U.S. patent application number 16/747181 was filed with the patent office on 2020-12-10 for systems, devices and methods for bilateral caloric vestibular stimulation.
The applicant listed for this patent is Scion NeuroStim LLC. Invention is credited to Robert D. Black, Lesco L. Rogers, Lanty L. Smith.
Application Number | 20200383828 16/747181 |
Document ID | / |
Family ID | 1000005046680 |
Filed Date | 2020-12-10 |
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United States Patent
Application |
20200383828 |
Kind Code |
A1 |
Rogers; Lesco L. ; et
al. |
December 10, 2020 |
SYSTEMS, DEVICES AND METHODS FOR BILATERAL CALORIC VESTIBULAR
STIMULATION
Abstract
An in-ear stimulation device for administering caloric
stimulation to the ear canal of a subject includes (a) first and
second earpieces configured to be insertable into the ear canals of
the subject; (b) at least first and second thermoelectric devices
thermally coupled to respective ones of the first and second
earpieces; (c) a first heat sink thermally coupled to the first
thermoelectric device opposite the first earpiece and a second heat
sink thermally coupled to the second thermoelectric device opposite
the second earpiece; and (d) a controller comprising a waveform
generator in communication with the first and second thermoelectric
devices, the waveform generator configured to generate a first
control signal to control a first caloric output to the first
thermoelectric device and a second control signal to control a
second caloric output to the second caloric device.
Inventors: |
Rogers; Lesco L.; (Raleigh,
NC) ; Smith; Lanty L.; (Raleigh, NC) ; Black;
Robert D.; (Chapel Hill, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Scion NeuroStim LLC |
Durham |
NC |
US |
|
|
Family ID: |
1000005046680 |
Appl. No.: |
16/747181 |
Filed: |
January 20, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15069552 |
Mar 14, 2016 |
10537467 |
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16747181 |
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13994266 |
May 15, 2014 |
9283111 |
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PCT/US11/65396 |
Dec 16, 2011 |
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15069552 |
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12970312 |
Dec 16, 2010 |
8460356 |
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13994266 |
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12970347 |
Dec 16, 2010 |
8603152 |
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12970312 |
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PCT/US10/60764 |
Dec 16, 2010 |
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12970347 |
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PCT/US10/60771 |
Dec 16, 2010 |
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PCT/US10/60764 |
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61424474 |
Dec 17, 2010 |
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61498131 |
Jun 17, 2011 |
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61497761 |
Jun 16, 2011 |
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61424132 |
Dec 17, 2010 |
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61498096 |
Jun 17, 2011 |
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61424326 |
Dec 17, 2010 |
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61498080 |
Jun 17, 2011 |
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61498911 |
Jun 20, 2011 |
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61498943 |
Jun 20, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 2/002 20130101;
A61F 2007/0095 20130101; A61F 2007/0093 20130101; A61F 7/007
20130101; A61F 2007/0005 20130101; A61F 2007/0295 20130101; A61F
2007/0075 20130101; A61N 2/006 20130101; A61F 7/12 20130101; A61N
1/0456 20130101 |
International
Class: |
A61F 7/12 20060101
A61F007/12; A61F 7/00 20060101 A61F007/00 |
Claims
1. An in-ear stimulation device for administering caloric
stimulation to the ear canal of a subject, comprising: (a) first
and second earpieces configured to be insertable into the ear
canals of the subject; (b) at least first and second thermoelectric
devices thermally coupled to respective ones of the first and
second earpieces; (c) a first heat sink thermally coupled to the
first thermoelectric device opposite the first earpiece and a
second heat sink thermally coupled to the second thermoelectric
device opposite the second earpiece; and (d) a controller
comprising a waveform generator in communication with the first and
second thermoelectric devices, the waveform generator configured to
generate a first control signal to control a first caloric output
to the first thermoelectric device and a second control signal to
control a second caloric output to the second thermoelectric
device.
Description
RELATED APPLICATIONS
[0001] This application is a continuation U.S. patent application
Ser. No. 15/069,552 filed Mar. 14, 2016, which is a continuation of
U.S. patent application Ser. No. 13/994,266 filed on Jun. 14, 2013
which is a 35 US .sctn. 371 national phase entry of PCT Application
No. PCT/US2011/065396, filed on Dec. 16, 2011 and published in
English on Jun. 21, 2012 as International Publication No. WO
2012/083126, which application claims priority to United States
Provisional Patent Application Nos. 61/424,474, filed Dec. 17,
2010; 61/498,131, filed Jun. 17, 2011; 61/497,761, filed Jun. 16,
2011; 61/424,132, filed Dec. 17, 2010; 61/498,096, filed Jun. 17,
2011; 61/424,326, filed Dec. 17, 2010; 61/498,080, filed Jun. 17,
2011; 61/498,911, filed Jun. 20, 2011 and 61/498,943, filed Jun.
20, 2011; and U.S. patent application Nos. 12/970,312, filed Dec.
16, 2010 and 12/970,347, filed Dec. 16, 2010 and PCT Application
Nos. PCT/US2010/060764, filed Dec. 16, 2010, PCT/US2010/060771,
filed Dec. 16, 2010, the disclosure of each of which is
incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to caloric vestibular
stimulation, and in particular, to bilateral caloric vestibular
stimulation.
BACKGROUND
[0003] Caloric vestibular stimulation ("CVS") has long been known
as a diagnostic procedure for testing the function of the
vestibular system. In the traditional hospital setting, water
caloric tests are used to assess levels of consciousness during
acute or chronic brain injury. The brain injury may be due to head
trauma or a central nervous system event such as a stroke. Other
brain injuries occur in the presence of metabolic abnormalities
(e.g., kidney disease, diabetes), seizures, or toxic levels of
controlled substances or alcohol.
[0004] U.S. Patent Publication No. 2003/0195588 to Fischell et al.
discusses a stimulator in an ear canal that is adapted to provide
magnetic, electrical, audible, tactile or caloric stimulation.
Fischell proposes a ring-shaped caloric transducer strip on an ear
canal sensor/stimulator system that may result in relatively slow
thermal changes of the ear canal.
[0005] Accordingly, apparatuses and associated methods useful for
delivering stimulation to the nervous system and/or the vestibular
system of an individual that may be capable of relatively fast
temperature changes are potentially beneficial to take full
advantage of physiological responses that are useful in diagnosing
and/or treating a variety of medical conditions.
SUMMARY OF EMBODIMENTS OF THE INVENTION
[0006] In some embodiments, an in-ear stimulation device for
administering caloric stimulation to the ear canal of a subject
includes (a) first and second earpieces configured to be insertable
into the ear canals of the subject; (b) at least first and second
thermoelectric devices thermally coupled to respective ones of the
first and second earpieces; (c) a first heat sink thermally coupled
to the first thermoelectric device opposite the first earpiece and
a second heat sink thermally coupled to the second thermoelectric
device opposite the second earpiece; and (d) a controller
comprising a waveform generator in communication with the first and
second thermoelectric devices, the waveform generator configured to
generate a first control signal to control a first caloric output
to the first thermoelectric device and a second control signal to
control a second caloric output to the second caloric device.
[0007] In some embodiments, the first control signal is different
from the second control signal.
[0008] In some embodiments, the first control signal is
out-of-phase with the second control signal. When a slope of the
first control signal is increasing, a slope of the second control
signal decreases, and when a slope of the first control signal is
decreasing, a slope of the second control signal increases.
[0009] In some embodiments, the in-ear stimulation device comprises
an electrical connection between the first and second earpieces,
and the controller comprises an impedance monitor configured to
measure an impedance value between the first and second earpieces.
The impedance monitor may generate an estimate of a thermal contact
of the first and second earpieces responsive to the impedance
value. The impedance monitor may estimate a poor thermal contact of
the first and second earpieces when the impedance value indicates
an open circuit. The impedance monitor may be configured to
determine whether the first and second earpieces were in position
in the subject's ear canals during administration of the first and
second control signals to thereby determine a patient compliance
with treatment protocol.
[0010] In some embodiments, the first and second heat sinks each
comprise an outer portion positioned outside of the respective
first and second earpieces and an inner portion positioned inside
respective earpiece internal cavities. The first and second heat
sink outer portions may include a plurality of fins.
[0011] In some embodiments, the first and second heat sinks
comprise aluminum and have a weight between about 30 grams and
about 70 grams.
[0012] In some embodiments, the first and second earpieces are
formed from a rigid, thermally-conductive material.
[0013] In some embodiments, the first and second earpieces comprise
aluminum.
[0014] In some embodiments, the first and second earpieces weigh
about 9 grams or less or about 4 grams or less.
[0015] In some embodiments, each of the first and second
thermoelectric devices comprise a first plurality of thermoelectric
devices and a second plurality of thermoelectric devices
respectively. The first plurality of thermoelectric devices may be
thermally coupled to one another and the second plurality of
thermoelectric devices may be thermally coupled to one another.
[0016] In some embodiments, the first and second thermoelectric
devices comprise a thin film thermoelectric device.
[0017] In some embodiments, the device includes a headpiece
configured to position the first earpiece in the right ear canal of
the subject and to position the second earpiece in the left ear
canal of the subject.
[0018] In some embodiments, the first and second control signals
are configured such that the first and second caloric outputs are
continuously temporally varying thermal waveforms and/or actively
controlled waveforms.
[0019] In some embodiments, the first and second control signals
are configured such that the first and second caloric outputs
comprise at least one period of a temporally varying thermal
waveform, and at least one period of stasis.
[0020] In some embodiments, the first caloric output cools one of
the subject's ear canals and the second caloric output heats
another of the subject's ear canals.
[0021] In some embodiments, the first and second caloric outputs
are configured to maintain a vestibular stimulation of the subject
for at least five minutes.
[0022] In some embodiments, the vestibular stimulation for at least
five minutes is sufficient to alter a vestibular phasic firing rate
to thereby induce nystagmus over a period of at least five minutes.
The nystagmus may be sufficient to be detected using
videonystagmography and/or electronystagmography.
[0023] In some embodiments, the first and second earpieces, the
first and second heat sinks, and the first and second
thermoelectric devices are configured so that the first and second
earpieces are cooled by the respective first and second
thermoelectric devices at a rate of about 15.degree. C. per minute
or more and heated by the respective first and second
thermoelectric devices at a rate of about 20.degree. C. per minute
or more.
[0024] In some embodiments, the device includes first and second
fans configured to increase thermal dissipation from the first and
second heat sinks, respectively. The at least one fan may include
at least two fans. In some embodiments, the at least one fan is
configured to direct air in a direction toward the heat sink.
[0025] In some embodiments, the device includes a securing member
configured to secure the first and second earpieces in the ear
canal such that an impedance value between the first and second
earpieces is substantially constant.
[0026] In some embodiments, the securing member comprises a first
ear enclosure having at least one adjustable bladder configured to
increase in size to thereby decrease a pressure from the first
earpiece in the ear canal, and to decrease in size to thereby
increase a pressure from the first earpiece in the ear canal.
[0027] In some embodiments, the first and second earpieces further
comprise a distal end configured to be inserted in the ear canal
and a proximal end connected to the respective first and second
thermal electric devices, and the first and second earpieces
further comprise a insulating member on the proximal end thereof.
The insulating member may comprise silicone and may be configured
for positioning in the concha of the ear.
[0028] In some embodiments, the first and second earpieces include
a pressure relief channel that is sized and configured such that
fluid flows through the pressure relief channel during insertion of
the earpiece into the ear canal to thereby relieve pressure in the
ear canal of the subject during earpiece insertion.
[0029] In some embodiments, a first temperature sensor is coupled
to the first earpiece and a second temperature sensor is coupled to
the second earpiece. The controller may be in communication with
the first and second temperature sensors and may be configured to
receive temperature information from the first and second
temperature sensors. The controller is configured to cease
operation of the waveform generator if the temperature information
indicates a temperature above or below a predefined temperature
range.
[0030] In some embodiments, a first temperature sensor is coupled
to the first heat sink and a second temperature sensor is coupled
to the second heat sink. The controller may be in communication
with the first and second temperature sensors and may be configured
to receive temperature information from the first and second
temperature sensors, and the controller may be configured to cease
operation of the waveform generator if the temperature information
indicates a temperature above or below a predefined temperature
range. The controller may be configured to store the temperature
information and to analyze the temperature information to determine
a likelihood that the first and second earpieces are in thermal
contact with the ear canals of the subject during use.
[0031] In some embodiments, the controller comprises a voltage
monitor that detects a voltage delivered by the waveform generator
to the first and/or second thermoelectric devices, and the
controller may be configured to cease operation of the waveform
generator if the voltage is greater than a predefined voltage
threshold.
[0032] In some embodiments, a wired connection is between the
controller and the first and second thermoelectric devices, and the
wired connection is configured to deliver the first and second
control signals to the first and second thermoelectric device. A
first temperature sensor may be coupled to the first heat sink and
a second temperature sensor coupled to the second heat sink. The
first and second temperature sensors may be configured to transmit
temperature information wirelessly. The first and second
temperature sensors may be configured to transmit temperature
information wirelessly to the controller. In some embodiments, the
first and second temperature sensors may be configured to transmit
temperature information wirelessly to an external device.
