13 shows an example process 1300 for providing
mechanical stimulation in a monaural fashion. As shown in FIG. 13,
in process 1300 the same electronic drive signal 1301 is used to
generate two mechanical waves--a first mechanical wave 1302a and a
second mechanical wave 1302b. The first and second mechanical waves
are delivered to first and second body locations (1306a and 1306b).
The electronic drive signal is controlled 1304 to produce desired
first and second mechanical waves and, accordingly, a desired
response.
E. Indications
[0535] The systems, methods, and devices described herein may be
used for a variety of indications. In certain embodiments, the
device is included in a kit, along with a label describing the
indication for which the device is to be used. FIG. 22 shows an
example of a label. Other labels indicating that the device is to
be used for other indications, including, without limitation, any
of the indications described herein, may be including in a kit as
appropriate.
[0536] i. Improved Interoception
[0537] In certain embodiments, the device, systems, and methods
described herein can be used for enhancement of interoception. As
described herein, enhanced interoception can improve a number of
conditions that are related to dysregulated or otherwise impaired
interoception. For example, many contemporary health problems
involve dysregulated interoceptive processes, including affective
disorders, addiction, eating disorders, chronic pain, dissociative
disorders, post-traumatic stress disorder, and somatoform disorders
(Farb, 2015). Accordingly, in certain embodiments, nerve
stimulation using the present device and method provides for
improving resilience to and symptoms of common stress-related
disorders such as insomnia, reduced anxieties including,
performance anxiety, social anxiety and blushing, vertigo,
stress-induced infertility, fear, PTSD, and ADHD. Other benefits
may include enhanced attention and engagement, lower blood
pressure, and reduced blood cortisol levels. Interventions aimed at
enhancing beneficial interoceptive signaling may provide enhanced
quality of life and benefit for a variety of common stress-induced
ailments, and psychiatric conditions such as panic disorder,
depression, withdrawal symptoms of addiction, somatic symptom
disorders, anorexia nervosa, and bulimia nervosa (Khalsa,
2016).
[0538] For example, in certain embodiments, the approaches describe
herein may be used to generate a mechanical wave having a
vibrational waveform selected to improve interoception in a
subject. Such a mechanical wave may be generated by applying an
electronic drive signal to a mechanical transducer, wherein a
waveform of the electronic drive signal comprises (i) an isochronic
signal and/or a TTVW with at least one component designed to
enhance one or more EEG frequency(ies), brain-wave frequencies, and
the like, (ii) a frequency component in the 5 to 15 Hz band, 10 to
48 Hz band, and/or other modulation components. The mechanical wave
may be delivered to the subject by placing the transducer in
proximity to afferent nerve complexes on the head ear or neck.
Stimulation of these complexes and associated pathways and networks
can bring individuals enhanced control over their subjective
responses to internal bodily changes before those changes manifest
behaviorally (panic, depression, rage, etc.).
[0539] In certain embodiments, enhanced interoception can generate
enhanced empathy and sensitivity to others, through neural pathways
directly associated with interoception and found only in higher
social mammals. In another example, improving interoception may
enhance sexual responsiveness in women who engaged in interoceptive
training. Interoceptive sensitizing and training can be assessed by
the concordance between quiet unaided heart-beat counting and
actual heart best over a period. Higher scoring means improving
interoception.
[0540] ii. Promotion of Relaxation and Stress Management
[0541] In certain embodiments, the approaches described herein may
be used to promote relaxation and/or to manage stress. For example,
in certain embodiments, the approaches described herein may be used
to generate a mechanical wave having a vibrational waveform
selected to promote relaxation and/or reduce stress in a subject.
Such a mechanical wave may be generated by applying an electronic
drive signal to a mechanical transducer, wherein a waveform of the
electronic drive signal comprises (i) an isochronic signal and/or a
TTVW with at least one component designed to enhance one or more
EEG frequency(ies), brain-wave frequencies, and the like, (ii) a
frequency component in the 5 to 15 Hz band, 10 to 48 Hz band,
and/or other modulation components. The mechanical wave may be
delivered to the subject by placing the transducer in proximity to
afferent nerve complexes on the head ear or neck. Stimulation of
these complexes and associated pathways and networks can improve
the ability to sense somatic stress and remediate it to create a
more calm and/or focused feeling. In certain embodiments, the
stimulation may include components that generate a soothing
acoustic experience. In certain embodiments, such approaches can
improve and hasten the onset of meditative and/or mindfulness
states and enhance those practices. These effects can be assessed,
for example, via EEG, EKG, pupillometry, blood pressure, heart rate
variability, and other metrics.
[0542] iii. Improvement of Mental Acuity and/or Concentration
[0543] In certain embodiments, the approaches described herein may
be used to improve mental acuity and/or concentration. For example,
in certain embodiments, the approaches describe herein may be used
to generate a mechanical wave having a vibrational waveform
selected to improve mental acuity and/or concentration in a
subject. Such a mechanical wave may be generated by applying an
electronic drive signal to a mechanical transducer, wherein a
waveform of the electronic drive signal comprises (i) an isochronic
signal and/or a TTVW with at least one component designed to
enhance one or more EEG frequency(ies), brain-wave frequencies, and
the like, (ii) a frequency component in the 5 to 15 Hz band, 10 to
48 Hz band, and/or other modulation components. The mechanical wave
may be delivered to the subject by placing the transducer in
proximity to afferent nerve complexes on the head ear or neck of
the subject. Stimulation these complexes and associated pathways
and networks may improve focus, concentration or mental acuity
directly or coupled with the appropriate cognitive, mental or
emotional task or additional stimuli. In certain embodiments, the
mechanical wave stimulation provided by the approaches described
herein facilitates neuroplasticity, which, in the context of
training, can accelerate performance in the targeted domain. In EEG
biometrics as well as objective performance on tasks within the
domain of interest (e.g. concentration, memory, memory
consolidation, working memory) can be used to assess effects.
[0544] iv. Enhanced Learning Capacity and Memory
[0545] In certain embodiments, the approaches described herein can
be used to enhance learning capacity and/or memory in a subject.
For example, in certain embodiments, the approaches describe herein
may be used to generate a mechanical wave having a vibrational
waveform selected to improve enhance learning capacity and/or
memory in the subject. Such a mechanical wave may be generated by
applying an electronic drive signal to a mechanical transducer,
wherein a waveform of the electronic drive signal comprises (i) an
isochronic signal and/or a TTVW with at least one component
designed to enhance one or more EEG frequency(ies), brain-wave
frequencies, and the like, (ii) a frequency component in the 5 to
15 Hz band, 10 to 48 Hz band, and/or other modulation components.
The mechanical wave may be delivered to the subject by placing the
transducer in proximity to afferent nerve complexes on the head ear
or neck. Stimulation of these complexes and associated pathways and
networks can improve rate and depth of learning, either with the
use of the mechanical stimulation alone or in the context of one or
more of (i) specific types of training (e.g. stimulation while
learning a new language, learning a new surgical technique,
learning to assess financial data and markets in real time), (ii)
didactic learning (e.g. in traditional teacher led classrooms or
virtual analogs), (iii) in real-time assessment, situational
awareness, and (iv) a particular environment (e.g. physical,
virtual, etc.). EEG biometrics as well as objective performance on
tasks within a domain of interest (e.g. proficiency at robotic
surgery) can be used to assess effects.
[0546] v. Additional Indications
[0547] In certain embodiments, the approaches described herein may
be used to improve a subject's quality of life when the subject has
a particular conditions. Specific conditions for which the device
may provide for improvements in quality of life through its use
include, without limitation, high blood pressure, tinnitus, and
anxiety.
[0548] In certain embodiments, the approaches described herein may
be used to address a variety of other indications, including,
without limitation, one or more of the following: management of a
social phobia (e.g., reducing negative effects of the social
phobia; e.g., provide relief from the social phobia); reducing
performance anxiety; reducing (e.g., frequency of; e.g., intensity
of) stress-induced headaches; reducing stress-induced infertility;
managing stress-induced high blood pressure; improving peripheral
nerve sensitivity; improving peripheral nerve sensitivity;
improving and/or supporting immune system function; managing
stress-induced anger and/or mood problems; managing stress-induced
sleep problems; reducing stress-induced menstrual cramping;
improving appetite and/or salivation; improving balance; improving
alpha brain waves; enhancing heart rate variability; improving
vagal tone; promoting sleep management; reducing stress induced
ringing in the ears; enhancing sexual function; and enhancing
libido, sexual arousal, and/or orgasm.
[0549] As used herein, stress induced ringing in the ears refers to
a specific sensation of ringing in ears of a subject, which may or
may not physiologically originate (e.g., be produced) in the
subjects ears (e.g., it may originate from a neurological condition
not including nerves in the subject's ears).
F. Treatment of Anxiety Via Mechanical Stimulation
[0550] In certain embodiments, the devices, systems, and methods
described herein are used for treatment of anxiety in a subject. As
described herein, treatment of anxiety related clinical indications
in a subject may be achieved by tailoring mechanical stimulation to
stimulate particular biological targets in order to produce a
particular state in the subject. Treatment efficacy for various
mechanical stimulation types (e.g., different waveforms) can be
validated via EEG and HRV analysis, as well as via measurement of
stress hormone levels in a subject. In certain embodiments, as
described herein, treatment via mechanical stimulation may be
combined with other therapy, such as psychotherapy, exposure
therapy [e.g., for treatment of various phobias (e.g., fear of
heights, fear of public speaking, social phobia, panic attack, fear
of flying, germ phobia, and the like)], cognitive behavioral
therapy (CBT), and acceptance and commitment therapy (ACT).