[0033] In some embodiments, the first and second caloric outputs
are actively controlled waveforms. The waveforms of the first and
second caloric outputs may be independently controlled based on one
or more of the following parameters: temperature amplitude,
frequency, time varying frequency, a phasic relationship between
the waveforms of the first and second caloric outputs, stochastic
and/or structured noise modulation of a temperature, frequency
and/or phase of the waveforms of the first and second caloric
outputs.
[0034] In some embodiments, methods for delivering caloric
stimulation to a subject, the method include positioning at least a
portion of an in-ear stimulation device in the ear canals of the
subject. The in-ear stimulation device includes (a) first and
second earpieces configured to be insertable into the ear canals of
the subject; (b) at least first and second thermoelectric devices
thermally coupled to respective ones of the first and second
earpieces; and (c) a first heat sink thermally coupled to the first
thermoelectric device opposite the first earpiece and a second heat
sink thermally coupled to the second thermoelectric device opposite
the second earpiece. The methods further include delivering a first
control signal to control a first caloric output to the first
thermoelectric device and a second control signal to control a
second caloric output to the second caloric device such that the
first and second thermoelectric devices effect corresponding
temperature changes to the first and second earpieces,
respectively, to deliver caloric stimulation to the subject.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] The accompanying drawings, which are incorporated in and
constitute a part of the specification, illustrate embodiments of
the invention and, together with the description, serve to explain
principles of the invention.
[0036] FIG. 1 is a side view of a bilateral caloric vestibular
stimulation device and controller according to some embodiments of
the present invention;
[0037] FIG. 2 is an exploded view of the bilateral caloric
vestibular stimulation device of FIG. 1;
[0038] FIG. 3 is a front and side view of a bilateral caloric
vestibular stimulation device according to some embodiments of the
present invention;
[0039] FIG. 4 is a side view of an earpiece with an inflatable
cushion according to some embodiments of the present invention;
[0040] FIG. 5 is a side view of an earpiece with an insulative
sleeve according to some embodiments of the present invention;
[0041] FIG. 6A is an exploded perspective view of an earpiece and
heat sink according to some embodiments of the present
invention;
[0042] FIG. 6B is a side view of an earpiece and heat sink
according to some embodiments of the present invention;
[0043] FIGS. 6C-6E are perspective, side and cross-sectional views,
respectively, of an earpiece according to some embodiments of the
present invention;
[0044] FIG. 7 is a schematic diagram of a bilateral caloric
vestibular stimulation system according to some embodiments of the
present invention;
[0045] FIG. 8 is a schematic diagram of the controller and
earpieces of the bilateral thermal stimulation system of FIG. 7;
and
[0046] FIGS. 9-20 are exemplary treatment waveforms that may be
delivered using a bilateral caloric vestibular stimulation device
according to embodiments of the present invention.
[0047] FIG. 21 is a graph of nystagmus measured by
electronystagmography according to some embodiments of the present
invention.
[0048] FIG. 22 is a graph of a 1/f weighted waveform over time
according to some embodiments of the present invention.
[0049] FIGS. 23A-F are schematic diagrams of various non-limiting
examples of waveform stimuli that may be used to carry out the
present invention. While each line A through E illustrates several
cycles of a given frequency and waveform shape, note that
"waveform" herein generally refers to a single cycle of a given
frequency and waveform shape.
DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION
[0050] The present invention now will be described hereinafter with
reference to the accompanying drawings and examples, in which
embodiments of the invention are shown. This invention may,
however, be embodied in many different forms and should not be
construed as limited to the embodiments set forth herein. Rather,
these embodiments are provided so that this disclosure will be
thorough and complete, and will fully convey the scope of the
invention to those skilled in the art.
[0051] Like numbers refer to like elements throughout. In the
figures, the thickness of certain lines, layers, components,
elements or features may be exaggerated for clarity.
Definitions
[0052] The terminology used herein is for the purpose of describing
particular embodiments only and is not intended to be limiting of
the invention. As used herein, the singular forms "a," "an" and
"the" are intended to include the plural forms as well, unless the
context clearly indicates otherwise. It will be further understood
that the terms "comprises" and/or "comprising," when used in this
specification, specify the presence of stated features, steps,
operations, elements, and/or components, but do not preclude the
presence or addition of one or more other features, steps,
operations, elements, components, and/or groups thereof. As used
herein, the term "and/or" includes any and all combinations of one
or more of the associated listed items. As used herein, phrases
such as "between X and Y" and "between about X and Y" should be
interpreted to include X and Y. As used herein, phrases such as
"between about X and Y" mean "between about X and about Y." As used
herein, phrases such as "from about X to Y" mean "from about X to
about Y."
[0053] Unless otherwise defined, all terms (including technical and
scientific terms) used herein have the same meaning as commonly
understood by one of ordinary skill in the art to which this
invention belongs. It will be further understood that terms, such
as those defined in commonly used dictionaries, should be
interpreted as having a meaning that is consistent with their
meaning in the context of the specification and relevant art and
should not be interpreted in an idealized or overly formal sense
unless expressly so defined herein. Well-known functions or
constructions may not be described in detail for brevity and/or
clarity.
[0054] It will be understood that when an element is referred to as
being "on," "attached" to, "connected" to, "coupled" with,
"contacting," etc., another element, it can be directly on,
attached to, connected to, coupled with or contacting the other
element or intervening elements may also be present. In contrast,
when an element is referred to as being, for example, "directly
on," "directly attached" to, "directly connected" to, "directly
coupled" with or "directly contacting" another element, there are
no intervening elements present. It will also be appreciated by
those of skill in the art that references to a structure or feature
that is disposed "adjacent" another feature may have portions that
overlap or underlie the adjacent feature.
[0055] Spatially relative terms, such as "under," "below," "lower,"
"over," "upper" and the like, may be used herein for ease of
description to describe one element or feature's relationship to
another element(s) or feature(s) as illustrated in the figures. It
will be understood that the spatially relative terms are intended
to encompass different orientations of the device in use or
operation in addition to the orientation depicted in the figures.
For example, if the device in the figures is inverted, elements
described as "under" or "beneath" other elements or features would
then be oriented "over" the other elements or features. Thus, the
exemplary term "under" can encompass both an orientation of "over"
and "under." The device may be otherwise oriented (rotated 90
degrees or at other orientations) and the spatially relative
descriptors used herein interpreted accordingly. Similarly, the
terms "upwardly," "downwardly," "vertical," "horizontal" and the
like are used herein for the purpose of explanation only unless
specifically indicated otherwise.
[0056] It will be understood that, although the terms "first,"
"second," etc. may be used herein to describe various elements,
these elements should not be limited by these terms. These terms
are only used to distinguish one element from another. Thus, a
"first" element discussed below could also be termed a "second"
element without departing from the teachings of the present
invention. The sequence of operations (or steps) is not limited to
the order presented in the claims or figures unless specifically
indicated otherwise.
[0057] The present invention is described below with reference to
block diagrams and/or flowchart illustrations of methods, apparatus
(systems) and/or computer program products according to embodiments
of the invention. It is understood that each block of the block
diagrams and/or flowchart illustrations, and combinations of blocks
in the block diagrams and/or flowchart illustrations, can be
implemented by computer program instructions. These computer
program instructions may be provided to a processor of a general
purpose computer, special purpose computer, and/or other
programmable data processing apparatus to produce a machine, such
that the instructions, which execute via the processor of the
computer and/or other programmable data processing apparatus,
create means for implementing the functions/acts specified in the
block diagrams and/or flowchart block or blocks.
[0058] These computer program instructions may also be stored in a
computer-readable memory that can direct a computer or other
programmable data processing apparatus to function in a particular
manner, such that the instructions stored in the computer-readable
memory produce an article of manufacture including instructions
which implement the function/act specified in the block diagrams
and/or flowchart block or blocks.
[0059] The computer program instructions may also be loaded onto a
computer or other programmable data processing apparatus to cause a
series of operational steps to be performed on the computer or
other programmable apparatus to produce a computer-implemented
process such that the instructions which execute on the computer or
other programmable apparatus provide steps for implementing the
functions/acts specified in the block diagrams and/or flowchart
block or blocks.
[0060] Accordingly, the present invention may be embodied in
hardware and/or in software (including firmware, resident software,
micro-code, etc.). Furthermore, embodiments of the present
invention may take the form of a computer program product on a
computer-usable or computer-readable non-transient storage medium
having computer-usable or computer-readable program code embodied
in the medium for use by or in connection with an instruction
execution system.
[0061] The computer-usable or computer-readable medium may be, for
example but not limited to, an electronic, optical,
electromagnetic, infrared, or semiconductor system, apparatus, or
device. More specific examples (a non-exhaustive list) of the
computer-readable medium would include the following: an electrical
connection having one or more wires, a portable computer diskette,
a random access memory (RAM), a read-only memory (ROM), an erasable
programmable read-only memory (EPROM or Flash memory such as an SD
card), an optical fiber, and a portable compact disc read-only
memory (CD-ROM).
[0062] As used herein, the term "vestibular system" has the meaning
ascribed to it in the medical arts and includes but is not limited
to those portions of the inner ear known as the vestibular
apparatus and the vestibulocochlear nerve. The vestibular system,
therefore, further includes, but is not limited to, those parts of
the brain that process signals from the vestibulocochlear
nerve.
[0063] "Treatment," "treat," and "treating" refer to reversing,
alleviating, reducing the severity of, delaying the onset of,
inhibiting the progress of, or preventing a disease or disorder as
described herein, or at least one symptom of a disease or disorder
as described herein (e.g., treating one or more of tremors,
bradykinesia, rigidity or postural instability associated with
Parkinson's disease; treating one or more of intrusive symptoms
(e.g., dissociative states, flashbacks, intrusive emotions,
intrusive memories, nightmares, and night terrors), avoidant
symptoms (e.g., avoiding emotions, avoiding relationships, avoiding
responsibility for others, avoiding situations reminiscent of the
traumatic event), hyperarousal symptoms (e.g., exaggerated startle
reaction, explosive outbursts, extreme vigilance, irritability,
panic symptoms, sleep disturbance) associated with post-traumatic
stress disorder). In some embodiments, treatment may be
administered after one or more symptoms have developed. In other
embodiments, treatment may be administered in the absence of
symptoms. For example, treatment may be administered to a
susceptible individual prior to the onset of symptoms (e.g., in
light of a history of symptoms and/or in light of genetic or other
susceptibility factors). Treatment may also be continued after
symptoms have resolved--for example, to prevent or delay their
recurrence. Treatment may comprise providing neuroprotection,
enhancing cognition and/or increasing cognitive reserve. Treatment
may be as an adjuvant treatment as further described herein.
[0064] "Adjuvant treatment" as described herein refers to a
treatment session in which the delivery of one or more thermal
waveforms to the vestibular system and/or the nervous system of a
patient modifies the effect(s) of one or more active agents and/or
therapies. For example, the delivery of one or more thermal
waveforms to the vestibular system and/or the nervous system of a
patient may enhance the effectiveness of a pharmaceutical agent (by
restoring the therapeutic efficacy of a drug to which the patient
had previously become habituated, for example). Likewise, the
delivery of one or more thermal waveforms to the vestibular system
and/or the nervous system of a patient may enhance the
effectiveness of counseling or psychotherapy. In some embodiments,
delivery of one or more thermal waveforms to the vestibular system
and/or the nervous system of a patient may reduce or eliminate the
need for one or more active agents and/or therapies. Adjuvant
treatments may be effectuated by delivering one or more thermal
waveforms to the vestibular system and/or the nervous system of a
patient prior to, currently with and/or after administration of one
or more active agents and/or therapies.
[0065] "Chronic treatment," "Chronically treating," or the like
refers to a therapeutic treatment carried out at least 2 to 3 times
a week (or in some embodiments at least daily) over an extended
period of time (typically at least one to two weeks, and in some
embodiments at least one to two months), for as long as required to
achieve and/or maintain therapeutic efficacy for the particular
condition or disorder for which the treatment is carried out.
[0066] "Waveform" or "waveform stimulus" as used herein refers to
the thermal stimulus (heating, cooling) delivered to the ear canal
of a subject through a suitable apparatus to carry out the methods
described herein. "Waveform" is not to be confused with
"frequency," the latter term concerning the rate of delivery of a
particular waveform. The term "waveform" is used herein to refer to
one complete cycle thereof, unless additional cycles (of the same,
or different, waveform) are indicated. As discussed further below,
time-varying waveforms may be preferred over constant temperature
applications in carrying out the present invention.
[0067] "Actively controlled waveform" or "actively controlled
time-varying waveform" as used herein refers to a waveform stimulus
in which the intensity of the stimulus or temperature of the
earpiece delivering that stimulus, is repeatedly adjusted, or
substantially continuously adjusted or driven, throughout the
treatment session, typically by control circuitry or a controller
in response to active feedback from a suitably situated temperature
sensor (e.g., a temperature sensor mounted on the earpiece being
driven by a thermoelectric device), so that drift of the thermal
stimulus from that which is intended for delivery which would
otherwise occur due to patient contact is minimized
[0068] In general, a waveform stimulus used to carry out the
present invention comprises a leading edge, a peak, and a trailing
edge. If a first waveform stimulus is followed by a second waveform
stimulus, then the minimal stimulus point therebetween is referred
to as a trough.
[0069] The first waveform of a treatment session is initiated at a
start point, which start point may be the at or about the subject's
body temperature at the time the treatment session is initiated
(typically a range of about 34 to 38 degrees Centigrade, around a
normal body temperature of about 37 degrees Centigrade. The lower
point, 34, is due to the coolness of the ear canal. It typically
will not be above about 37 unless the patient is febrile). Note
that, while the subject's ear canal may be slightly less than body
temperature (e.g., about 34 to 36 degrees Centigrade), the starting
temperature for the waveform is typically body temperature (the
temp of the inner ear), or about 37 degrees Centigrade. In some
embodiments, however, the temperature of the treatment device may
not have equilibrated with the ear canal prior to the start of the
treatment session, and in such case the start point for at least
the first waveform stimulus may be at a value closer to room
temperature (about 23 to 26 degrees Centigrade).
[0070] The waveform leading edge is preferably ramped or
time-varying: that is, the amplitude of the waveform increases
through a plurality of different temperature points over time
(e.g., at least 5, 10, or 15 or more distinct temperature points,
and in some embodiments at least 50, 100, or 150 or more distinct
temperature points, from start to peak). The shape of the leading
edge may be a linear ramp, a curved ramp (e.g., convex or concave;
logarithmic or exponential), or a combination thereof. A vertical
cut may be included in the waveform leading edge, so long as the
remaining portion of the leading edge progresses through a
plurality of different temperature points over time as noted
above.
[0071] The peak of the waveform represents the amplitude of the
waveform as compared to the subject's body temperature. In general,
an amplitude of at least 5 or 7 degrees Centigrade is preferred for
both heating and cooling waveform stimulation. In general, an
amplitude of up to 20 degrees Centigrade is preferred for cooling
waveform stimulation. In general, an amplitude of up to 8 or 10
degrees Centigrade is preferred for heating waveform stimulus. The
peak of the waveform may be truncated (that is, the waveform may
reach an extended temperature plateau), so long as the desired
characteristics of the leading edge, and preferably trailing edge,
are retained. For heating waveforms, truncated peaks of long
duration (that is, maximum heat for a long duration) are less
preferred, particularly at higher heats, due to potential burning
sensation. In some embodiments, the temperature applied in the ear
canal is between about 13.degree. C. and 43.degree. C. The
temperature applied in the ear canal range from about 22-24.degree.
C. below body temperature to about 6-10.degree. C. above body
temperature.
[0072] The waveform trailing edge is preferably ramped or
time-varying: that is, the amplitude of the waveform decreases
through a plurality of different temperature points over time
(e.g., at least 5, 10, or 15 or more distinct temperature points,
or in some embodiments at least 50, 100, or 150 or more distinct
temperature points, from peak to trough). The shape of the trailing
edge may be a linear ramp, a curved ramp (e.g., convex or concave;
logarithmic or exponential), or a combination thereof. A vertical
cut may again be included in the waveform trailing edge, so long as
the remaining portion of the trailing edge progresses through a
plurality of different temperature points over time as noted
above.
[0073] The duration of the waveform stimulus (or the frequency of
that waveform stimulus) is the time from the onset of the leading
edge to either the conclusion of the trailing edge or (in the case
of a vertically cut waveform followed by a subsequent waveform). In
general, each waveform stimulus has a duration, or frequency, of
from one or two minutes up to ten or twenty minutes.
[0074] A treatment session may have a total duration of five or ten
minutes, up to 20 or 40 minutes or more, depending on factors such
as the specific waveform or waveforms delivered, the patient, the
condition being treated, etc. For example, in some embodiments a
treatment session may be 60 minutes or more. In some embodiments,
treatment sessions may include breaks between stimulation, such as
breaks of a minute or more.
[0075] In a treatment session, a plurality of waveforms may be
delivered in sequence. In general, a treatment session will
comprise 1, 2 or 3 waveforms, up to about 10 or 20 or more
waveforms delivered sequentially. Each individual waveform may be
the same, or different, from the other. When a waveform is followed
by a subsequent waveform, the minimum stimulus point (minimum
heating or cooling) between is referred to as the trough. Like a
peak, the trough may be truncated, so long as the desired
characteristics of the trailing edge, and the following next
leading edge, are retained. While the trough may represent a return
to the subject's current body temperature, in some embodiments
minor thermal stimulation (cooling or heating; e.g., by 1 or 2
degrees up to 4 or 5 degrees Centigrade) may continue to be applied
at the trough (or through a truncated trough).
[0076] Treatment sessions are preferably once a day, though in some
embodiments more frequent treatment sessions (e.g. two or three
times a day) may be employed. Day-to-day treatments may be by any
suitable schedule: every day; every other day; twice a week; as
needed by the subject, etc. The overall pattern of treatment is
thus typically chronic (in contrast to "acute," as used in one-time
experimental studies).
[0077] Subjects may be treated with the present invention for any
reason. In some embodiments, disorders for which treatment may be
carried out include, include, but are not limited to, migraine
headaches (acute and chronic), depression, anxiety (e.g. as
experienced in post-traumatic stress disorder ("PTSD") or other
anxiety disorders), spatial neglect, Parkinson's disease, seizures
(e.g., epileptic seizures), diabetes (e.g., type II diabetes),
etc.
[0078] Headaches that may be treated by the methods and apparatuses
of the present invention include, but are not limited to, primary
headaches (e.g., migraine headaches, tension-type headaches,
trigeminal autonomic cephalagias and other primary headaches, such
as cough headaches and exertional headaches) and secondary
headaches. See, e.g., International Headache Society Classification
ICHD-II.
[0079] Migraine headaches that may be treated by the methods and
apparatuses of the present invention may be acute/chronic and
unilateral/bilateral. The migraine headache may be of any type,
including, but not limited to, migraine with aura, migraine without
aura, hemiplegic migraine, opthalmoplegic migraine, retinal
migraine, basilar artery migraine, abdominal migraine, vestibular
migraine and probable migraine. As used herein, the term "vesibular
migraine" refers to migraine with associated vestibular symptoms,
including, but not limited to, head motion intolerance,
unsteadiness, dizziness and vertigo. Vestibular migraine includes,
but is not limited to, those conditions sometimes referred to as
vertigo with migraine, migraine-associated dizziness,
migraine-related vestibulopathy, migrainous vertigo and
migraine-related vertigo. See, e.g., Teggi et al., HEADACHE
49:435-444 (2009).
[0080] Tension-type headaches that may be treated by the methods
and apparatuses of the present invention, include, but are not
limited to, infrequent episodic tension-type headaches, frequent
episodic tension-type headaches, chronic tension-type headache and
probable tension-type headache.
[0081] Trigeminal autonomic cephalagias that may be treated by the
methods and apparatuses of the present invention, include, but are
not limited to, cluster headaches, paroxysmal hemicranias,
short-lasting unilateral neuralgiform headache attacks with
conjunctival injection and tearing and probable trigeminal
autonomic cephalagias. Cluster headache, sometimes referred to as
"suicide headache," is considered different from migraine headache.
Cluster headache is a neurological disease that involves, as its
most prominent feature, an immense degree of pain. "Cluster" refers
to the tendency of these headaches to occur periodically, with
active periods interrupted by spontaneous remissions. The cause of
the disease is currently unknown. Cluster headaches affect
approximately 0.1% of the population, and men are more commonly
affected than women (in contrast to migraine headache, where women
are more commonly affected than men).
[0082] Other primary headaches that may be treated by the methods
and apparatuses of the present invention, include, but are not
limited to, primary cough headache, primary exertional headache,
primary headache associated with sexual activity, hypnic headache,
primary thunderclap headache, hemicranias continua and new
daily-persistent headache.
[0083] Additional disorders and conditions that can be treated by
the methods and systems of the present invention include, but are
not limited to, neuropathic pain (e.g., migraine headaches),
tinnitus, brain injury (acute brain injury, excitotoxic brain
injury, traumatic brain injury, etc.), spinal cord injury, body
image or integrity disorders (e.g., spatial neglect), visual
intrusive imagery, neuropsychiatric disorders (e.g. depression),
bipolar disorder, neurodegenerative disorders (e.g. Parkinson's
disease), asthma, dementia, insomnia, stroke, cellular ischemia,
metabolic disorders, (e.g., diabetes), post-traumatic stress
disorder ("PTSD"), addictive disorders, sensory disorders, motor
disorders, and cognitive disorders.
[0084] Sensory disorders that may be treated by the methods and
apparatuses of the present invention include, but are not limited
to, vertigo, dizziness, seasickness, travel sickness cybersickness,
sensory processing disorder, hyperacusis, fibromyalgia, neuropathic
pain (including, but not limited to, complex regional pain
syndrome, phantom limb pain, thalamic pain syndrome, craniofacial
pain, cranial neuropathy, autonomic neuropathy, and peripheral
neuropathy (including, but not limited to, entrapment-, heredity-,
acute inflammatory-, diabetes-, alcoholism-, industrial toxin-,
Leprosy-, Epstein Barr Virus-, liver disease-, ischemia-, and
drug-induced neuropathy)), numbness, hemianesthesia, and nerve/root
plexus disorders (including, but not limited to, traumatic
radiculopathies, neoplastic radiculopathies, vaculitis, and
radiation plexopathy).
[0085] Motor disorders that may be treated by the method and
apparatuses of the present invention include, but are not limited
to, upper motor neuron disorders such as spastic paraplegia, lower
motor neuron disorders such as spinal muscular atrophy and bulbar
palsy, combined upper and lower motor neuron syndromes such as
familial amyotrophic lateral sclerosis and primary lateral
sclerosis, and movement disorders (including, but not limited to,
Parkinson's disease, tremor, dystonia, Tourette Syndrome,
myoclonus, chorea, nystagmus, spasticity, agraphia, dysgraphia,
alien limb syndrome, and drug-induced movement disorders).
[0086] Cognitive disorders that may be treated by the method and
apparatuses of the present invention include, but are not limited
to, schizophrenia, addiction, anxiety disorders, depression,
bipolar disorder, dementia, insomnia, narcolepsy, autism,
Alzheimer's disease, anomia, aphasia, dysphasia, parosmia, spatial
neglect, attention deficit hyperactivity disorder, obsessive
compulsive disorder, eating disorders, body image disorders, body
integrity disorders, post-traumatic stress disorder, intrusive
imagery disorders, and mutism.
[0087] Metabolic disorders that may be treated by the present
invention include diabetes (particularly type II diabetes),
hypertension, obesity, etc.
[0088] Addiction, addictive disorders, or addictive behavior that
may be treated by the present invention includes, but is not
limited to, alcohol addiction, tobacco or nicotine addiction (e.g.,
using the present invention as a smoking cessation aid), drug
addictions (e.g., opiates, OxyContin, amphetamines, etc.), food
addictions (compulsive eating disorders), etc.
[0089] In some embodiments, the subject has two or more of the
above conditions, and both conditions are treated concurrently with
the methods and systems of the invention. For example, a subject
with both depression and anxiety (e.g., PTSD) can be treated for
both, concurrently, with the methods and systems of the present
invention.
[0090] The methods and systems according to embodiments of the
present invention utilize thermoelectric devices (TEDs) to induce
physiological and/or psychological responses in a subject for
medically diagnostic and/or therapeutic purposes. Subjects to be
treated and/or stimulated with the methods, devices and systems of
the present invention include both human subjects and animal
subjects. In particular, embodiments of the present invention may
be used to diagnose and/or treat mammalian subjects such as cats,
dogs, monkeys, etc. for medical research or veterinary
purposes.
[0091] As noted above, embodiments according to the present
invention utilize TEDs to provide an in-ear stimulator for
administering thermal stimulation in the ear canal of the subject.
The ear canal serves as a useful conduit to the individual's
vestibular system and to the vestibulocochlear nerve. Without
wishing to be bound by any particular theory, it is believed that
thermal stimulation of the vestibular system is translated into
electrical stimulation within the central nervous system ("CNS")
and propagated throughout the brain, including but not limited to
the brain stem, resulting in certain physiological changes that may
be useful in treating various disease states (increased blood flow,
generation of neurotransmitters, etc). See, e.g., Zhang, et al.
Chinese Medical J. 121:12:1120 (2008) (demonstrating increased
ascorbic acid concentration in response to cold water CVS).
System
[0092] As illustrated in FIGS. 1-2, an in-ear stimulation apparatus
10 includes a support or headband 12, earphones 14 and a controller
and/or power connection or cable 16. The earphones 14 include
respective earpieces 100 that are configured to be positioned in
the ear of a patient or subject. As illustrated in FIG. 2, the
earphones 14 include a cushion 20 connected a housing 22 having
housing members 24 and 26, the earpiece 100, a thermoelectric (TED)
device 30, a temperature sensor 40, a heat sink 50 with a heat sink
spacer 52 and a heat sink base 54 with heat dissipating fins 56 and
apertures 58, and two air flow devices or fans 60 and 62. The
housing 22 includes ventilation apertures 27 for increasing air
flow, e.g., via the fans 60, 62 for increasing dissipation of
thermal energy. The housing 22 also includes cable apertures 28 for
holding electrical connections to the cable 16 such as a power
and/or communication cable that controls operations of the fans 60,
62, the TED 30, and/or the temperature sensor 40. The electrical
connections (not shown) may further pass through the apertures 58
in the heat sink base to connect with the TED 30 and/or temperature
sensor 40.