[0551] i. Signal Design
[0552] Turning to FIG. 23, different types of feelings and states
in a subject may be produced via different types of stimulation. In
particular, stimulus type applied to a body location of a subject
(e.g., at their skin) determines response in the brain. For
example, from the cell membrane through mechanoreceptors, to
associated nerves (e.g., C-tactile afferents), to the brain, there
are endogenous preferences for signals. In certain embodiments,
signals that are most effective at generating relaxation, positive
feelings, and enhancing social interactions are slow and gentle.
For example, a preferred speed of affective touch is approximately
3 centimeters per second (cm/s). For example, a frequency
associated with enhanced social interaction may correspond to a
breathing rate of a subject (e.g., corresponding to 6 to 10 breaths
per minute; e.g., approximately 0.1 Hz)
[0553] Turning to FIG. 24, mechanotransduction, as used herein,
refers to any of various mechanisms by which cells convert
mechanical stimulus into electrochemical activity. Without wishing
to be bound to any particular theory, it is believed that this form
of sensory transduction is responsible for a number of senses and
physiological processes in the body, including proprioception,
touch, balance, and hearing.
[0554] FIG. 24 shows an example mechanotransduction pathway for
stimulating an insula region of a brain of a subject. As shown in
FIG. 24, specialized ion channels--Piezo2 proteins respond to
mechanical stimulation and cause firing of specialized Merkel cells
that stimulate nerves leading up to the insula.
[0555] In certain embodiments, mechanical stimulation can be
tailored to stimulate a particular pathway, such as that shown in
FIG. 24, in order to produce a particular response (e.g., state) in
a subject. FIG. 25 illustrates several stimulation characteristics
that can be tailored according to an understanding of a particular
pathway and mechanism of action for producing a desired response in
a subject. In particular, as described herein, an isochronic wave
having a particular carrier frequency and duration of low-amplitude
sub-intervals was designed to target specific biological targets
that are part of the pathway described in FIG. 24, and produce a
relaxation response and treat anxiety related clinical indications
in a subject.
[0556] In particular, as described herein, for example in section
D.i, an isochronic signal having frequency components falling
within a range of those to which Merkel cells respond, along with
low-amplitude sub-intervals that allow for recovery of Piezo2
proteins was discovered to be effective at producing a relaxation
state in a subject, and, accordingly, for use in treatment of
anxiety. FIG. 4 shows an example of such an isochronic signal.
[0557] FIG. 26 summarizes an embodiment of use of a device for
treatment of anxiety and increasing feelings of calm in a subject.
Transducers of the device are placed in proximity to a mastoid
region, for example, behind an ear of the subject (2602).
Mechanical vibration produced by the transducers of the device
stimulates various receptors (e.g., mechanoreceptors) in the skin
(in particular, in glabrous, hairy skin), as described herein
(2604). While certain mechanoreceptors are not impacted, waveform
and frequency of the mechanical stimulation produced by the
transducers is designed to target receptors involved in afferent
pathways, in particular mechanoreceptors and C-tactile afferents.
Signal may be propagated down unmyelinated and myelinated nerves
(2606). Myelinated signals travel to the somatosensory cortex,
while unmyelinated signals travel to the insular cortex. Slower
nerve fibers (e.g., unmyelinated) stimulate the insula longer than
the myelinated nerves stimulate the somatosensory cortex (2612).
The insular cortex 2614a and somatosensory cortex 2614b are shown
in a side view of the subject's head 2614. Sensations such as fast
touch, pokes, pinpricks, pressure, vibration, and spatial location
are picked up (e.g., stimulate) by the somatosensory cortex (2616),
while the insular cortex is involved in sensations such as deep
pain, temperature, pleasant touch, taste, and emotion (2622).
Moreover, research findings have implicated the insula in an
overwhelming variety of functions ranging from sensory processing
to representing feelings of motion, autonomical and motor control,
risk prediction and decision-making, bodily and self-awareness, and
complex social functions like empathy. Accordingly, by supplying
mechanical vibration that targets pathways that stimulate the
insula, the devices and methods described herein can, in certain
embodiments, provide treatment of anxiety and related disorders
(2624). In certain embodiments, mechanical stimulation provided by
devices and methods as described herein can result in changes in
levels of particular stress-related hormones. For example, by
increasing release of hormones such as oxytocin and serotonin
and/or reducing levels of cortisol, mechanical stimulation can
mitigate anxiety in a subject (2626).
[0558] ii. Validation Results
[0559] Efficacy of mechanical stimulation treatment of anxiety was
evaluated using EEG and HRV measurements and analysis. Turning to
FIG. 27, EEG captures fluctuations of electrical voltage in a
cortex of a subject through electrodes placed on scalp. Power
spectral analysis of EEG data can show changes in EEG frequencies
that may be relevant to physiological activities of the brain. FIG.
28A shows an example of different regions of a brain, identifying
different collections of electrodes associated with each region. As
shown in FIG. 28A, different collections of electrodes are used to
measures signals from a Temporal region of the brain (T--red
contours), a Frontal region (F--green contour), a Central region
(C--cyan contour), a Parietal region (P--purple contour), and an
Occipital region (O--orange contour). FIG. 28B is a set of three
graphs showing changes in absolute power in three different
frequency bands associated with three different types of brain
waves following mechanical stimulation using the isochronic wave
shown in FIG. 4. Each graph corresponds to a particular brain wave
type and shows changes in absolute power measured in each of the
five aforementioned regions of the brain (T, F, C, P, and O). The
left graph shows changes in absolute power of frequencies
associated with theta brain waves, the middle graph shows changes
in absolute power of frequencies associated with alpha brain waves,
and the right graph shows changes in absolute power of frequencies
associated with beta brain waves. The measurements show that alpha
waves were increased in the temporal, occipital, and parietal
regions. As shown in FIG. 21, an increase in alpha waves is
associated with relaxation.
[0560] Turning to FIG. 29 and FIG. 30, coherence analysis of EEG
data was also used for validation of treatment efficacy. Coherence
is a mathematical technique that quantifies frequency and amplitude
of synchronicity of neuronal patterns of oscillating brain
activity. Complex connectivity analysis can be executed to target
interactions between different brain regions. Coherence provides an
understanding of communication (e.g., working together or
independently) between different brain regions. Coherence analysis
tends to be more meaningful when reviewing functional effects. The
coherence data shown in FIG. 30 indicates a high change over the
insula when a subject receives mechanical stimulation produced by
the isochronic wave of FIG. 4.
[0561] FIG. 31 shows a comparison of two mechanical waveforms
tailored for eliciting relaxation in a subject (ISO Sine 10 Hz 60V
and ISO Clipped 10 Hz 60V) in comparison with sham stimulation. The
figure shows response before (bars labelled "B") and after (bars
labelled "A") stimulation for three different types of
stimulation--sham (control), a 10 Hz isochronic sine wave, and a 10
Hz clipped isochronic sine wave. As shown in the Figure, a
significant increase in HRV of the subjects stimulated with the
waveforms relative to those subjected to the sham condition was
observed. Increased HRV has been shown to be a measure of
parasympathetic and vagal tone, the benefits of which include,
without limitation, raising physical recovery, cognitive function,
and relaxation.
[0562] iii. Controlling Stress Hormone Levels
[0563] In certain embodiments, efficacy of anxiety treatment via
mechanical stimulation as described herein can be evaluated via
measurement of stress hormone levels. For example, a level of
cortisol in a subject can be measured following mechanical
stimulation. Stimulation that produces a reduction in cortisol
levels can be used for treatment of anxiety. Other stress hormones
such as oxytocin and serotonin may also be measured. For example,
stimulation that increases levels of oxytocin and serotonin may be
useful for treatment of anxiety.
[0564] In certain embodiments, a length of a telomere of a subject
may also be used as a physical measurement for evaluating efficacy
of anxiety treatment. In particular, without wishing to be bound to
a particular theory, stress is believed to shorten telomeres (see,
e.g., Mathur et al., Perceived stress and telomere length: a
systematic review, meta-analysis, and methodologic considerations
for advancing the field, Brain Behavior, and Immunity, volume 54
(2016), pages 158-159). Accordingly, in certain embodiments, the
systems, devices, and methods described herein may reduce a rate of
shortening of telomeres.
[0565] iv. Case Study Reports
[0566] In one case study, a user that typically experienced
migraine headaches received mechanical stimulation via an
embodiment of the devices described herein. The user reported that
while they were typically woken from sleep with a pounding
headache, following use of the device they woke from sleep early
morning without a pounding headache or any associated nausea. In
another case report, a user reported a lack of anxiety in a
situation that typically provoked anxiety for them with use of a
device as described herein. In particular, the user reported a
feeling similar to use of propranolol.