[0093] As illustrated, the temperature sensor 40 may be inserted
into a cavity or void in the earpiece 100. However, the temperature
sensor 40 may be positioned in any suitable position to sense a
temperature of the earpiece 100. As shown in FIG. 6E, the
temperature sensor 40 may be inserted into a cavity 102.
[0094] The TED 30 is thermally coupled between the earpiece 100 and
the heat sink 50 as illustrated in FIG. 2. Although the device 10
is illustrated with one TED 30 in FIG. 2, it should be understood
that, in some embodiments, two or more TEDs may be used. In some
embodiments, the TEDs are impregnated with and/or connect to the
earpiece 100 and heat sink 50 with epoxy to increase a thermal
conductivity between the TEDs, the earpiece 100 and/or the heat
sink 50. Thus, the TEDs between the earpiece 100 and the heat sink
50 create a temperature difference between the earpiece 100 and the
heat sink 50 when a voltage is applied to the TEDs so that the
temperature of the earpiece 100 may be increase and/or decreased.
The TEDs may be controlled by a controller 200, and the efficiency
with which the temperature of the earpiece 100 is changed may be
increased by the heat sink 50, which dissipates excess heat or cold
from the side of the TEDs opposite the earpiece 100 into the
surrounding environment. The heat sink 50 may be passively cooled
or actively cooled, for example, by using a fan or other cooling
system to further increase heat dissipation. As discussed above,
the ear canal may serve as a useful conduit to the subject's
vestibular system and/or to the vestibulocochlear nerve for thermal
stimulation for providing caloric vestibular stimulation (CVS)
and/or cranial nerve stimulation. In some embodiments, commercially
available heat sinks may be used, such as from Wakefield Thermal
Solutions, Inc., Pelham, N.H., U.S.A. (e.g., Part Number:
609-50AB).
[0095] In some embodiments, the slew rate for the earpieces 100 is
about 15.degree. C./minute or greater for cooling the earpiece 100
and 20.degree. C./minute or greater for heating the earpiece 100.
Heating the earpiece may be faster and more efficient than
cooling.
[0096] Thin film TEDs, Peltier coolers/heaters or transducers may
be used as transducers in some embodiments, including, but not
limited to, the thin film TEDs described in U.S. Pat. No. 6,300,150
and U.S. Patent Publication Nos. 2007/0028956 and 2006/0086118;
however, any suitable TED, such as semiconductor diode TED's, may
be used. Such TEDs may also incorporate a temperature sensing
function, so that temperature sensing can be accomplished through
the same device without the need for a separate temperature sensor.
In some embodiments, the temperature sensor 40 may be a thermistor
or other temperature sensing element that is disposed in the distal
end of the earpiece and used as a feedback sensor to allow the
controller 200 to maintain the proper temperature for a given
thermal waveform. TEDs are commercially available from TE
Technology, Inc, (Traverse City, Mich., USA), Nextreme Thermal
Solutions (Durham, N.C., USA)(e.g., OptoCooler.TM. Series (UPT40
and UPF4), Eteg.TM. UPF40) and Micropelt, GmbH (Freiburg,
Germany)(e.g., MPC-D303 and MPC-D305). Although embodiments
according to the invention are described herein with respect to
TEDs, it should be understood that any suitable type of thermal
device may be used, including optical heating (e.g., using a laser)
and ultrasound heating (e.g., a piezoelectric heating device). TEDs
may be provided that include a heat flux of 80-120 W/cm.sup.2 or
more. The TEDs may be generally rectangular in shape, with typical
rectangular areas being about 2.times.1 mm or 5.times.2 mm or more
and having a height profile of 1 mm or 0.65 mm or 0.5 mm or less.
In particular embodiments, the TED is about a rectangular shape
having sides of about 12-13 mm and a height profile of about 3 mm.
When more than one TED is used, the TEDs may be connected in
parallel or in series to provide thermal changes to a desired
region of an earpiece and/or heat sink.
[0097] In some embodiments, the cushion 20 and/or heat sink spacer
52 may be sized and/or configured to increase comfort and/or the
fit of the earpiece 100 in the subject's ear canal. The cushion 20
and/or spacer 52 may be sized or may be adjustable so as to place
the earpiece 100 in the ear canal with sufficient thermal contact,
but without placing excessive pressure on the ear canal. In some
embodiments, the controller 200 controls operation of the TED 30
via additional electrical connections/controllers, such as a PCB
(not shown), which may be electrically connected to the TED 30
either via cables or between the earpiece 100 and the heat sink 50
and may provide a power supply and control signals for operating
the TEDs, such as control signals to control desired temperatures
and temperature changes, from the controller. The controller 200
receives feedback from the temperature sensor 40 in the distal end
of the earpiece that may properly modulate the power applied to the
TED so as to generate the desired thermal waveform. In addition,
the cable 16 may include an electrical connection between the two
earpieces 100 that may be used to provide an impedance measurement
to estimate a degree of electrical and thermal contact between the
earpieces. The earpiece 100 may further include a temperature
sensor/controller so that the TEDs may provide a temperature
stability, e.g., of about 0.1-0.5.degree. C.
[0098] It should be understood that other configurations for
supporting the headphones and/or earpieces may be used, including
support bands that are positioned under the chin or over the ear,
for example, as may be used with audio earphones. For example, FIG.
3 illustrates four straps or headbands 12' and earphones 14'. The
headbands 12' may provide increased stability of the earphones 14'
to provide potentially improved thermal contact of the earpieces
(not shown).
[0099] Additional configurations may be used to potentially
increase comfort and/or fit of the headset and/or improve a thermal
contact between the earpiece 100 and the ear canal. For example, as
shown in FIG. 4, the cushion 20 can include an inlet 21 for
inflating an inner chamber of the cushion 20. In this
configuration, the distance of the earpiece 100 from the subject's
head may be controlled by adjusting an amount of fluid, such as
air, that is added into or released from the cushion 20. As the
cushion 20 inflates, the earpiece 100 is pushed further away from
the subject's head, and when the cushion 20 is deflated, the
earpiece 100 may be pressed closer to the subject's head for a
tighter fit between the earpiece 100 and the ear canal.
Earpiece
[0100] In some embodiments as shown in FIG. 5, a sheath 101 may be
provided to insulate the base portion of the earpiece 100. Without
wishing to be bound by theory, is currently believed that changes
in temperature of the earpiece should be concentrated at a part of
the earpiece 100 that is inserted the deepest into the ear canal
for increasing caloric vestibular stimulation. Accordingly, the
sheath 101 may reduce a thermal coupling of the base of the
earpiece 100 with the subject's ear to provide more efficient
heating and cooling to the distal end of the earpiece 100. In
addition, the sheath 101 in some embodiments may provide additional
cushioning or padding for increased comfort to the user. The sheath
101 may be formed of any suitable material, such as elastomer or
polymeric material, medical grade silicone and the like. Moreover,
in some embodiments, the earpiece 100 may be covered with a
thermally conductive material to increase a thermal contact with
the ear canal. In some embodiments, a thermally conductive material
may be applied only to the distal end of the earpiece 100; however,
any portion of the earpiece 100 may incorporate thermally
conductive materials. Any suitable thermally conductive material
may be used, including gels, water, water-based lubricants, and the
like. In some embodiments, the thermally conductive material is a
coating material that is applied and reapplied to the earpiece 100
before each use. In some embodiments, the thermally conductive
material may be a sheath or sleeve (e.g., a gel or plastic sleeve)
that is fitted to the earpiece during use and may be reusable.
Therefore, it should be understood that coatings or sheath
materials may be provided to selectively thermally insulate the
earpiece 100 or to increase a thermal conductivity between the
earpiece 100 and the ear canal.
[0101] In some embodiments, the sheath 101 may be a layer (e.g.,
around 1 mm) that is selectively applied to the base of the
earpiece 100 but not the distal tip portion that is inserted into
the ear canal. In addition to thermally insulating the base of the
earpiece 100, the sheath 101 may also provide a cushion against the
inward pressure of the headset, thus enhancing patient comfort
during the CVS therapy application. The sheath 101 may also be
electrically insulating as well as thermally insulating.
[0102] As shown in FIG. 6A, the earpiece 100 may be connected to
the heat sink 50 by the TED 30. The heat sink 50 is thermally
isolated from the earpiece 100. The TEDs 30 are positioned on a
surface 53 of a spacer portion 52 of the heat sink 50 so that
thermal coupling between the TED 30 and the earpiece 100 may be
achieved. The TEDs 30 are also thermally coupled to the heat sink
50 on a side of the TEDs that are opposite to the earpiece 100 so
as to create a thermal differential between the heat sink 50 and
the earpiece 100. The TED 30 may be adhered to the earpiece 100
using a thermally conductive adhesive, such as silver. It should be
understood that the TED 30 may be thermally connected to the
earpiece 100 and heat sink 50 at any suitable location to provide a
thermal differential between the heat sink 50 and the earpiece
100.
[0103] In some embodiments, the earpiece 100 may be connected to an
electrical connection or electrode 45. Although the electrode 45 is
illustrated on an outer surface of the earpiece 100, it should be
understood that the electrode 45 may be connected to interior
surfaces or embedded in the earpiece in any configuration that is
suitable to electrically connect the electrode 45 with the
earpiece. In this configuration, a relatively small electrical
current may be applied via the electrode 45 to both earpieces 100
shown, e.g., in FIG. 1. Without wishing to be bound by theory, it
is believed that if generally good thermal contact between the
earpiece 100 and the ear canal is achieved, then the patient's
body/head will generally complete an electrical circuit between the
earpieces 100. Thus, the impedance or other equivalent electrical
measurement between the earpieces 100 may be measured to estimate a
thermal contact between the earpieces 100 and the ear canal of the
patient and/or to measure patient compliance with treatment.
[0104] As shown in FIG. 6B, the TEDs 30 may be disposed between the
base of the earpiece 100 and the heat sink 50 and impregnated with
epoxy 32. In some embodiments, the epoxy 32 provides structural
stability to the earpiece 100, TED 30 and heat sink 50 assembly.
However, it should be understood that any suitable configuration
may be used, and in some embodiments, the epoxy may be omitted
and/or thermally conductive adhesives may be used. Additional
configurations of heat sinks, TEDs and earpieces that may be used
in some embodiments of the present invention are discussed in U.S.
patent application Ser. Nos. 12/970,347 and 12/970,312, filed Dec.
16, 2010, the disclosures of which are hereby incorporated by
reference in their entireties. In this configuration, caloric
vestibular stimulation may be administered to a subject via the
subject's ear canal.
[0105] As shown in FIGS. 6C-6E, the earpiece 100 includes a tip
cavity 102, a base cavity 104, base apertures 106, and an pressure
relief channel 110. The tip cavity 102 is configured to receive a
thermistor or temperature sensor, such as the temperature sensor 40
so that the temperature of the tip of the earpiece 100 may be
monitored. The base cavity 104 is configured to receive the TED 30
such that the TED 30 is mounted on an interior cavity surface of
the earpiece 100 on one side, and the TED 30 is mounted on the heat
sink 50 on the opposite side as described in FIG. 2. The base
apertures 106 are configured to provide a passageway for wires
and/or cables to connect a power source and/or control signal to
the TED 30 and/or temperature sensor 40 or other sensors and/or
monitors that may be used with the earpiece 100.
[0106] The pressure relief channel 110 is configured to provide a
pathway through which air may flow during and/or after insertion of
the earpiece 100 into the ear canal of the patient. Accordingly,
the earpiece 100 may be formed of a rigid material, e.g., a metal
such as aluminum that has an associated specific heat such that the
earpiece may provide a slew rate that is about 15.degree. C./minute
or greater for cooling the earpiece 100 and 20.degree. C./minute or
greater for heating the earpiece 100. However, the rigid surface of
the earpiece 100 may result in a increased pressure during
insertion because the generally non-conformable surface of the
earpiece 100 may seal air inside the ear canal. Thus, the pressure
relief channel 110 may permit additional airflow through the
channel 110 to reduce the pressure in the ear canal during and/or
after the insertion of the earpiece 100 into the ear canal of the
patient. In this configuration, the earpiece comfort and/or fit may
be improved to provide a close thermal contact between the
generally rigid surface of the earpiece 100 and the ear canal of
the patient to increase the efficiency with which the vestibular
nerve may be thermally stimulated. The pressure relief channel 110
may be of a length and depth that is sufficient to provide air flow
from the interior of the ear canal at the distal tip of the
earpiece to the external air outside of the ear canal. For example,
the channel 110 may be generally as long as a side of the earpiece
100 and may be between about 0.5 mm and about 2.0 mm deep.
[0107] Although the pressure relief channel 110 is illustrated as
being on a side of the earpiece 100 that extends nearly vertically
away from the base, it should be understood that the pressure
relief channel 110 may be positioned on any portion of the outer
surface of the earpiece 100. Moreover, in some embodiments, a
pressure relief channel may be positioned on an interior portion of
the earpiece 100 to provide a conduit between the interior ear
canal of the patient and the exterior air.
[0108] In some embodiments, the earpiece 100 may be coated to
prevent degradation of the surface quality. Depending on the
application, the coating may be electrically conductive,
electrically non-conductive, or a combination of both. For example,
the surface of the earpiece 100 may be anodized such that a
non-conductive coating is grown on aluminum using an anodization
process. This process creates an aluminum oxide coating that
renders the surface electrically insulting. The coating is very
thin, however, and there is little if any degradation of the
thermal conductivity. Colorants may be added during the anodization
for a visually enhanced appearance. The aluminum may also be coated
with an electrically conductive material, which can be applied by
painting, dipping, spraying, etc. Such a coating may also prevent
surface degradation by keeping the underlying aluminum from being
exposed to air. The layer can be applied so as to have a minimal
change or no change in the degradation of thermal conductivity. In
particular embodiments, the earpiece 100 may be patterned with more
than one coating, using techniques common in the art, so that both
electrically conductive and non-conductive coatings may coexist on
the earpiece.
[0109] In some embodiments, impedance may be measured using the
electrode 45 in FIG. 6A. Impedance is a complex quantity (that is,
having both real and imaginary parts) that may combine both
resistive (real) and capacitive (imaginary) components, and
impedance may be measured with an alternating current/voltage
method. The capacitance may be measured with electrically insulated
earpieces (e.g., anodized), but electrically insulated earpieces
would generally not permit a measurement of resistance, which would
typically require electrical contact between the earpiece 100 and
the ear canal. The earpiece 100 may be patterned with electrically
insulating and electrically conductive portions so that the base is
anodized and the distal tip has a conductive coating. This would
allow both resistance and capacitance to be measured (or the entire
earpiece could be coated with an electrically conductive material).
In summary, either coating type could be used to measure an
impedance value for estimating a thermal conductivity.
[0110] Although embodiments according to the present invention are
described herein with respect to a device with two earpieces (see,
e.g., the earpieces 100A, 100B in FIG. 8), it should be understood
that in some embodiments, a single earpiece may be used to deliver
thermal vestibular stimulation to one ear canal of a patient. A
single earpiece caloric vestibular stimulation device may utilize a
single earpiece having various combinations of the features
described herein.
Controllers
[0111] FIG. 7 is a block diagram of exemplary embodiments of
controller systems 200 of the present invention for controlling a
thermal output to two earpieces 100A, 100B to administer various
thermal treatment protocols or thermal "prescriptions." As shown in
FIG. 7, in some embodiments, the controller 200 includes a memory
236, a processor 225 and I/O circuits 246 and is operatively and
communicatively coupled to the earpieces 100A, 100B. The processor
225 communicates with the memory 236 via an address/data bus 248
and with the I/O circuits via an address/data bus 249. As will be
appreciated by one of skill in the art, the processor 225 may be
any commercially available or custom microprocessor. The memory 236
is representative of the overall hierarchy of memory devices
containing software and data used to implement the functionality of
the controller 200. Memory 236 may include, but is not limited to,
the following types of devices: cache, ROM, PROM, EPROM, EEPROM,
flash memory, SRAM and DRAM.
[0112] As shown in FIG. 7, the controller memory 236 may comprise
several categories of software and data: an operating system 252,
applications 254, data 256 and input/output (I/O) device drivers
258.
[0113] As will be appreciated by one of skill in the art, the
controller may use any suitable operating system 252, including,
but not limited to, OS/2, AIX, OS/390 or System390 from
International Business Machines Corp. (Armonk, N.Y.), Window CE,
Windows NT, Windows2003, Windows2007 or Windows Vista from
Microsoft Corp. (Redmond, Wash.), Mac OS from Apple, Inc.
(Cupertino, Calif.), Unix, Linux or Android.
[0114] The applications 254 may include one or more programs
configured to implement one or more of the various operations and
features according to embodiments of the present invention. The
applications 254 may include a thermal waveform control module 220
configured to communicate a waveform control signal to one or both
of the TED's of the earpieces 100A, 100B. The applications 254 may
also include an impedance module 222 for measuring an impedance or
other analogous electrical characteristic (e.g., capacitance)
between the earpieces 100A, 100B, a patient module 223 for
monitoring patient-specific data, such as compliance and/or a
safety monitoring module 227. In some embodiments, the memory 236
comprises additional applications, such as a networking module for
connecting to a network, for example, as discussed in U.S.
Provisional Application Ser. No. 61/424,474 filed Dec. 17, 2010,
the disclosure of which is incorporated by reference in its
entirety. In some embodiments, the waveform module 220 may be
configured to activate at least one TED (i.e., to control the
magnitude, duration, waveform and other attributes of stimulation
delivered by the at least one TED). In some such embodiments, the
control module 220 is configured to activate at least one TED based
upon a prescription from a prescription database, which may include
one or more sets of instructions for delivering one or more
time-varying thermal waveforms to the vestibular system of a
subject as described in U.S. Provisional Application Ser. No.
61/424,474 filed Dec. 17, 2010. In some such embodiments, the
waveform module 220 is configured to selectively and separately
activate a plurality of TEDs (e.g., by activating only one of the
plurality of TEDs, by heating one TED and cooling another, by
sequentially activating the TEDs, by activating different TEDs
using different temperature/timing parameters, combinations of some
or all of the foregoing, etc.).
[0115] The data 256 may comprise static and/or dynamic data used by
the operating system 252, applications 254, I/O device drivers 258
and other software components. The data 256 may include a thermal
waveform database 226 including one or more thermal treatment
protocols or prescriptions. In some embodiments, the data 256
further includes impedance data 224 including impedance
measurements between the earpieces and/or estimates of thermal
contact based on electrical impedance measurements. Electrical
impedance measurements may include resistive and capacitive
components, which may be correlated with a thermal impedance or
thermal conductance of the interface between the earpieces 100A,
100B and the ear canal. In some embodiments, the memory 236
includes additional data, such as data associated with the delivery
of one or more time-varying thermal waveforms, including patient
outcomes, temperature measurements of the ear as a result of the
thermal stimulation, and the like.
[0116] I/O device drivers 258 typically comprise software routines
accessed through the operating system 252 by the applications 254
to communicate with devices such as I/O ports, memory 236
components and/or the TED device 30.
[0117] In some embodiments, the TED thermal waveform control module
220 is configured to activate at least one TED in the earpieces
100A, 100B to stimulate the nervous system and/or the vestibular
system of a subject. In particular embodiments, the TED thermal
control waveform module 220 is configured to activate at least one
TED based upon a thermal prescription comprising a set of
instructions for delivering one or more time-varying thermal
waveforms to the vestibular system of a subject.
[0118] In some embodiments, the controller 200 is communicatively
connected to at least one TED in the earpiece 100 via a thermal
stimulation conductive line. In some embodiments, the controller
200 is operatively connected to a plurality of TEDs, and the
controller 200 may be operatively connected to each TED via a
separate thermal stimulation conductive line. In some such
embodiments, each of the plurality of separate thermal stimulation
conductive lines is bundled together into one or more leads (e.g.,
the thermal stimulation conductive lines connected to the TED(s)
thermally coupled to the right earpiece may be bundled separately
from the thermal stimulation conductive lines connected to the
TED(s) thermally coupled to the left earpiece). In some such
embodiments, the thermal stimulation conductive lines are connected
to the controller 200 via a lead interface (e.g., one or more leads
may be connected to the controller 200 using an 18-pin
connector).
[0119] In some embodiments, the controller 200 is operatively
connected to at least one TED in the earpieces 100A, 100B via an
electrical stimulation conductive line. In some embodiments, the
controller 200 is operatively connected to a plurality of TEDs, and
the controller may be operatively connected to each TED via a
separate electrical stimulation conductive line. In some such
embodiments, each of the plurality of separate electrical
stimulation conductive lines is bundled together into one or more
leads (e.g., two leads, with the conductive lines connected to the
TEDs in the right ear being bundled separately from the conductive
lines connected to the TEDs in the left ear). In some such
embodiments, the electrical stimulation conductive lines are
connected to the controller via a lead interface (e.g., two leads
may be plugged into the controller using a shared 18-pin
connector).
[0120] In some embodiments, the controller 200 is operatively
connected to at least one TED in the earpieces 100A, 100B via a
wireless connection, such as a Bluetooth connection. In some
embodiments, the controller 200 is configured to activate the TED
30 to deliver one or more actively controlled, time-varying thermal
waveforms to the vestibular system and/or the nervous system of a
patient.
[0121] In some embodiments, the impedance module 222 is configured
to detect and/or monitor an impedance between the two earpieces
100A, 100B. For example, as illustrated in FIG. 8, an electrical
connector 221 is used to electrically connect the two earpieces
100A, 100B. the electrical connector 221 may be any electrically
conductive material, such as a metal wire that may be physically
connected to the earpieces 100A, 100B and connected through, for
example, the cable 16 and/or controller 200 as illustrated in FIG.
1.
[0122] In some embodiments, the patient module 223 is configured to
analyze patient-specific parameters and/or data. For example, the
patient module 223 may combine data from the waveform module 220
and the impedance module 222 to determine if the patient has
complied with a treatment plan based on whether the impedance
values are consistent with the earpieces 100A, 100B being correctly
positioned during administration of the treatment. In some
embodiments, the patient module 223 may be used to enter and record
patient diary information, such as pain scores, occurrences of a
conditions (e.g., a headache), additional treatments that are being
administered, and the like.
[0123] As illustrated in FIG. 8, the impedance module 222 may
deliver an electrical current via the electrical connector 221 to
one of the earpieces 100A, 100B. Again without wishing to be bound
by theory, it is believed that if the earpieces 100A, 100B are in
generally good thermal contact with the subject's ear canal, then
the earpieces 100A, 100B will also be in substantially good
electrical contact with the subject's ear canal and the subject's
head will substantially complete an electrical circuit between the
earpieces 100A, 100B. However, if the earpieces 100A, 100B are not
in good thermal contact with the subject's ear canal, then there
will also be poor electrical contact with the subject's ear canal,
the subject's head will not complete the electrical circuit between
the earpieces 100A, 100B, and an open circuit will be detected by
the impedance module 122.
[0124] In this configuration, the impedance and/or capacitance
value between the earpieces 100A, 100B may be used to estimate the
thermal contact between the earpieces 100A, 100B. In some
embodiments, impedance and/or capacitance values may be detected
for a range of subjects to determine a range of impedance and/or
capacitance values in which it may be assumed that the earpieces
100A, 100B are in sufficient thermal contact with the subject's ear
canal. When a headset is being fitted to a new patient, the
impedance and/or capacitance between the earpieces 100A, 100B may
be detected, and if the impedance value is within the acceptable
range, it may be assumed that there is good thermal contact between
the earpieces 100A, 100B and the subject's ear canal.
[0125] In some embodiments, when the headset is being fitted to a
new patient, the impedance and/or capacitance value between
earpieces 100A, 100B may be detected and used as a patient specific
baseline to determine if the patient is later using the headset and
a proper configuration. For example, the patient may use a headset
according to embodiments of the present invention in a setting that
may or may not be supervised by a medical professional. In either
environment, the impedance module 222 may record an impedance
and/or capacitance value at a time that is close in time or
overlapping with the time in which the treatment waveforms are
delivered to the earpieces. The medical health professional or the
impedance module 222 may analyze the impedance value to determine
whether the earpieces 100A, 100B were properly fitting during
treatment. In some embodiments, the impedance module 222 may be
configured to provide feedback to the user when impedance values
detected on the electrical connector 120 that are inconsistent with
properly fitting earpieces 100A, 100B in good thermal contact with
the ear canal. In this configuration, the impedance module 222 may
provide an estimation of a degree of thermal contact between the
earpieces 100A, 100B and the ear canal in real-time or in data
recorded and analyzed at a later time. Accordingly, patient
compliance with treatment protocols may be monitored based on the
detected impedance during or close in time to treatment.
[0126] In particular embodiments, the impedance module 222 may also
provide feedback to the waveform module 220, for example, so that
the waveform module 220 may increase or decrease in amplitude of
the waveform control signal responsive to the degree of thermal
contact determined by the impedance module 222 based on the
impedance and/or capacitance value of the electrical connector 221.
For example, if the impedance module 222 determines based on the
impedance value of the electrical connector 221 that there is a
poor fit and poor thermal contact with the ear canal, then the
waveform module 220 may increase the thermal output to the
earpieces 100A, 100B to compensate for the poor thermal contact. In
some embodiments, the impedance module 222 may determine patient
compliance, e.g., whether the patient was actually using the device
during administration of the waveforms.
[0127] Although embodiments of the present invention are
illustrated with respect to two earpieces 100A, 100B, it should be
understood that in some embodiments, a single earpiece may be used,
and an electrical contact may be affixed to another location on the
user's head instead of the second earpiece to thereby provide an
electrical circuit for determining impedance values and estimating
thermal contact as described herein.
[0128] As illustrated in FIG. 8, the waveform module 220 may be
configured to communicate first and second waveforms to the TEDs 30
of the earpieces 100A, 100B. It should be understood that the first
and second waveforms may be the same, or in some embodiments, the
first and second waveforms may be different such that the thermal
output delivered from the TEDs 30 to the earpieces 100A, 100B are
independently controlled and may be different from one another.