[0567] v. Combined Therapy
[0568] In certain embodiments, the mechanical stimulation
approaches described herein may be combined with a therapy, such as
such as psychotherapy, exposure therapy [e.g., for treatment of
various phobias (e.g., fear of heights, fear of public speaking,
social phobia, panic attack, fear of flying, germ phobia, and the
like)], cognitive behavioral therapy (CBT), and acceptance and
commitment therapy (ACT). Treating psychological disorders with
psychotherapeutic, cognitive, and/or behavioral interventions (of
which there are many types) often include developing behavioral and
cognitive techniques to alter maladaptive responses. Development of
those techniques includes recognizing one's own visceral or
emotional responses and acting to mitigate the sequence of events
that leads to the maladaptive outcome. In certain embodiments, the
devices, systems, and methods described herein enhance EEG activity
associated with neural circuits and brain areas associated with
evaluating internal bodily responses and integrating those with
external stimuli. Combining mechanical stimulation at the time of
therapy, and/or when practice techniques and/or when in a situation
or environment that can provoke symptoms may improve and/or
accelerate the individual's ability to successfully apply
therapeutic insights. This form of mechanical stimulation can
stimulate neural circuits associated with processing of internal,
visceral sensations, improving an individual's ability to respond
and more effectively manage maladaptive responses. In practice,
individuals may be wearing and using the stimulation immediately
prior to, during, or immediately after a therapeutic session. They
may also use stimulation when they are practicing techniques to
reduce maladaptive responses outside of therapy. They may also use
stimulation before, during, or after exposure to some stimulus
(such as flooding for phobias) that produces or situation (like
public speaking) a maladaptive response.
G. Physical Embodiments
[0569] FIG. 32A depicts one embodiment of a transcutaneous
neuromodulation device 3200 that includes two separate ergonomic
support components 3208a, 3208b (generally, 3208); however, in some
applications, the transcutaneous neuromodulation device 3200
includes only a single ergonomic support component 3208. In some
embodiments, the transcutaneous neuromodulation device 3200
includes two ergonomic support components 3208, but only one may
need to be used to suit a particular application.
[0570] As shown in FIG. 32A, each ergonomic support component 3208
includes an elastomeric arm 3220a, 3220b (generally 3220), or
similar structure for comfortably engaging with a portion of a
human subject 3212. For example, in the embodiment shown, the
elastomeric arm 3220 is configured to "hug" or otherwise engage the
subject's ear (see, e.g., 3214a in FIG. 32D). In some embodiments,
the entire device can be fully supported by the subject's ear via
the ergonomic support component.
[0571] Each ergonomic support component comprises a housing 3226a,
3226b (generally 3226) for supporting and/or enclosing at least one
mechanical transducer. The housings 3226 may also support and/or
enclose other components, such as at least one controller board,
and at least one battery or other power source (e.g., a
photovoltaic cell), as shown in greater detail in FIGS. 34A and
34B, and described in further detail herein. In certain
embodiments, controller boards and batteries or other power sources
are not enclosed within or supported by the housing, but rather
within other portions of the ergonomic support component(s) 3208,
for example within the elastomeric arms 3220. The housing(s) 3226
is/are positioned within the ergonomic support component(s) 3208
such that when the ergonomic support component(s) are worn by a
human subject, the mechanical transducer(s) within the housing are
positioned in proximity to a specific desired body location on the
subject, such as a mastoid region. Accordingly, in this manner,
mechanical vibration produced by the mechanical transducers is
delivered to the specific desired body location.
[0572] In certain embodiments, each housing 3326 comprises a
window, adjacent to which the mechanical transducers are disposed,
and which contacts skin (or other surface) of the subject when the
ergonomic support component(s) is/are worn. The window (along with
other portions of the housing) may include and be covered with
insulating material and/or a tactile fabric so as to prevent direct
contact between the transducer surface and skin of the subject. The
tactile fabric may be selected to provide a specific sensation
(e.g., to mimic touch), and thereby enhance the treatment delivered
by the mechanical transducer.
[0573] The housing 3226 can also support or include a variety of
sensors 3216, controls (e.g., on/off button, indicator light),
and/or other interface components (e.g., an external communication
interface 3228 (e.g., for charging the device; e.g., for
transferring data to and/or from the device)). In various
embodiments, at least a portion of each ergonomic support component
3208 can be covered in a conductive fabric or other material that
allows the subject 3212 to interface/control the device 3220.
[0574] FIG. 32B depicts a perspective view of the device of FIG.
32A. An external communication interface 3228 disposed at a distal
end of the elastomeric arm 3220, at least one sensor 3216 are all
shown in FIG. 32B.
[0575] The sensor(s) 3216 can be mounted within the housing or
disposed on an exterior surface thereof, depending on the type of
sensor and characteristic to be measured. Typically, the sensor(s)
will be monitoring at least one biometric identifier of the human
subject 3212, such as galvanic skin response (GSR), pulse, blood
pressure (BP), oxygen levels, temperature, or electrical signals
(e.g., EEG and EKG). In some embodiments, the sensors include an
accelerometer, a pressure transducer for BP, and a conductance
sensor for GSR. The sensor(s) can be in communication with the
controller so as to provide a signal representative of the
biometric identifier (i.e., biofeedback) that the controller
board(s) can use to modify a treatment protocol as needed. In some
embodiments, the waveform can be adjusted based on user feedback,
statistical data, or via machine learning (e.g., artificial
intelligence (AI)).
[0576] External communication port 3228 can include an interface
for use with a wireless or inductive charger or could include a
port configured to receive a power cord, for example, a USB port.
As can be seen in FIGS. 32A and 32B, the two ergonomic support
components 3208 are wireless. In an application where both
components 3208 are used, the devices can communicate via
Bluetooth.RTM., near-field magnetic induction (NFMI), or similar
technology. The components 3208, can communicate wirelessly with
one or more peripheral devices, such as a smart phone or watch, a
Fitbit.RTM. or similar device, a heart rate monitor, a blood
pressure monitor, or a personal computer. In some embodiments, the
device 3200 may be connected to other devices via a cord.
[0577] For example, in various embodiments, the two ergonomic
support components 3208 are wirelessly synchronized to deliver a
coordinated waveform output; however, not necessarily the same
waveform. For example, in some embodiments, each wearable component
may deliver the same waveform, but in other embodiments, the
wearable components 3208 deliver different, but coordinated
waveforms to suit a particular application. In some embodiments,
the interface components communicate via NFMI. Communication via
NFMI may be advantageous since magnetic field based signals are
less likely to be blocked (e.g., scattered and/or attenuated) by a
subject's head.
[0578] FIG. 32C depicts the various ways a subject can control the
transcutaneous neuromodulation device 3200. For example, the
elastomeric arm 3220 can be covered in a conductive fabric or other
material that is responsive to human touch. As shown in FIG. 32C,
it is possible to turn the device on by touching a specific
location (e.g., a logo) on the device (3250a), adjust the intensity
of the device output by a swiping motion across the arm (3250b),
tap the arm to pause the device (3250c), and double tap to perform
other functions, such as extending a treatment session (3250d).
[0579] FIG. 32D depicts an embodiment of the transcutaneous
neuromodulation device wherein the ergonomic support component 3208
is secured around the subject's ear 3214a. However, in other
embodiments, the ergonomic support component 3208 can be placed on
the human subject's neck 3214b, back of neck 3214c, skull 3214d,
temples 3214e, face 3214f, or arms (not shown) depending on a
specific treatment protocol. In a particular embodiment, the device
3200 is placed on the human subject 3212 to maintain the mechanical
transducer substantially proximate the subject's mastoid region
3214g. In some embodiments, the elastomeric arm 3220 has a wire
frame core that allows the arm 3220 to be shaped to optimize the
fit of the ergonomic support component 3208 to the subject 3212 and
to best position the transducer housing 3226 relative to the
desired treatment area of the subject 3212. In some embodiments,
the frame is made of aluminum wire and covered with a plastic resin
to form the arm 3220. In some embodiments, the elastomeric arm
includes a resilient material, such that the arm provides a
pressing force to hold the transducer against the subject's mastoid
or other body part. In some embodiments, the arm 3220 can also be
covered in a fabric, such as a conductive, tactile, or haptic
fabric to enhance the subject's experience.
[0580] Referring back to FIGS. 32A and 32B, the transducer housing
3226 can generally be disposed anywhere on the ergonomic support
component; however, in most embodiments, the transducer housing
3226 will be disposed proximate a distal end of the elongate arm,
so as to eliminate or reduce any structural resistance (e.g.,
dampening) of the vibrations. Specifically, the elongate arm acts
like a cantilever beam and it is desirable for the transducer to
operate as close as possible in a free vibration state, such that
the desired treatment is delivered to the subject.
[0581] Referring now to FIGS. 34A and 34B, one possible mounting
arrangement for the transducer(s) 3404 is shown. Generally, the at
least one mechanical transducer should be mounted in an essentially
intrinsically safe manner, such that the subject is shielded from
electrical shocks or the transfer of excessive heat. For example,
the electrical connections between the battery (or other electrical
components) and the transducer (e.g., solder joints) can be located
within the housing, with the transducer disposed on an exterior
surface of the housing and any wires extending therebetween being
insulated, potted, or otherwise shielded. In some embodiments, the
at least one mechanical transducer itself is encased in an
insulated material to prevent direct contact with the human
subject. In various embodiments, the mechanical transducers can be
covered in a polymeric material, wrapped in a fabric, or encased in
an adhesive compound.