[0129] The safety monitoring module 227 my receive sensor data from
the earpieces 100A, 100B, the heat sinks 50 (FIGS. 1-2), or from
various electrical components of the system, including a power
output from the waveform module 220. The safety monitoring module
227 is configured to analyze the sensor data or other data such as
power output data to determine if elements of the system may be
operating outside of a predefined safety range and to disable or
cease operation of the waveform module 220 in the event that unsafe
parameters are detected. For example, the sensor data may include
temperature data from the earpieces 100A, 100B and/or the heat
sinks 50 such that if the earpieces 100A, 100B and/or the heat
sinks 50 are operating above or below a given temperature (for
example, greater than about 50-55.degree. C.), then the safety
monitoring module 227 ceases operation of the device, for example,
by halting the delivery of different waveforms and/or by driving
the earpieces 100A, 100B to a safer temperature. The safety
monitoring module 227 may implement safety procedures, such as
halting the delivery of different waveforms and/or driving the
earpieces 100A, 100B to a safer temperature, if a voltage to drive
the TED 30 is above a threshold value, if the safety monitoring
module 227 detects that the fans 60, 62 are not properly operating,
and/or if other conditions are detected that indicate patient
safety issues may occur.
[0130] In some embodiments, the power from the waveform module 220
may be delivered to the TED 30 of the earpieces 100A, 100B via a
power cable, and sensor data, for example, from the temperature
sensor 40 and/or temperature sensors positioned in other suitable
locations of the device, such as to measure a temperature of the
heat sink 50, may be communicated to the controller 200 via a
wireless connection. Such a wireless sensor connection may reduce
or eliminate signal interferences between a power cable and the
sensor signal over configurations in which the sensor signal would
be supplied via the same cable as the power to the TED 30. A
wireless sensor signal connection to the control 200 may also
reduce a weight of the cable and thus increase patient comfort.
Waveforms
[0131] Without wishing to be bound by theory, functional imaging
studies may indicate that there is a generally dominant laterality
to caloric stimulation. See Marcelli et al., Spatio-Temporal
Pattern of Vestibular Information Processing after Brief Caloric
Stimulation, European Journal of Radiology, vol. 70, 312-316
(2009). Stated otherwise, cold calories tend to activate
contralateral brain regions, and warm calories tend to activate
ipsilateral brain regions. For example, it has been found that
short; left ear stimulation lead to right brain activation. See id.
Accordingly, it is currently believed that independent dual ear
stimulation may allow combinations to target specific regions
and/or hemispheres of the brain. For example, and again without
wishing to be bound by theory, warm stimulation may increase the
phasic firing rate of the afferents of the vestibular system, and
cold stimulation may decrease phasic firing rates. Thus, it is
currently believed that the laterality of activation for a given
temperature above or below body temperature and a sawtooth waveform
may cover a spectrum of phasic frequencies for vestibular
stimulation, and a square wave may favor larger magnitude
frequencies. Moreover, it is currently believed that cold
stimulation leads to reduced phasic firing rates and warm
stimulation leads to increased phasic firing rates. In some
embodiments, time-varying thermal waveforms may be selected for
administration based on a region of the brain in which stimulation
is desired. In some embodiments, different thermal waveforms may be
used in respective ears. For example, a warm treatment waveform
that oscillates between warm temperatures in one ear and a cold
treatment waveform that oscillates between cold temperatures in the
other ear may increase a stimulation into a particular region of
the brain. However, it should be understood that any suitable
combination of waveforms may be used. In some embodiments,
waveforms are varied over the same or different treatment periods.
For example, various thermal waveforms, including, but not limited
to, those described in U.S. Provisional Patent Application Nos.
61/424,132 (attorney docket number 9767-38PR), 61/498,096 (attorney
docket number 9797-38PR2), 61/424,326 (attorney docket number
9767-39PR), 61/498,080 (attorney docket number 9767-39PR2),
61/498,911 (attorney docket number 9767-44PR) and 61/498,943
(attorney docket number 9767-45PR) may be used
[0132] In some embodiments, two eigen functions or general shapes
for time-varying thermal waveforms may be used: the square wave and
the sawtooth (or triangular) wave. Both of these waveforms vary in
time, which may be useful to maintain robust vestibular stimulation
for time periods that may be therapeutically useful. In addition,
these waveforms may employ periods of stasis or continuous
variability. For example, in the case of the square wave, a
specific temperature is applied to the ear canal and that
stimulation may set up a heat flow pattern that may be eventually
propagated over to the proximal wall of the ear canal. However, the
period of statis should not be so long that the cupula adapts to a
new position, which may result in a return to the tonic firing
rate, which typically occurs in about 2-3 minutes during constant
temperature applications such as that delivered by traditional
diagnostic caloric irrigators or other caloric devices that
typically do not apply time-varying waveforms. In contrast, a
sawtooth waveform constantly varies, and thus the cupula may be
always out of equilibrium and the phasic firing rate may be
continuously varying. However, if the change in temperature of the
sawtooth waveform is too small or the rate of change is too fast
for the bony structure of the ear to keep up, the variations in
temperature will tend to be homogenized, and an insufficient
thermal gradient may be established, for example, across the
horizontal semicircular canal and other vestibular structures such
as the utricle and saccule.
[0133] In some embodiments, the frequency or period of the waveform
may not be constant and/or may be irregular, e.g., so as to
introduce "noise" into the caloric stimulation. The variations in
frequency/period of the waveform can be stochastic variations
(i.e., a random variation in frequency), structured variations
(such as based on a function, e.g., "1/f noise"), or monotonic
variations. Although in conventional electrical neurostimulation,
the frequency of the stimulation may be rapidly varied, for
calorics, the thermal conduction time may limit the speed with
which one can vary the frequency. Without wishing to be bound by
theory, injecting low frequency noise (e.g., 2 Hz or less) may
improve a therapeutic benefit. In some embodiments, the
frequency/period may be changed from one session to the next.
Moreover, the variations in frequency/period may be independently
controlled such that different periods/frequencies may be used or
varied differently in each of the patient's ears.
[0134] In some embodiments, the time-varying thermal waveforms are
sufficient to induce nystagmus over periods longer than about four
or five minutes or for longer than ten to fifteen minutes or more.
Nystagmus may be as measured by videonystagmography and/or by
electronystagmography, and may increase or decrease or even cease
for brief periods over the treatment period, but may be
substantially present over four or five minutes or for longer than
ten to fifteen minutes or more.
[0135] Nystagmus generally refers to involuntary eye movements
enabled by the vestibulo-ocular reflex (VOR) or loop. The starting
point of the loop is afferents leaving the vestibular bodies, going
to the vestibular nuclei in the brainstem. From the brainstem the
loop continues through the cerebellum and to the motor cortex
controlling eye movements as would be understood by one of skill in
the art. The VOR makes possible the tracking of an object with
one's eyes while the head is moving, for instance. In this case,
input from the horizontal semicircular canal may be primarily
responsible for such tracking to be possible. Rotating the head
about the vertical axis deforms the cupula in the horizontal SCC
and alters the tonic firing rate of the afferent nerves and
innervating the hair cells associated with the horizontal SCC. Head
rotation in one direction increases the (phasic) firing rate above
the tonic rate and head rotation in the opposite direction
decreases the firing rate.
[0136] Without wishing to be bound by theory, caloric vestibular
stimulation may provide an artificial mechanism to activate the
VOR. By tilting the head (.about.20 degrees above the horizontal),
the horizontal SCC is placed in a vertical orientation. Creating a
differential temperature across this canal may result in convection
currents that act to displace the cupula. Warm caloric vestibular
stimulation may lead to cupular displacement such that the phasic
firing rate increases, whereas cold caloric vestibular stimulation
may lead to a decrease in the firing rate. Further, warm caloric
vestibular stimulation may lead to nystagmus that is manifested by
a rapid movement of the eyes towards the simulated ear. Cold
caloric vestibular stimulation may result in the rapid phase of
nystamus away from the stimulated ear. Therefore, by noting the
existence and the direction of nystagmus, it may be determined that
the VOR is being activated and whether the phasic firing rate is
greater than or less than the tonic firing rate. In some
embodiments, the results of nystagmus may be used to select a
therapeutically effective treatment waveform, including the
introduction of variations, such as noise, as described herein.
[0137] The use of continuous caloric vestibular stimulation
irrigation or stimulation at a constant temperature may induce
nystagmus. However, after a time on the order of 2-3 minutes (e.g,
Bock et al., "Vestibular adaptation to long-term stimuli," Biol.
Cybernetics, vol. 33, pgs. 77-79, 1979), the cupula may adapt to
its new, displaced position and the phasic firing rate typically
returns to the tonic rate. Thus, nystagmus will effectively cease
and the vestibular nerve afferents will no longer be
stimulated.
[0138] In some embodiments of the current invention, the use of
time-varying thermal waveforms enables the persistent stimulation
of the vestibular nerve afferents, beyond the time period at which
adaptation to a constant thermal stimulus occurs. In contrast to
continuous caloric vestibular stimulation, time-varying thermal
waveforms may allow for stimulation for a longer or even an
indefinite period of time. However, treatments of about 10-20
minutes may be therapeutically effective.
[0139] In one example, a sawtooth waveform going between
temperatures of 34 to 20.degree. C. was applied to the right ear of
a subject who was reclined such that his head was .about.20 degrees
above the horizontal. Electronystagmography was used to measure the
movement of his eyes. Segments of the time series of the nystagmus
are shown in FIG. 21, demonstrating the existence of nystagmus both
early in a 12 minute period and near the end of the 12 minute
period. Accordingly, nystagmus may be used to confirm vestibular
stimulation during a treatment period.
[0140] Although nystagmus may be used to confirm vestibular
stimulation during a treatment period, it should be understood that
other techniques may be used, such as medical imaging techniques.
Moreover, in some embodiments, nystagmus from the stimulation of
one ear canal may be nulled by stimulation using an appropriate
waveform in the other ear canal; therefore, vestibular stimulation
may still occur even in the absence of observed nystagmus.
Example Waveforms
[0141] Exemplary waveforms that may be delivered by the TEDs 30 of
the earpieces 100A, 100B by the waveform module 220 are illustrated
in FIGS. 9-15. The waveforms on the left side of FIGS. 9-15 are
generally administered into the left ear, and the waveforms on the
right side of FIGS. 9-15 are generally delivered into the right
ear. However, it should be understood that the treatment waveforms
may be delivered into either ear, e.g., so that the waveforms on
the right side of FIGS. 9-15 may be administered into the right
ear, and the waveforms on the left side may be administered into
the left ear.
[0142] FIG. 9 illustrates in-phase square waves, with warm left ear
and cold right ear stimulation, which may provide enhanced left
hemispheric activation with predominantly higher and predominantly
lower phasic frequencies. FIG. 10 illustrates in-phase square waves
with warm left and right ear stimulation, which may lead to
bi-lateral hemispheric activation with predominantly higher phasic
frequencies. FIG. 11 illustrates out-of-phase square waves with
warm left and right ear stimulation, which may lead to bi-lateral
hemispheric activation with predominantly higher phasic
frequencies, but with the maximum phasic frequency being reached at
different times in the two hemispheres during a treatment session.
FIG. 12 illustrates in-phase square waves in which warm and cold
are administered to the left ear, and warm stimulation is provided
to the right ear, which may lead to predominantly higher phasic
frequencies being achieved in both hemispheres, but also with a
predominantly lower phasic frequency component in the right
hemisphere. FIG. 13 illustrates out-of-phase square waves with warm
and cold stimulation in the left ear and warm stimulation in the
right ear, which may lead to bi-lateral hemispheric activation with
predominantly higher phasic frequencies being achieved in both
hemispheres at different times in the treatment cycle, but also
with a predominantly lower phasic frequency component in the right
hemisphere that is roughly in phase with the predominantly higher
phasic frequencies in the right hemisphere. FIG. 14 illustrates an
in-phase sawtooth wave with warm stimulation in the left ear and
cold stimulation in the right ear, which may lead to enhanced left
hemispheric activation with a range of phasic frequencies being
achieved both above and below and equilibrium or unstimulated rate.
FIG. 15 illustrates an in-phase sawtooth wave with warm stimulation
in both the left and right ear, which may lead to bilateral
hemispheric activation with a range of phasic frequencies above the
tonic or unstimulated rate. FIG. 16 illustrates sawtooth waves
having an equal period with warm and cold stimulation in the left
ear and warm stimulation in the right ear, which may lead to
bilateral hemispheric activation with a range of phasic frequencies
being achieved.
[0143] In some embodiments, different waveform shapes and/or
periods may be delivered to respective ears of the patient. For
example, FIG. 17 illustrates an in-phase sawtooth left ear waveform
and a square wave right ear waveform that are both warm
stimulations and may lead to bilateral hemispheric activation with
a range of phasic frequencies being achieved above the tonic rate
in the left ear and predominatntly higher phasic frequencies being
achieved in the right ear. Additional configurations of other
"unmatched" waveform shapes and/or periods may be used.