[0582] As shown in FIG. 34A, the controller 3402, battery 3406, and
transducer 3404 are all disposed within the housing 3426 adjacent
in an opening or window in the housing 3426. The housing 3426 may
comprise an injection molded casing; however, other configurations
are contemplated and considered within the scope of the invention.
The various components can be secured within the housing 3426 via
various approaches. Alternatively or additionally, the mechanical
transducer 3404 can be flexibly coupled to the housing 3426. The
window and transducer 3404 are covered by an insulating material
3430, as described above. In certain embodiments, the insulating
material 3430 is selected to prevent direct contact between the
transducer 3404 and the subject's skin, but not impart a dampening
effect to the vibrations. Exemplary insulating materials include,
without limitation, elastomeric materials such as rubber, silicone,
EDTM, nitrile, neoprene, as well as engineered fabrics utilizing
blends of nylon, spandex, polyester, and other flexible fibers.
Generally, the transducer 3404 can be of any of the types disclosed
herein (e.g., piezo).
[0583] As shown in FIG. 34B, the housing 3426 and associated
components are located at the distal end 3421 of the elongate arm
3420. In some embodiments, the housing is butt mounted to the
distal end 3421 to avoid any overlap between the window and the
elongate arm 3420. In some embodiments, the housing 3426 can be
removably attached to the arm 3420, such that it can be exchanged
with a different housing (e.g., to change a treatment protocol,
replace a malfunctioning device, or for hygienic reasons.) In some
embodiments, the housings 3426 may be disposable.
[0584] The overall shape and dimensions of the housing may vary to
suit a particular application considering, for example, a treatment
area, the nature of the subject (e.g., adult vs. child), and the
number of transducers required. The device shown in FIGS. 34A and
34B includes a single transducer 3404 disposed in each housing;
however, any number and arrangement of transducers can be selected
to suit a particular application. For example, multiple transducers
3404 can be mounted side by side along a length of the housing 3426
and connected electrically in series or parallel depending on the
treatment protocol.
[0585] FIG. 32E depicts the ergonomic support components disposed
within a storage case 3242. In some embodiments, the case 3242
provides a secure, hygienic environment for storing and
transporting the device. However, in other embodiments, the case
3242 can include components to provide charging or to even exchange
data (e.g., a smart case) that allows the subject to keep track of
their usage, such as dates used, time of day used, and duration of
use.
[0586] FIGS. 33A and 33B depict another embodiment of an ergonomic
support component of a transcutaneous neuromodulation device. The
ergonomic support component 3300 comprises a linkage component
formed to engage (e.g., wrap around) a body part of a subject
(e.g., a head). As shown in FIGS. 33A and 33B, two transducer
housings are disposed at opposite ends of the linkage component,
for example so as to be positioned on opposite sides of the
subject's head. Each transducer housing 3338 supports and/or
encloses a corresponding transducer set. Each transducer set may
comprise one or more transducers, for example arranged in
transducer arrays as described herein.
[0587] In certain embodiments, the linkage component can be
adjusted (e.g., via an adjustment mechanism 3334) to accommodate
natural variations the body parts of subjects to which it is formed
to engage. For example, in certain embodiments the linkage
component is formed to engage (e.g., wrap around) a head of a
subject and comprises two interlocking curved arms (e.g.,
elastomeric arms) 3340a and 3340b. The curved arms are maintained
in alignment to form an arc, and can slide with respect to each
other so as to vary an amount that the two arms overlap. In this
manner, a size of the arc can be adjusted so as to accommodate a
variety of sizes of human heads. While described herein with regard
to adjustments made to accommodate variations in human heads,
similar approaches can be used to provide for adjustable linkage
components formed to engage with other parts of the body, for
example around arms, wrists, etc.
[0588] As shown in FIGS. 33A and 33B, the housings 3338 are
flexibly coupled to opposite distal ends 3321a and 3321b of the
linkage component 3332. In some embodiments, the housings 3338 are
adjustably mounted, such that their relative position can be
changed to better interface with the subject and maintained in the
position. In some embodiments, the linkage component comprises two
curved elastomeric arms 3340a and 3340b similar to those previously
described. The curved elastomeric arms 3340a and 3340b can be
adjusted to optimize comfort and transducer location and, in some
cases, provide a pressing force to hold the transducer against the
subject's body.
[0589] In certain embodiments, the transducer housing(s) enclose or
support at least one mechanical transducer, at least one controller
board, and at least one battery or other power source. However, in
some embodiments, the controller board(s) and/or power source can
be disposed within the linkage mechanism (e.g., within the curved
elastomeric arms 3340a and 3340b).
[0590] FIGS. 33B-H also depicts the adjustment mechanism 3334 for
adjusting a length and/or circumference of the linkage component
3332 as described herein. As shown, the adjustment mechanism 3334
includes two curved arms 3340a, 3340b that are interconnected and
slide relative to one another. For example, FIGS. 33C-H show detail
of one embodiment of such an adjustment mechanism. As shown in FIG.
33C, a metal slide 3352 bolts into a plastic mate and slides along
plastic ramp 3354. Plastic ramp 3354 allows metal slide 3352 to
glide and extend headband size. As shown in FIGS. 33E and 33F, the
adjustment mechanism may be designed to accommodate electronics
included in the support component. For example, metal slide 3352
may include a cable routing slot 3362 through which a
communication/power cable is routed to connect controller boards in
each of the interface components. As shown in FIGS. 33G and 33H,
positioning grooves 3372 may be included as well to allow for
controlled extension and positioning of the headband, with a spring
insert in mating component 3352 providing for a gentle stopping
force as mating component 3352 slides along grooves 3372.
[0591] FIGS. 331 and 33J are enlarged views of the devices showing
the housings 3338 in greater detail. As shown in FIG. 33I, housing
3338b is coupled to the distal end 3321b of arm 3340b and includes
an on/off button 3324a and an LED indicator 3324b to indicate
whether the device 3300 is on. In some embodiments, the LED
indicator 3324b may change colors to indicate a change in state,
such as green for on, red for low charge, yellow for charging, etc.
Housing 3338a is coupled to arm 3340a similarly and may include the
same controls, or other controls, for example a volume control as
described herein.
[0592] FIG. 33J depicts a coupling mechanism 3322a used to flexibly
couple interface component 3338a to the distal end 3321a of arm
3340a. In certain embodiments, the coupling mechanism is an
elastomeric hinge. Generally, an elastomeric hinge is a thinned
area of an elastomeric component that allows for flexure at the
thinned area, with the thickness of the thinned area determining
the stiffness of the hinge. The elastomeric hinge allows the
interface portions 3338 to flex relative to the arms 3340a and
3340b of the linkage mechanism 3332 to accommodate the subject's
body part and/or provide a pressing force to the transducer. In
some embodiments, the hinge may include a wire core to assist in
positioning the interface portions 3338 relative to the linkage
mechanism 3332. In other embodiments, the coupling mechanism 3322
include a ball and socket joint encased in the elastomeric material
or an articulated joint for stepped adjustment of the interface
portions' relative position.
[0593] FIGS. 331 and 33J also depict an insulating or interface
material 3330 (e.g., fabric) disposed on the housing 3338 to
prevent direct contact between the transducer surfaces and the
subject's skin. Also shown in FIG. 33J are additional controls
3324, in this case a volume button 3324c that is configured to
adjust at least one of intensity (i.e., amplitude) or a frequency
of the waveform, or the duration of the treatment.
[0594] FIG. 33K depicts an embodiment of the transcutaneous
neuromodulation device 3300 positioned on a human subject 3312. As
shown, the device 3300 is secured around the subject's head such
that the housings 3338, specifically the region where mechanical
transducers are positioned substantially proximate the subject's
mastoid region 3314g and are held in place via the resilient arm or
elastomeric hinge.
H. Computer System and Network Architecture
[0595] As shown in FIG. 35, an implementation of a network
environment 3500 for use in providing systems, methods, and devices
described herein is shown and described. In brief overview,
referring now to FIG. 35, a block diagram of an exemplary cloud
computing environment 3500 is shown and described. The cloud
computing environment 3500 may include one or more resource
providers 3502a, 3502b, 3502c (collectively, 3502). Each resource
provider 3502 may include computing resources. In some
implementations, computing resources may include any hardware
and/or software used to process data. For example, computing
resources may include hardware and/or software capable of executing
algorithms, computer programs, and/or computer applications. In
some implementations, exemplary computing resources may include
application servers and/or databases with storage and retrieval
capabilities. Each resource provider 3502 may be connected to any
other resource provider 3502 in the cloud computing environment
3500. In some implementations, the resource providers 3502 may be
connected over a computer network 3508. Each resource provider 3502
may be connected to one or more computing device 3504a, 3504b,
3504c (collectively, 3504), over the computer network 3508.
[0596] The cloud computing environment 3500 may include a resource
manager 3506. The resource manager 3506 may be connected to the
resource providers 3502 and the computing devices 3504 over the
computer network 3508. In some implementations, the resource
manager 3506 may facilitate the provision of computing resources by
one or more resource providers 3502 to one or more computing
devices 3504. The resource manager 3506 may receive a request for a
computing resource from a particular computing device 3504. The
resource manager 3506 may identify one or more resource providers
3502 capable of providing the computing resource requested by the
computing device 3504. The resource manager 3506 may select a
resource provider 3502 to provide the computing resource. The
resource manager 3506 may facilitate a connection between the
resource provider 3502 and a particular computing device 3504. In
some implementations, the resource manager 3506 may establish a
connection between a particular resource provider 3502 and a
particular computing device 3504. In some implementations, the
resource manager 3506 may redirect a particular computing device
3504 to a particular resource provider 3502 with the requested
computing resource.
[0597] FIG. 36 shows an example of a computing device 3600 and a
mobile computing device 3650 that can be used to implement the
techniques described in this disclosure. The computing device 3600
is intended to represent various forms of digital computers, such
as laptops, desktops, workstations, personal digital assistants,
servers, blade servers, mainframes, and other appropriate
computers. The mobile computing device 3650 is intended to
represent various forms of mobile devices, such as personal digital
assistants, cellular telephones, smart-phones, and other similar
computing devices. The components shown here, their connections and
relationships, and their functions, are meant to be examples only,
and are not meant to be limiting.
[0598] The computing device 3600 includes a processor 3602, a
memory 3604, a storage device 3606, a high-speed interface 3608
connecting to the memory 3604 and multiple high-speed expansion
ports 3610, and a low-speed interface 3612 connecting to a
low-speed expansion port 3614 and the storage device 3606. Each of
the processor 3602, the memory 3604, the storage device 3606, the
high-speed interface 3608, the high-speed expansion ports 3610, and
the low-speed interface 3612, are interconnected using various
busses, and may be mounted on a common motherboard or in other
manners as appropriate. The processor 3602 can process instructions
for execution within the computing device 3600, including
instructions stored in the memory 3604 or on the storage device
3606 to display graphical information for a GUI on an external
input/output device, such as a display 3616 coupled to the
high-speed interface 3608. In other implementations, multiple
processors and/or multiple buses may be used, as appropriate, along
with multiple memories and types of memory. Also, multiple
computing devices may be connected, with each device providing
portions of the necessary operations (e.g., as a server bank, a
group of blade servers, or a multi-processor system). Thus, as the
term is used herein, where a plurality of functions are described
as being performed by "a processor", this encompasses embodiments
wherein the plurality of functions are performed by any number of
processors (one or more) of any number of computing devices (one or
more). Furthermore, where a function is described as being
performed by "a processor", this encompasses embodiments wherein
the function is performed by any number of processors (one or more)
of any number of computing devices (one or more) (e.g., in a
distributed computing system).
[0599] The memory 3604 stores information within the computing
device 3600. In some implementations, the memory 3604 is a volatile
memory unit or units. In some implementations, the memory 3604 is a
non-volatile memory unit or units. The memory 3604 may also be
another form of computer-readable medium, such as a magnetic or
optical disk.
[0600] The storage device 3606 is capable of providing mass storage
for the computing device 3600. In some implementations, the storage
device 3606 may be or contain a computer-readable medium, such as a
floppy disk device, a hard disk device, an optical disk device, or
a tape device, a flash memory or other similar solid state memory
device, or an array of devices, including devices in a storage area
network or other configurations. Instructions can be stored in an
information carrier. The instructions, when executed by one or more
processing devices (for example, processor 3602), perform one or
more methods, such as those described above. The instructions can
also be stored by one or more storage devices such as computer- or
machine-readable mediums (for example, the memory 3604, the storage
device 3606, or memory on the processor 3602).
[0601] The high-speed interface 3608 manages bandwidth-intensive
operations for the computing device 3600, while the low-speed
interface 3612 manages lower bandwidth-intensive operations. Such
allocation of functions is an example only. In some
implementations, the high-speed interface 3608 is coupled to the
memory 3604, the display 3616 (e.g., through a graphics processor
or accelerator), and to the high-speed expansion ports 3610, which
may accept various expansion cards (not shown). In the
implementation, the low-speed interface 3612 is coupled to the
storage device 3606 and the low-speed expansion port 3614. The
low-speed expansion port 3614, which may include various
communication ports (e.g., USB, Bluetooth.RTM., Ethernet, wireless
Ethernet) may be coupled to one or more input/output devices, such
as a keyboard, a pointing device, a scanner, or a networking device
such as a switch or router, e.g., through a network adapter.
[0602] The computing device 3600 may be implemented in a number of
different forms, as shown in the figure. For example, it may be
implemented as a standard server 3620, or multiple times in a group
of such servers. In addition, it may be implemented in a personal
computer such as a laptop computer 3622. It may also be implemented
as part of a rack server system 3624. Alternatively, components
from the computing device 3600 may be combined with other
components in a mobile device (not shown), such as a mobile
computing device 3650. Each of such devices may contain one or more
of the computing device 3600 and the mobile computing device 3650,
and an entire system may be made up of multiple computing devices
communicating with each other.
[0603] The mobile computing device 3650 includes a processor 3652,
a memory 3664, an input/output device such as a display 3654, a
communication interface 3666, and a transceiver 3668, among other
components. The mobile computing device 3650 may also be provided
with a storage device, such as a micro-drive or other device, to
provide additional storage. Each of the processor 3652, the memory
3664, the display 3654, the communication interface 3666, and the
transceiver 3668, are interconnected using various buses, and
several of the components may be mounted on a common motherboard or
in other manners as appropriate.
[0604] The processor 3652 can execute instructions within the
mobile computing device 3650, including instructions stored in the
memory 3664. The processor 3652 may be implemented as a chipset of
chips that include separate and multiple analog and digital
processors. The processor 3652 may provide, for example, for
coordination of the other components of the mobile computing device
3650, such as control of user interfaces, applications run by the
mobile computing device 3650, and wireless communication by the
mobile computing device 3650.
[0605] The processor 3652 may communicate with a user through a
control interface 3658 and a display interface 3656 coupled to the
display 3654. The display 3654 may be, for example, a TFT
(Thin-Film-Transistor Liquid Crystal Display) display or an OLED
(Organic Light Emitting Diode) display, or other appropriate
display technology. The display interface 3656 may comprise
appropriate circuitry for driving the display 3654 to present
graphical and other information to a user. The control interface
3658 may receive commands from a user and convert them for
submission to the processor 3652. In addition, an external
interface 3662 may provide communication with the processor 3652,
so as to enable near area communication of the mobile computing
device 3650 with other devices. The external interface 3662 may
provide, for example, for wired communication in some
implementations, or for wireless communication in other
implementations, and multiple interfaces may also be used.
[0606] The memory 3664 stores information within the mobile
computing device 3650. The memory 3664 can be implemented as one or
more of a computer-readable medium or media, a volatile memory unit
or units, or a non-volatile memory unit or units. An expansion
memory 3674 may also be provided and connected to the mobile
computing device 3650 through an expansion interface 3672, which
may include, for example, a SIMM (Single In Line Memory Module)
card interface. The expansion memory 3674 may provide extra storage
space for the mobile computing device 3650, or may also store
applications or other information for the mobile computing device
3650. Specifically, the expansion memory 3674 may include
instructions to carry out or supplement the processes described
above, and may include secure information also. Thus, for example,
the expansion memory 3674 may be provide as a security module for
the mobile computing device 3650, and may be programmed with
instructions that permit secure use of the mobile computing device
3650. In addition, secure applications may be provided via the SIMM
cards, along with additional information, such as placing
identifying information on the SIMM card in a non-hackable
manner.
[0607] The memory may include, for example, flash memory and/or
NVRAM memory (non-volatile random access memory), as discussed
below. In some implementations, instructions are stored in an
information carrier. that the instructions, when executed by one or
more processing devices (for example, processor 3652), perform one
or more methods, such as those described above. The instructions
can also be stored by one or more storage devices, such as one or
more computer- or machine-readable mediums (for example, the memory
3664, the expansion memory 3674, or memory on the processor 3652).
In some implementations, the instructions can be received in a
propagated signal, for example, over the transceiver 3668 or the
external interface 3662.
[0608] The mobile computing device 3650 may communicate wirelessly
through the communication interface 3666, which may include digital
signal processing circuitry where necessary. The communication
interface 3666 may provide for communications under various modes
or protocols, such as GSM voice calls (Global System for Mobile
communications), SMS (Short Message Service), EMS (Enhanced
Messaging Service), or MMS messaging (Multimedia Messaging
Service), CDMA (code division multiple access), TDMA (time division
multiple access), PDC (Personal Digital Cellular), WCDMA (Wideband
Code Division Multiple Access), CDMA2000, or GPRS (General Packet
Radio Service), among others. Such communication may occur, for
example, through the transceiver 3668 using a radio-frequency. In
addition, short-range communication may occur, such as using a
Bluetooth.RTM., Wi-Fi.TM., or other such transceiver (not shown).
In addition, a GPS (Global Positioning System) receiver module 3670
may provide additional navigation- and location-related wireless
data to the mobile computing device 3650, which may be used as
appropriate by applications running on the mobile computing device
3650.
[0609] The mobile computing device 3650 may also communicate
audibly using an audio codec 3660, which may receive spoken
information from a user and convert it to usable digital
information. The audio codec 3660 may likewise generate audible
sound for a user, such as through a speaker, e.g., in a handset of
the mobile computing device 3650. Such sound may include sound from
voice telephone calls, may include recorded sound (e.g., voice
messages, music files, etc.) and may also include sound generated
by applications operating on the mobile computing device 3650.