[0144] FIG. 18 illustrates square wave right and left ear warm
square waves with a higher frequency square wave being administered
to the right ear. This may lead to bilateral hemispheric activation
with predominantly higher phasic frequencies and with the lower
frequency left ear waveform resulting in a higher phasic frequency
firing of the vestibular nerve than the higher frequency right ear
waveform. FIG. 19 illustrates a warm left ear and warm right ear
square wave with a time-varying period in the left ear. The
waveforms in FIG. 19 may lead to bilateral hemispheric activation
with predominantly higher phasic frequencies, but with the changing
frequency of the left ear waveform leading to a variation in how
long the higher phasic rate is maintained in the left ear
stimulation. FIG. 20 illustrates a square waveform of both warm and
cold stimulation in the left ear with a time-varying waveform
period and a regular period, warm, square wave form in the right
ear. The waveforms in FIG. 20 may lead to bilateral hemispheric
activation with predominantly higher phasic frequencies in both
hemispheres but with generally lower phasic frequencies in the
right hemisphere. The temperature change in the left ear may lead
to different phasic frequencies being achieved (above and below the
tonic rate). The frequency variation may affect the time over which
a given phasic frequency is achieved. The waveforms in FIG. 21 may
lead to bilateral hemispheric activation with predominantly higher
phasic frequencies in both hemispheres but with generally lower
phasic frequencies in the right hemisphere. The frequency variation
in the left ear may be randomly changed over time or the frequency
variation may be structured, for example, increasing or decreasing
over time be a given rate.
[0145] It should be understood that the treatment waveforms that
may be provided are not limited to those in FIGS. 9-21. For
example, the right ear stimulation and the left ear stimulation may
be reversed, the shape and/or period of the waveform may be
changed, and/or the warm/cold characteristics may be reversed.
Without wishing to be bound by any particular theory, functional
imaging studies have shown that there may be a dominant, but not
complete, laterality to caloric stimulation. For example, cold
caloric stimulation may have a tendency to activate contralateral
brain regions and warm caloric stimulation may have a tendency to
activate ipsilateral brain regions (above the vestibular nuclei in
the brainstem). Marcelli et al. ("Spatio-temporal pattern of
vestibular information processing after brief caloric stimulation,"
Eur J Radiol, vol 70, pg. 312-316, 2009) discusses that left ear,
short stimulation leads to right brain activation. Accordingly,
independent dual ear stimulation may allow for interesting
combinations to target specific regions and hemispheres of the
brain. Moreover, warm stimulation may increase the phasic firing
rate of the afferents of the vestibular system and cold stimulation
may decrease phasic firing.
[0146] For example, FIGS. 9-21 generally illustrate sawtooth (or
triangular) wave forms and square waveforms. It should be
understood that these wave forms are illustrative, and any suitable
shape of waveform may be used. Both of these waveforms vary in
time, which may assist in maintaining robust vestibular stimulation
for times of therapeutic utility. Square and sawtooth wave forms
may also embody the two primary types of variation: periods of
constancy or continuous variability. In the case of the square
wave, a specific temperature may be applied to the ear canal, which
provides a heat flow pattern that is eventually propagated over to
the proximal wall of the inner ear and thus the first of the
vestibular structures of interest (the horizontal semicircular
canal or "SCC"). The horizontal SCC may develop a temperature
gradient across its diameter, which may drive the convective
endolymph motion and distortion of the cupula. The square wave may
"switch" temperatures before the cupula accommodates a terminal
position and thus ceases to alter the tonic firing rate of its
associated hair cells. In the interim, a pseudo-equilibrium
condition may be established with heat flow. By contrast, the
sawtooth waveform is generally constantly varying and thus the
cupula may be in a state of being always out of equilibrium, and
consequently, the phasic firing rate may be continuously varying. A
potential limitation of a sawtooth waveform is that if the
amplitude (or temperature delta) is too small or the rate of change
is too fast for the specific heat of the bony structure of the ear,
the variations in temperature may be homogenized and an
insufficient thermal gradient may be established across the
horizontal SCC.
[0147] Therefore, in general, the activation for a given
temperature above or below body temperature is generally a lateral
relationship, and a sawtooth may be useful for covering the
spectrum of phasic frequencies, and the square wave may be useful
for providing the larger magnitude (farther away from the tonic
firing rate) frequencies. Cold temperatures (i.e., lower than body
temperatures) may lead to phasic firing below the tonic rate and
warm temperatures (i.e., above body temperatures) may lead to
phasic firing above the tonic rate (in the horizontal SCC). Various
examples are provided in FIGS. 9-21.
[0148] It may also be noted that a variety of stimulation
combinations, which may be provided according to embodiments of the
present invention, may address challenges that may be presented by
electrical neurostimulators (including implanted electrode devices
and transcranial magnetic stimulation devices). Adaptation to
neurostimulation is discussed, e.g., by Krack et al.,
"Postoperative management of subthalamic nucleus stimulation for
Parkinson's disease," Movement Disorders, vol. 17, pg. S188, 2002.
For instance, for an implanted neurostimulator that is generating a
specific pulse train for many hours during the day over many days,
the tendency is for synaptic plasticity to accommodate this new
stimulus and potentially decrease the efficacy of the therapy. Some
modern neurostimulators attempt to include adaptive changes to the
stimulation to account for changes in efficacy, but such systems
work under a narrow range of parametric settings and the risk of
side effects developing from changes in the stimulation pattern is
significant. Side effects resulting from caloric stimulation
according to some embodiments of the present invention may be
transient and easily observed, and thus. the prescribing medical
health professional can try a range of treatment paradigms to
balance continued efficacy and low side effects.
[0149] In some embodiments, waveforms may be altered over time so
as to reduce adaptation by the nervous system and provide continued
efficacy over time.
[0150] Although various examples of waveforms are provided in FIGS.
9-21, additional waveforms may be provided by varying one or more
of the following parameters:
TABLE-US-00001 Parameter Control .DELTA. temperature Control of the
TED's upper and low temperature ranges .DELTA. frequency Software
programming that allows time- varying waveforms to be created Vary
freq. during Software programming that allows time- treatment
varying waveforms to be created Vary range of .DELTA. temp.
Software programming that allows time- during treatment varying
waveforms to be created Time-varying Software programming that
allows time- waveform type varying waveforms to be created Phase
relationship Timing relationship between the independent between
left and right waveform controllers for the left and right applied
waveforms earpieces Stochastic or structured The ability to import
a designed waveform noise modulation of into the waveform
controllers waveform temperature, frequency, or phase
[0151] Again, without wishing to be bound by any particular theory,
the human body is currently believed to have naturally developed
systems that are not strictly periodic in terms of activation or
neuronal spiking. For example, the power spectrum of EEG
measurements has a slope that is close to 1/f (the inverse of the
frequency). This may imply that the dynamical system underlying the
EEG spectrum (the summation of all cortical neural activity) has
properties like scale similarity (one part of the EEG power
spectrum, when expanded, looks like the whole spectrum) and
self-organized criticality, which may imply that the state of the
system is in a sense poised between predictable periodic behavior
and unpredictable chaos (see, e.g., Buzsaki, "Rhythms of the
Brain," Oxford Press, 2006). There are also well-studied
pathological conditions reflecting abnormal synchronous behavior,
such as cardiac fibrillation and epileptic seizures.
Neurostimultors have made use of random (stochastic) or aperiodic
(structured noise, like 1/f noise) pulse sequences to evaluate
enhanced efficacy. For example, instead of maintaining a 100 Hz
electrical firing rate the frequency might be varied with
structured or unstructured noise. Caloric vestibular stimulation
may act to modify the phasic firing rate of the hair cells
indirectly by, primarily, modulating the position of the cupula.
Thus, to introduce noise into the phasic firing rate, a
time-varying thermal waveform may be provided to move the cupula in
a way such that the transduced effect is to produce the desired
phasic firing frequency spectrum. As a specific example, the
summation of five sine waves is considered. A sine wave may be used
as a basis function from which time-varying thermal waveforms may
be created. In fact, the sawtooth wave considered herein may be
provided by a series of sine waves (e.g., a Fourier series). The
amplitude as a function of time is:
A ( t ) = 2 .pi. k = 1 .infin. sin ( 2 .pi. kft ) k
##EQU00001##
[0152] Now, for the example of the summation of five sine waves,
1/f weighting is included as follows:
A(t)=(1/f.sub.i)*sin(2pf.sub.1t)+(1/f.sub.2)*sin(2pf.sub.2t)+(1/f.sub.3)-
*sin(2pf.sub.3t)+(1/f.sub.4)*sin(2pf.sub.4t)+(1/f.sub.5)*sin(2pf.sub.5t)
wherein values of f.sub.1-5 are chosen as follows: f.sub.1=0.003
Hz, f.sub.2=0.004 Hz, f.sub.3=0.005 Hz, f.sub.4=0.006 Hz and
f.sub.5=0.008 Hz, and the sign and offset of the function is
adjusted. This results in the temperature profile illustrated in
FIG. 22.
[0153] As discussed herein, the change in phasic firing rate is
currently believed to be approximately linear with the change in
caloric stimulation temperature, and therefore, the phasic rate may
be changed according to the spectral character of the caloric
waveform. Thus, the 1/f-weighted waveform above may induce
1/f-weighting into the phasic frequency spectrum. It should be
understood that additional or alternative weighting coefficients
may be used to provide time-varying waveforms according to
embodiments of the present invention.
[0154] It should be understood that the treatment waveforms may be
used as an adjuvant treatment, alone (e.g., monotherapy) or as
neoadjuvant therapy (e.g., the delivery of a treatment waveform
before or after another therapy).
Example Impedance Measurements
[0155] An Agilent.RTM. LCR meter was connected to metallic parts
that roughly matched the diameter and contour of the earpieces
described herein. Resistance values were taken at 1 KHz, within 10
seconds of insertion, and with either firm pressure on the ear or
light pressure on the ear as follows:
TABLE-US-00002 Firm Pressure (kilo-ohms) Light Pressure (kilo-ohms)
50 Typical: 150-200 40 46 Typical 40-50
[0156] Capacitance values were taken at 1 KHz, within 10 seconds of
insertion for firm pressure on the ear or light pressure on the ear
for three subjects as follows:
TABLE-US-00003 Firm Pressure (pF) Light Pressure (pF) 3500 1700
3500 1700 3500
[0157] Comparative capacitance values were measured on the pinna at
.about.600 pF and on the outer ear canal at .about.500 pF.
Therefore significantly higher values for both capacitance and
resistance were measured when firm pressure was applied to the
device to improve contact with the ear canal.
[0158] In addition, three different subjects were tested for both
capacitance and resistance with firm pressure, which yielded values
within a consistent range. The test values were C=3.5-3.9 nF and
R=30-32 k-ohm for the first subject, C=3.7-4.0 nF and R=20-24 k-ohm
for the second subject, and C=3.5-4.0 nF and R=35 k-ohm for the
third subject.
[0159] Thus, the capacitance values seemed generally consistent
when hard pressure was used. The resistance values seemed more
variable, but still provided a consistent range of values with firm
pressure. The values recorded when one of the ear probes was palced
on the pinna or outer ear canal were significantly different from
both firm pressure and light pressure reading well into the canal.
Such measurements may be used, e.g., by the impedance module 222 in
FIG. 8 to verify earpiece placement and thermal contact and/or to
verify patient compliance with applying the treatment waveforms
during operation of the earpiece in the ear canal.
Example Treatment Protocols
[0160] Embodiments according to the present invention will now be
described with respect to the following non-limiting examples
EXAMPLE 1
Long Duration Square Wave Administration
[0161] A male subject in his forties and good health, naive to CVS
treatment, was administered cold caloric vestibular stimulation to
his right ear in a square waveform pattern. The pattern was of
cooling to 10 degrees Centigrade (as compared to normal body
temperature of about 37 degrees Centigrade) as a "step" function or
"square wave" with one symmetric square wave being delivered for a
time period of 20 minutes. The subject was observed by others to be
slurring his words, and was asked to remain seated for a time of
two hours following the treatment session as a precaution.
Otherwise, no long-term deleterious effects were observed.
EXAMPLE 2
Sawtooth Wave Administration
[0162] The same subject described in EXAMPLE 1 was subsequently
treated by administering cold caloric vestibular stimulation to the
right ear in a sawtooth waveform pattern of cooling to 20 degrees
Centigrade (as compared to normal body temperature of about 37
degrees Centigrade) in a symmetric sawtooth waveform pattern,
without gaps, at a frequency of one cycle or waveform every five
minutes, for a total duration of approximately 10 minutes and a
delivery of a first and second waveform. Unlike the situation with
the square wave pattern described in Example 1, the subject
continued to perceive the temperature cycling up and down.
EXAMPLE 3
Maximum Waveform Amplitude
[0163] The same subject described in Examples 1-2 was administered
cold caloric vestibular stimulation to the right ear as a sawtooth
cooling waveform at different amplitudes in a titration study. A
maximum perceived sensation of cyclic cooling was perceived at a
peak amplitude of about 17 degrees Centigrade (or cooling from
normal body temperature to a temperature of about 20 degrees
Centigrade). Cooling beyond this did not lead to additional gains
in the sensation of cyclic cooling perceived by the subject.
EXAMPLE 4
Minimum Waveform Amplitude
[0164] Modeling of the human vestibular system indicates that the
cupula (the structure within the semicircular canals pushed by the
movement of fluid therein and which contain hair cells that convert
the mechanical distortion to electrical signals in the vestibular
nerve), is stimulated by caloric vestibular stimulation at chilling
temperatures of 5 or 7 degrees Centigrade below body
temperature.