[0610] The mobile computing device 3650 may be implemented in a
number of different forms, as shown in the figure. For example, it
may be implemented as a cellular telephone 3680. It may also be
implemented as part of a smart-phone 3682, personal digital
assistant, or other similar mobile device.
[0611] Various implementations of the systems and techniques
described here can be realized in digital electronic circuitry,
integrated circuitry, specially designed ASICs (application
specific integrated circuits), computer hardware, firmware,
software, and/or combinations thereof. These various
implementations can include implementation in one or more computer
programs that are executable and/or interpretable on a programmable
system including at least one programmable processor, which may be
special or general purpose, coupled to receive data and
instructions from, and to transmit data and instructions to, a
storage system, at least one input device, and at least one output
device.
[0612] These computer programs (also known as programs, software,
software applications or code) include machine instructions for a
programmable processor, and can be implemented in a high-level
procedural and/or object-oriented programming language, and/or in
assembly/machine language. As used herein, the terms
machine-readable medium and computer-readable medium refer to any
computer program product, apparatus and/or device (e.g., magnetic
discs, optical disks, memory, Programmable Logic Devices (PLDs))
used to provide machine instructions and/or data to a programmable
processor, including a machine-readable medium that receives
machine instructions as a machine-readable signal. The term
machine-readable signal refers to any signal used to provide
machine instructions and/or data to a programmable processor.
[0613] To provide for interaction with a user, the systems and
techniques described here can be implemented on a computer having a
display device (e.g., a CRT (cathode ray tube) or LCD (liquid
crystal display) monitor) for displaying information to the user
and a keyboard and a pointing device (e.g., a mouse or a trackball)
by which the user can provide input to the computer. Other kinds of
devices can be used to provide for interaction with a user as well;
for example, feedback provided to the user can be any form of
sensory feedback (e.g., visual feedback, auditory feedback, or
tactile feedback); and input from the user can be received in any
form, including acoustic, speech, or tactile input.
[0614] The systems and techniques described here can be implemented
in a computing system that includes a back end component (e.g., as
a data server), or that includes a middleware component (e.g., an
application server), or that includes a front end component (e.g.,
a client computer having a graphical user interface or a Web
browser through which a user can interact with an implementation of
the systems and techniques described here), or any combination of
such back end, middleware, or front end components. The components
of the system can be interconnected by any form or medium of
digital data communication (e.g., a communication network).
Examples of communication networks include a local area network
(LAN), a wide area network (WAN), and the Internet.
[0615] The computing system can include clients and servers. A
client and server are generally remote from each other and
typically interact through a communication network. The
relationship of client and server arises by virtue of computer
programs running on the respective computers and having a
client-server relationship to each other.
[0616] In some implementations, modules described herein can be
separated, combined or incorporated into single or combined
modules. Any modules depicted in the figures are not intended to
limit the systems described herein to the architectures shown
therein.
I. Example 1--IRB Approved Randomized and Placebo Controlled
Study
[0617] Example 1 is a protocol for an IRB-approved, randomized and
placebo-controlled study for testing the devices and waveforms
(e.g., the transformed time-varying waveform) described herein. In
particular, the study tested the whether the devices and waveforms
are safe for both episodic and daily use over three weeks. Results
and benefits of mechanical nerve stimulation were reported from
users and study coordinators and gathered in surveys. Case reports
from the study of Example 1 are described in Example 2.
[0618] Research participants were subjected to mechanical
stimulation comprising acoustic noise, with amplitudes at levels of
tactile vibration. Waveforms applied comprised stochastic resonance
signals including random noise of various frequencies, standard and
modified sine waves, incidentally transformed waves, and
multi-scalar modulation of carrier waves.
[0619] Devices were placed on locations on the subjects, such as
neck, back of neck, ear, skull (e.g. mastoid), temples, face, and
arms depending on specific sub-protocol. The device as described
herein, included adhesive material to contact transducers to the
subjects, helmet or hat like devices, over-the-head bands to site
transducers on the subject with or without providing external
pressure, a band-like device that goes around the back of the head
site transducers on the subject with or without providing external
pressure, eye-glass like bands to site transducers on the subject
with or without providing external pressure, headphone-like devices
to site transducers on the subject with or without providing
external pressure among other methods of siting the transducers on
the subject or in combination with other devices (e.g. headphones)
to site transducers on subject. Stimulation sessions lasted from
10-60 minutes.
[0620] A goal of the transcutaneous mechanoacoustic stimulation
(TAS) research was to assess the potential to improve productivity,
cognition, and quality of life as well as to alleviate symptoms of
diseases. To do this, the effects of various TAS parameters on
mental state (mood, alertness, relaxation, stress, sleep etc.--as
measured by questionnaires and established biomarkers) and
cognitive performance (as measured by established tests) were
examined. The study included both naturalistic and non-naturalistic
settings. Naturalistic settings were useful to determine the
relevance of TAS protocols in the daily life of normal healthy
individuals. Non-naturalistic settings were useful for the
controlled administration of cognitive tests, evoking specific
mental states, and the use of biometric sensors.
[0621] Device placement, timing, duration, and waveform were varied
in a rigorous manner using a common set of dependent variables
(including cognitive tasks, questionnaires, and biometrics). One
goal was to determine the optimal parameters for improving mental
states and to identify and examine the physiological mechanisms and
dynamical responses underlying these improvements.
[0622] The study tested approximately 2400 subjects over up to 24
months.
[0623] i. Stimulation Device
[0624] An embodiment of the stimulation device as described herein
is used. The device incorporates an amplifier and mechanoelectric
vibrating elements that generate and deliver small, gentle
vibrations. The amplifier increases output of the signal generator
to drive the vibrating elements. The vibrating elements are
insulated to avoid skin contact with the transducers delivering the
vibratory stimulation. Electrical circuit components for
controlling the vibration amplitude are housed in an electronics
housing and are attached to the vibrating element via an insulated
cable--similar to off-the-shelf headphones. Neither the mechanical
transducers nor the circuit housing come into direct contact with
the participant, thereby eliminating the risk for electric shock
from traditional neurostimulation devices. Furthermore, the circuit
board has an included battery safety circuit to protect the
participant. The system delivers mechanical stimulation at
specified levels of power or within specified modulating levels of
power.
[0625] ii. Data Collection and Monitoring
[0626] Data is collected using paper forms, online survey
collection tools, audio or video recordings, or automated software.
If software is used, it can coordinate the inputs from biometric
testing and behavioral tasks based on both subject Study ID (SID)
number and time of day. Electronic data can be saved in a
password-protected location only accessible to the research team.
Subjects can be monitored intermittently or continuously during
data collection to ensure that the automated software remains
operational, the biometric assessment devices remain in place, and
the subject remains engaged with the task.
[0627] Questionnaire data is collected online via an online survey
tool. Automated software is used to collect all the biometric
information. Audio and video are used for both collecting facial
expression data to be analyzed by coders or by automated software
and for post stimulation/home test interviews, which will be coded
by researchers.
[0628] All data are de-identified. Study ID (SID) numbers are used
to identify subjects in the study records. Master files linking
subject names to SID number are kept separate from the study
records, either in a locked drawer or on a password-protected file
only accessible to the research team.
[0629] In the study records, subjects are identified by SID number
only. No personal information such as name or contact information
will be included in the study records. The study records are stored
in password-protected files only accessible to the research
team.
[0630] Various biometric assessment that can be performed are
listed below: [0631] a. Blood pressure and respiration rate
measurement [0632] i. Biopatch or Bioharness 3 or similar device
[0633] b. Caloric expenditure measurement: [0634] i. Metabolic Cart
(e.g., http://emedicine.medscape.com/article/2009552-overview) or
similar device [0635] c. Electrophysiology measurement: [0636] i.
EEG: Brain Vision ACTIChamp, Emotiv EEG, B-Alert AT-Series EEG, or
similar device [0637] ii. EMG: [0638] iii. ECG-EKG: [0639] d.
Facial expression measurement: [0640] i. iMotions FACET sensor, web
camera, or similar device. [0641] e. GSR measurement: [0642] i.
Shimmer GSR, Affectiva Q-Sensor GSR bracelets, or similar device.
[0643] f. Heart rate measurement: [0644] i. The device may be
attached to the finger, arm, earlobe, chest, or wrist. [0645] ii.
Heart rate monitor: Heart Sensor HRS-07UE, iMotions sensor: Zephyr
echo gateway, Polar Chest Strap, Biopatch, or similar device.
[0646] g. Blood and Saliva Testing: [0647] i. Salivary assays
(e.g., cortisol and alpha-amylase) [0648] ii. Blood assays (e.g.
CRP, IL-2, IL-6, TGF-.beta., TNF, IgA, nitric oxide) [0649] h.
Movement measurement: [0650] i. Accelerometer such as the Biopatch,
Actiwatch, Fitbit.RTM., or similar technology may be used to
measure movement [0651] i. Pupilometry and eye movement measurement
(including rate of blinking): [0652] i. Tobii, web camera or
similar eye tracking or pupilometry device. [0653] j. Temperature
measurement: [0654] i. Evergen TemporalScanner.TM., infrared
thermometer, or similar device
[0655] iii. Mechanical Stimulation
[0656] This study includes multiple experimental conditions, which
differ in device placement, stimulating device, waveform of
stimulation, and timing of stimulation. Each subject is randomly
assigned to a condition and experimenters are blinded to conditions
where possible. Subjects are blinded to parameter values whenever
possible, except in cases where it is necessary for them to control
the parameter value to reduce the risk of discomfort. Importantly,
in the case that subjects receive both sham and real stimulation
within the same session, the ordering is not counterbalanced. This
is because real stimulation has expected carry-over effects. Sham
and real stimulation are counterbalanced with stimulation sessions
occurring on different days.
[0657] The following stimulation parameters are among those that
may be varied in a controlled manner between experimental groups
and/or between sessions over the course of the study:
[0658] 1. Duration of Stimulation: [0659] a. Up to 60 min of
stimulation per session [0660] b. Length of stimulation may vary
between conditions as the research aims to identify the lowest
doses needed to elicit the desired enduring effect.
[0661] 2. Waveform Parameters: [0662] a. Categories of Signals:
[0663] i. White noise: Uncorrelated Gaussian noise [0664] ii. White
noise plus signal: Uncorrelated Gaussian noise with an underlying
signal [0665] iii. Plain mechanical signal, no noise [0666] b.
Signal Parameters (within categories): [0667] i. Frequency (ranges
of frequencies (e.g., 0-320 Hz noise)) [0668] ii. Wave type:
Sinusoidal, Square, etc. [0669] iii. Amplitude: Of the noise, the
underlying signal, and the ratio between white noise and underlying
signal [0670] iv. Other waveform parameters such as duty cycle and
pulse rate
[0671] 3. Device Placement [0672] a. Anywhere on the head may be
chosen as a location; this will depend on which nerves are
targeted. Participants will be randomly assigned to condition.
[0673] b. Upper arm and back of neck may also be chosen as
locations. These areas will be tested later in the discovery arm
once locations on the head, specifically around the ear, have been
optimized.
[0674] iv. Sham Stimulation
[0675] Much of the stimulation is sub-threshold and is not
perceptible to the participants. Accordingly, participants can be
suited with a device that shows the power button on, but does not
work, as a control. Where stimulation parameters are detectable,
participants can be given a waveform that has been demonstrated not
to have an effect or placement can be altered so that different
nerves are stimulated resulting in a different effect. If the
waveform results in sound, participants can wear noise-cancelling
headphones or a counter signal can be used to cancel the acoustic
wave to mask to condition.
[0676] v. Study Arms
[0677] There are 3 main arms of this study. Each arm has an in-lab
and home component.
[0678] a. Discovery
[0679] In this arm of testing, participants complete mood
questionnaires, use the stimulation device, and wear biometric
monitors to capture changes in autonomic arousal. The stimulation
parameters and placement may vary depending on results from
previous assessments and nerves that are being targeted. In later
testing within this arm, learning and memory tasks are paired with
the stimulation to assess effects on cognitive abilities.
[0680] b. Systematic Validation (Phase I)
[0681] In this study arm, there is additional biometric
monitoring--eye tracking, EEG, biopatch for respiration rate--with
a similar design to discovery: pre-questionnaires, baseline
biometric assessment, post-baseline assessment, stimulation (sham
versus real), and post-stimulation assessment.
[0682] c. Systematic Validation (Phase II)
[0683] In the second phase of testing within this arm, participants
are subjected to stressors and the stimulation (real versus sham)
is examined for attenuating the stress or blunt the response.
Participants complete baseline mood questionnaires and mood
induction task(s) and receive stimulation (real or sham) followed
by post-test mood assessments. A subgroup of participants is yoked
to assess hormone levels. This subgroup is random, but only
comprises males (at least in the first subset) to avoid female
monthly hormonal fluctuations in cortisol.
[0684] In later testing within the systematic validation arm,
instead of sham stimulation, a positive control is used, such as
diaphragmatic breathing, meditation, or electrical stimulation,
with the procedures following those described above with regard to
the first and second systematic validation phases (Section b.
Systematic Validation (Phase I) and Section c. Systematic
Validation (Phase II)).
J. Example 2: Case Reports from IRB Study of Example 1
[0685] Example 2 summarizes case reports from the IRB study of
Example 1.
[0686] Modulation and practices associated with peripheral nerves
and specific neural circuits can produce changes in subjective
assessment of mood, which may correlate with enhanced vagal tone
(VT) and can be understood as related to improved interoception.
Short-term modulation of the cranial nerves with representative
waveforms with transducers place on the anatomy in the vicinity of
cranial and other peripheral nerves has produced a variety of
effects in a general sample of the population. The following case
reports have been received:
[0687] Alterations in conditions and symptoms that were noted using
the present device and methods include: deeper and accelerated
relaxation (via improved vagal tone as demonstrated in heart rate
variability and mean arterial pressure; improved Alpha wave
activity via electroencephalography); improved quality and length
of sleep; reduced sleep disturbance and insomnia; lucid dreaming;
regulated breathing and improved sleep apnea; spontaneous
self-reports of reduced anxieties including, performance anxiety,
social anxiety, stage fright, blushing, panic disorder, fear, PTSD,
and ADHD; stress-induced tachycardia; calm and receptive during
psychotherapy; calming an autistic child; spontaneous and
questionnaire based self-reports of focused attention, mental
acuity, cognitive performance, improved memory and engagement;
reduced chronic pain due to arthritis; reduced perception of pain;
reduced inflammation and edema; reduced vertigo and improved
balance; reduced menstrual cramping, menstrual headaches;
perimenopausal hot flashes, sleep and mood disturbance;
stress-induced infertility; prophylaxis and alleviation of migraine
and tension headache; reduced tinnitus and ringing in the ears;
improved appetite, salivation and gut motility; priming of the
limbic system; priming of sexual arousal, libido or desire;
enhanced pleasure, climax and orgasm; enhanced vagal tone by heart
rate variability; lower stress biomarkers, lower blood pressure as
measured.
[0688] In multiple cases, users reported a feeling of improved
focus or concentration. In multiple cases, users reported a feeling
of increased relaxation and increased calmness. In at least one
case a user reported increased sexual arousal and/or associated
sensation that can occur prior to and concurrent with sexual
activity. Concurrent with the reported subjective effects that are
similar to those seen in electrical stimulation of the vagus nerve
and elsewhere associated with enhancing interoceptive perception, a
subgroup of 48 subjects showed specific effects related to heart
activity and specifically a derived characteristic called `heart
rate variability` (HRV), which characterizes autonomic nervous
system (ANS) activity and control of cardiac function in terms of
the components of the ANS, where sympathetic (fight or flight
response) activity is characterized by the low frequency power
(pLF) of the heart rate variability and parasympathetic (rest and
relax) activity is characterized by the high frequency power (pHF).
Parasympathetic activation is associated with increased vagal tone
and the benefits mentioned about.
[0689] In at least one case, a user reported relief from chronic
headache and reduction in frequency of same. In at least one case,
a user reported a significant reduction in anxiety. In at least one
case, a user reported a reduction in social anxiety. In at least
one case, a user reported a significant reduction in panic attacks.
In multiple cases, users reported a significant reduction in
tinnitus. Tinnitus cases for which users have reported reductions
through use of embodiments of devices as described herein include
noise induced tinnitus as well as tinnitus resulting from
ototoxicity. Notably, many chemotherapy drugs are ototoxic. For
example, cisplatin is highly ototoxic and often creates ototoxic
tinnitus (Frisina, 2016). In one case, a 64 year old female
undergoing cisplatin chemotherapy reported a reduction in the
majority of ringing through use of the device. In at least one
case, a user reported a significant reduction in flushing and fear
prior to public speaking. In at least one case, a user reported
relief from extreme blushing (idiopathic erythema). In at least one
case, a user reported relief from menstrual headaches and cramping.
In at least one case, a user reported abatement of arthritic pain.
In at least one case, a user reported relief from stress-induced
hypertension. In at least one case, a user reported improved sleep
and relief from sleep apnea.
[0690] Notably, the group using the representative waveform here
sustained a lower drop in pHF than either a group using only a sham
(no waveform) device as well as one using a distinctly different
type of waveform (isochronic 18 Hz: ISO18). This means that there
was less parasympathetic inhibition in the representative waveform
than in either the sham or ISO18 waveforms. In addition, there was
a greater reduction in pLF, consistent with reduced sympathetic
activation. These results illustrate the use of a dynamical systems
measure for assessing the response to a given waveform (e.g.,
ISO18) as compared to sham stimulation. Concurrent with these
findings, there was a decrease in mean arterial blood pressure
compared to sham, another characteristic of decreased sympathetic
activation and improved vagal tone.
[0691] Taken together, these results show that the representative
waveform generates a novel response (as compared with no
stimulation and with a second active waveform). pHF remains higher
(so less parasympathetic inhibition) and pLF decreases (so less
sympathetic activation) which show improved vagal tone. The
concurrent finding that mean arterial pressure falls with only the
representative wave form (neither with sham nor another active
waveform) further supports an increase in relative parasympathetic
activation and improved vagal tone.
K. Example 3: EEG Measurement of Waveform Effects
[0692] Example 3 is an example showing differences in neural
activity resulting from different waveforms, as measured via
quantitative EEG (qEEG). The results of Example 3 show improved
performance via the use of transformed time varying waves as
described herein.
[0693] In Example 3, 3 subjects, older than 18 years old were
studied. Two subjects were female. Subjects were assessed as
follows: [0694] 3 minutes of EEG recording at rest in eyes closed
(EC) condition [0695] 20 minutes of stimulation with simultaneous
EEG EC recording (only 2 subjects) [0696] 3 minutes post
intervention EEG EC recording
[0697] EEG recording and data processing was as follows. A
32-channel pre-amplified EEG device was used for data acquisition.
Data was sampled at a rate of 500 Hz, amplified and filtered using
a bandpass of 0.1-45 Hz. EEG was recorded for a total of 9 min per
procedure (baseline, intervention, post-intervention). For offline
analysis a low-pass cut filter of 35 Hz and high-pass of 1 Hz was
used, followed by manual artifact detection and rejection. Power
spectra were calculated using BrainAnalizer. Fast Fourier
transformation (averaged windows of 5s with 50% overlap) was used
to calculate power (.mu.V2) for the following EEG bands: delta
(0.5-4 Hz), theta (4-8 Hz) and alpha (8-13 Hz) and the sub-bands:
low-alpha (8-10 Hz), high-alpha (10-13 Hz), low-beta (13-20 Hz) and
high beta (21-30 Hz). FIG. 37 illustrates the EEG data processing
approach.
[0698] All 3 subjects showed a normoreactive EEG. The EEG
architecture was found adequate, with no evidence of abnormal EEG
activity. A conventional 50 Hz sine wave was used for stimulation
for Subject #1. As demonstrated by the EEG data shown in FIG. 38A
and FIG. 38B, Subject #1 did not show significant changes from pre-
to post-intervention. Subject #2 and Subject #3 were stimulated via
unconventional waveforms. Subject #2 was stimulated using a
transformed time varying wave corresponding to a modified version
of a 50 Hz sine wave, shown in FIG. 38B. Subject #3 was stimulated
using a complex aperiodic waveform (corresponding to the sum of two
sines with two different frequencies which ratio equals Phi (the
golden ratio--(1+ 5)/2)). EEG data for both Subject #2 and Subject
#3 showed near-significant increase in the power of the alpha band
in occipital area. It was found that the alpha band increased its
power transiently in the areas closer to the stimulation
(occipito-temporal) during the stimulation period. EEG data for
Subject #2 is shown in FIG. 39A and EEG data for Subject #3 is
shown in FIG. 39B.
[0699] Accordingly, Example 3 shows that the stimulation was safe
and no adverse events were reported. Moreover, the results of
Example 3 show dependence of neural stimulation on waveform of the
signals used, with particular waveforms such as transformed time
varying waves and aperiodic waveforms offering higher levels of
stimulation in comparison with a 50 Hz sine wave. As described, two
out of the three subjects showed positive EEG modulation after
stimulation. As described, two subjects presented transient alpha
modulation through the active stimulation period. Post-intervention
analysis showed significant increase in the power of the alpha
band. The data shows that the main neuromodulatory effect occurred
in the occipital area. Increasing alpha power is associated with
general improvements in cognition (Hanslmayr, 2005).
L. Example 4: Design and Results of Pilot Study for Treatment of
Anxiety
[0700] Example 4 is an example showing results of a pilot study in
which an embodiment of the device described herein was used by
participants to manage anxiety.
[0701] In the study, 208 potential participants were screened, of
which 73 were approved, and 34 ultimately accepted for the study.
Nine participants were excluded as non-compliant or unreliable
reporters. A histogram showing age distribution of the study
participants is shown in FIG. 40A, and a breakdown of gender
distribution is shown in FIG. 40B. As shown in the demographic
information in FIG. 40B, gender of study participants was
predominantly female.
[0702] Study participants self-administered mechanical stimulation
using an embodiment of the device in which mechanical transducers
are incorporated into a wearable headset (shown in FIG. 42). The
headset positions the mechanical transducers behind a participant's
ears (one mechanical transducer behind each ear) allowing for
mechanical stimulation to be applied at the skin of the subject
near the mastoid. Participants thereby self-administered mechanical
stimulation by wearing the headset and turning on a controller
module. The controller module comprises a controller board that
generates and supplies an electronic signal to drive the mechanical
transducers in the headset and provide for generation of mechanical
stimulation having a particular waveform designed for treatment of
anxiety and anxiety related disorders. In particular, an isochronic
sine wave having a 10 Hz carrier frequency was used. An example of
such a signal is shown in FIG. 4. As described herein, this signal
is tailored supply stimulation that targets Merkel cells and that
also accommodates rest periods of Piezo2 proteins, both of which
are part of the stimulation pathway for the insula region.
[0703] Participants were instructed to self-administer stimulation
for 20 minutes, twice a day, as well as on an as needed basis
(e.g., when they felt an onset of anxiety symptoms). Of the study
participants, 73% adhered to the prescribed stimulation routine,
and 88% reported using the device twice every day for three or more
weeks, based on daily surveys. As shown in the survey data in FIG.
41, study participants found the device easy to use, with 96% of
the participants reporting none or minimal effort to use. Eighteen
headsets and controller modules were used in the study and
distributed among participants for use. During the study, three
headsets and eight controller modules malfunctioned during a second
cycle of use (overall 32% failure rate).
[0704] In order to assess efficacy of the device and mechanical
stimulation approach for treating and managing anxiety and anxiety
related disorders, participants answered questionnaires to evaluate
four established anxiety/pain metrics: a Generalized Anxiety
Disorder (GAD)-7 score, a Visual Analogue Scale (VAS) score, and a
state-trait anxiety inventory (STAI), which comprises two
metrics--a state (STAI-State) and a trait (STAI-Trait) anxiety
score.
[0705] FIGS. 43A-E show case studies (e.g., individual results) for
5 specific participants showing variation in the four
aforementioned scores for each individual participant. Feedback
provided by each of the 5 participants (along with demographic
information, where provided) is shown in Table 1, below.
TABLE-US-00001 TABLE 1 Case reports and open-ended feedback
Participant & demographic information Open-ended feedback 1.
Male, 34 years old "I can definitely report that I feel positive
effects from the device. It tends to make me a little more calm
than normal and I find I am not worrying as much about things. The
worries seem to disappear, at least partially and for a period of
time. I would absolutely be using the device on an as needed
basis." 2. Other, 26 years old "Felt like I wasn't being bothered
all the time by my anxiety and all that stuff that can make it
harder for me like work or whatever. Wasn't getting overwhelmed as
much, a lot more self-confident, wow I can do this, all these
ideas, more positive. Just overall more positive and happy,
everything was good." "I would try to think about things that would
make me anxious to see if it was a placebo effect and it didn't
make me anxious or stressed." 4. Female, 59 years old "I felt like
it was really in a different realm. I am really going to miss it.
This is really saving my life. I feel so awful on the medication,
and this makes me feel so much better. I really going to miss it. I
don't want to give it back." "I have decreased my usage of
anti-anxiety medication almost 90 percent since using the device.
The days are going a lot better and my anxiety moods and panic
attacks are decreasing." 4. Female, 31 years old "The device became
second nature to use and I didn't notice it on my head as the study
continued. It became something that was integrated into my schedule
pretty easily." "I dropped a glass container that spilled
EVERYWHERE. I think that wearing the device gave me some external
cues to remind me to chill out, listen to my body and deal with it
without getting stressed/anxious about the huge mess." 5. Female,
66 years old "Found it pleasant and it helps. Really addresses
anxiety." "For the most part I seem to be a little less anxious
over the last few days." "Felt more relaxed, didn't experience any
physical changes or side effects."
[0706] FIGS. 44A-D show overall results for the study. The data
from the study shows that changes in GAD-7, STAI-State and
STAI-Trait scores are significant between enrollment and exit.
Based on a one-tailed Wilcoxon test, there is enough statistical
evidence to conclude that median GAD-7, STAI-State, and STAI-Trait
scores are lower at exit than at enrollment. VAS scores appeared
inconsistent and insignificant.
[0707] Elements of different implementations described herein may
be combined to form other implementations not specifically set
forth above. Elements may be left out of the processes, computer
programs, databases, etc. described herein without adversely
affecting their operation. In addition, the logic flows depicted in
the figures do not require the particular order shown, or
sequential order, to achieve desirable results. Various separate
elements may be combined into one or more individual elements to
perform the functions described herein.
[0708] Throughout the description, where apparatus and systems are
described as having, including, or comprising specific components,
or where processes and methods are described as having, including,
or comprising specific steps, it is contemplated that,
additionally, there are apparatus and systems of the present
invention that consist essentially of, or consist of, the recited
components, and that there are processes and methods according to
the present invention that consist essentially of, or consist of,
the recited processing steps.
[0709] It should be understood that the order of steps or order for
performing certain action is immaterial so long as the invention
remains operable. Moreover, two or more steps or actions may be
conducted simultaneously.
[0710] While the invention has been particularly shown and
described with reference to specific preferred embodiments, it
should be understood by those skilled in the art that various
changes in form and detail may be made therein without departing
from the spirit and scope of the invention as defined by the
appended claims.
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