EXAMPLE 5
Maximum Waveform Frequency
[0165] Modeling of the human vestibular system indicates that a
slew rate faster than 20 degrees Centigrade per minute (which would
enable one 20 degree Centigrade waveform every two minutes) is not
useful because the human body cannot adapt to temperature changes
at a more rapid rate. While maximum frequency is dependent in part
on other factors such as waveform amplitude, a maximum frequency of
about one cycle every one to two minutes is indicated.
EXAMPLE 6
Minimum Waveform Frequency
[0166] Modeling of the human vestibular system indicates that a
continuous, time-varying waveform is most effective in stimulating
the vestibular system, as stagnation and adaptation of the cupula
is thereby minimized. While minimum frequency is dependent in part
on other factors such as the waveform amplitude, a minimum
frequency of about one cycle every ten to twenty minutes is
indicated.
EXAMPLE 7
Treatment Session Duration
[0167] To permit delivery of at least a first and second waveform,
a duration of at least one or two minutes is preferred. As noted
above and below, results have been reported by patients with
treatment durations of ten and twenty minutes. Hence, as a matter
of convenience, a treatment session duration of not more than 30 or
40 minutes is preferred (though longer sessions may be desired for
some conditions, such as acute care situations).
EXAMPLE 8
Treatment of Migraine Headache with Sawtooth Waveforms
[0168] A female patient in her early fifties with a long standing
history of migraine suffered an acute migraine episode with
symptoms that consisted of a pounding headache, nausea,
phonophobia, and photophobia. Right ear cold caloric vestibular
stimulation was performed using the sawtooth waveform, essentially
as described in Example 2 above, with a temperature maximum of 17
degrees (chilling from body temperature) for 10 minutes (for a
total delivery of two cycles). At the conclusion of the treatment
the patient reported that her headache and associated symptoms were
no longer present. At a reassessment one day later, the patient
reported that the headache had not returned.
EXAMPLE 9
Treatment of Diabetes with Sawtooth Waveforms
[0169] The same subject described in examples 1-3 suddenly
developed an episode of extreme urination (10 liters per day),
thirst for ice water, and associated fatigue. Urinary testing
suggested the onset of diabetes mellitus, for which there was
strong family history.
[0170] The patient's initial weight as taken at his primary care
physician indicated a recent 20 pound weight loss. The first
attempt to obtain a glucose reading from the patient resulted in an
out of range result (this result typically occurs with glucose
levels in excess of 600 mg/dl). The patient was hospitalized and
received hydration and IV insulin therapy. The patient's first
glucose level after this treatment was 700 mg/dl. The glucose level
were brought down to approximately 350 and treatment with an oral
antihyperglycemic agent was initiated.
[0171] Follow-up care after hospital discharge with the subject's
primary care physican. expanded the oral antihyperglycemic agent
therapy to include both metformin and JANUVIA.TM. sitagliptin. In
addition, a strict exercise program of 30-45 minutes 5 to 6 days
per week and diet control were instituted. Daily glucose levels via
finger stick were taken 2 to 3 times per day.
[0172] At this point the patient's baseline hemoglobin A1c (Hb A1c)
level was 9.8%, as compared to normal levels of 5 to 6%.
[0173] The patient then began daily treatment with caloric
vestibular stimulation. The treatment was carried out for a time of
ten minutes, once a day for about a month, after which the
treatment was continued two to three times a week for three
additional months (with each treatment session being about 10
minutes in duration). The caloric vestibular stimulation was
delivered to the patient's right ear, as a sawtooth cooling
waveform as described in Example 2. At the conclusion of these
treatments, the patient's HB A1c level was 5.3%. As a result, the
patient was removed from all hypoglemic agents.
[0174] Most oral antihyperglycemic agents lower a patient's Hb Al c
level by approximately 1 to 2% (see generally S. Inzucchi, Oral
Antihyperglycemic Therapy for Type 2 Diabetes, JAMA 287, 360-372
(Jan. 16, 2002)). In contrast, this patient's initial value was
9.5, and dropped to 5.3.
EXAMPLE 10
Alternate Waveform Shapes
[0175] The sawtooth waveform described in the examples above was
symmetric and linear, as illustrated in FIG. 23A, where line dashed
line "n" represents the subject's normal body temperature
(typically about 37 degrees Centigrade). Modeling of the vestibular
system indicates that waveforms of similar amplitude and frequency,
but with a variation in shape, are also effective, such as the
"logarithmic" or "convex" waveform of FIG. 23B, and the
"exponential" or "concave" waveform of FIG. 23C. All waveforms
generally include a leading edge ("le"), a trailing edge ("te"), a
peak ("p") and a trough ("t").
[0176] While FIGS. 23A through 23C all show three consecutive
waveforms of the same shape, amplitude, and frequency, the
consecutive waveforms can be varied in shape as shown in FIG. 23D,
and can be varied in amplitude or duration as well (preferably each
consecutive waveform within the parameters noted above), to produce
still additional waveforms and sequences of waveforms which are
useful in carrying out the present invention.
[0177] In addition, while the waveforms of FIGS. 23A through 23D
are shown as continuous, minor disruptions can be included therein,
such as truncations ("trn"; for example, as shown in FIG. 23E,) or
vertical cuts ("ct"; for example, as shown in FIG. 23F) to produce
still additional waveforms and sequences of waveforms which are
useful in carrying out the present invention.
[0178] The peak for all waveforms of FIGS. 23A-23F is cooling by 17
degrees Centigrade from normal body temperature to a temperature of
20 degrees Centigrade, and the trough for all waveforms is a return
to normal body temperature, giving an amplitude of 17 degrees
Centigrade. The frequency for all illustrated waveforms is 1 cycle
(or one complete waveform) every five minutes. While 3 cycles of
the same waveform are illustrated for clarity, note that in some of
the examples above only two cycles are delivered over a total
treatment or session duration of ten minutes.
EXAMPLE 11
Patient Orientation
[0179] It was noted that a patient who was sitting up (watching
television) and receiving a cold caloric vestibular stimulation
(CVS) treatment reported perceiving a different effect than
perceived in prior sessions. Upon reclining to about 45 degrees,
she did receive the earlier effect.
[0180] The "standard" angle of recline for diagnostic CVS is about
60 degrees (or equivalently 30 degrees above horizontal). The
reason for this positioning is that the "horizontal" SCC is tilted
up by about 30 degrees (higher on rostal side) (More recent x-ray
measurements put the angle at closer to 20 +/-7 degrees.) The
intent with diagnostic CVS is to reorient the horizontal SCC so
that it is substantially vertical, thus maximizing the effect of
the convective flow set up by calories.
[0181] Hence, if the subject is reclined to about 20 degrees above
horizontal (and supine), then a cold stimulus leads to inhibition
or a phasic rate less than the tonic rate. For a warm stimulus,
this situation is reversed (phasic rate increases above tonic).
[0182] Further, cold simulation tends to activate principally the
contralateral brain structures whereas hot leads to principally
ipsilateral activation. For example, in V. Marcelli et al. (Eur. J.
Radiol. 70(2): 312-6 (2009)), the authors did a left ear, cold
stimulation by water irrigation and saw right-side activation in
the brainstem, cerebellum, etc. The patient was presumably nearly
reclined in the MRI magnet.
[0183] Empirical tests and modeling indicate that approximately 20
degrees Centigrade absolute cooling (17 degrees Centigrade below
body temperature) is the lower limit beyond which the cupula is
maximally deformed and therefore the phasic rate change is maximal.
On the warming side, more than about 7 degrees or so above body
temperature becomes uncomfortable. This level of temperature
heating within the ear canal will not lead to maximal deformation
of the cupula. Therefore, there is an asymmetry in terms of ability
to span the full frequency spectrum of phasic firing rates.
However, the increase in the phasic firing rate is not constrained
in the manner of a decrease--that is, the phasic firing rate can
only approach zero, relative to the tonic rate of roughly 100 Hz,
whereas the phasic rate can exceed 200 Hz.
[0184] Since inverting the patient changes the sign of the
inhibitory/excitatory motion of the cupula, the following can be
seen: Using a cold stimulus, of 20 degrees absolute, but now orient
the patient so that his head is tilted forward by from 75 to 20
degrees from the vertical position. This will invert the horizontal
SCC relative to the image above and now the cold stimulus will
result in an excitatory increase in the phasic firing rate. For
clarity, tilting the head forward by 20 degrees makes the
horizontal SCC substantially horizontal. Tilting beyond that now
starts to invert it so that at 110 degrees (tilted forward), the
horizontal SCC will be in a vertical orientation, but now 180
degrees flipped from what is used in conventional diagnostic
caloric vestibular stimulation. So, the "general rule" for
treatment of having the patient reclined by 45-90 degrees can be
expanded to include "tilted forward" by 75-120 degrees.
[0185] Thus a protocol is seen where, using only cold stimulus, one
can cover the entire range of phasic firing rates simply by
reorienting the patient at the appropriate points during the time
course of treatment.
[0186] Note that this type of inversion should also lead to an
inversion in the side of the brain that is primarily activated.
Specifically, if cold stimulation leads to principally
contralateral activation in the "rightside up" orientation, then it
should lead to principally ipsilateral activation in the "upside
down" orientation.
EXAMPLE 12
Thermal Modeling of Caloric Vestibular Stimulation
[0187] Equation (4) of Proctor et al. (Acta Otolaryngol 79,
425-435, 1975) can be extended for an arbitrary sequence of heating
and/or cooling steps. Equation (4) is a fairly simple usage of the
1-dimensional diffusion equation. Therefore, the model is not
exact. The temperature difference across the horizontal canal
(i.e., the thermal driving gradient) is approximated:
.DELTA. T = A 1 t e - B / t + A 2 t - t 1 e - B / ( t - t 1 ) + + A
n t - t n e - B / ( t - t n ) where A n = - LT n .pi. a and B = x 2
4 a ( 1 ) ##EQU00002##
[0188] L=distance across horizontal canal (mm); default=6
[0189] T.sub.n=difference between applied temperature and previous
temperature (.degree. C.)
[0190] a="thermal diffusivity" of temporal bone (mm2/sec); this may
vary in patients, but compact bone paths will dominate the thermal.
The literature lists values from 0.14-0.25, but this is based on
the onset of nystagmus as the "stimulation time." Marcelli et al.
showed a much faster, actual brainstem activation time after CVS,
which did not relate to the onset of nystagmus. Literature
estimates for the thermal diffusivity of hard bone range from
0.45-0.55 to 1.6. A value of 0.5 is assumed here, based on x-rays
of the compact, wet bone in the region of interest.
[0191] x=the effective thermal distance (mm) between external ear
canal and the edge of horizontal semicircular canal; default=7.5
mm
[0192] .DELTA.T=the temperature difference across the semicircular
canal (.degree. C.); distal minus proximal temperature.
[0193] t.sub.n=time at which new stimulus starts.
[0194] Default values for the constants are listed next to the
definitions. CVS application times that are short compared to the
response time of the patient may not be very different from a
longer pulse at a lower temperature due to thermal smoothing
effects. Literature reports of the maximum phasic firing rate are
about 100 Hz. That is, +/-100 Hz away from the tonic firing rate,
which is on the order of 100 Hz. The maximum deformation of the
cupula at its center is, correspondingly, about 77 microns. Thermal
gradients that imply a deformation greater than this value would
tend to lead to saturation of the phasic firing rate. At the other
end of the scale, the minimum detectable volume change in the SCC
is on the order of 25 picoliters and this corresponds to a change
in the phasic rate of roughly 0.5 Hz. This indicates a minimum
temperature gradient across the SCC of .about.0.02.degree. C. The
obvious requirement is that the body's homeostatic temperature
regulation must ensure a constant temperature across the 6 mm wide
canal to a value on that order.
[0195] Another simplification used in the model was to ignore the
temperature dependence of the bulk coefficient of thermal expansion
of water (with the simplifying assumption that endolymph has
roughly the thermal properties of water). This assumption will lead
to an apparent saturation of the phasic firing rate at higher
temperature (roughly 27.degree. C.) than will actually occur. Below
body temperature, the phasic rate may not saturate until the lower
20's.
[0196] The volume of the horizontal SCC is estimated to be: 3.2E-3
cc. The change in volume due to a temperature difference .DELTA.T
is: 3.8E-4*3.2E-3*.DELTA.T=1.22E-6 .DELTA.T.
[0197] The volume of the "lens" of the cupula when deformed to its
maximal (saturation of the phasic firing rate) extent is roughly:
4.4E-6 cc Therefore, the change in the phasic rate:
.DELTA.f=27.7*.DELTA.T in Hz .
[0198] The relationship between the applied thermal waveform and
the phasic firing rate of the afferents of the vestibular branch of
the 8th cranial nerve can thus be modeled for a square waveform
stimulus (such as in Example 1 above), and for a time-varying, saw
tooth, waveform stimulus (such as in Example 2 above).
[0199] It was noted that there is little distortion of the
time-varying waveform of, as compared to the square waveform,
because the body can track the more gradual temperature
changes.
[0200] There is a tendency for the values to skew a small amount
vertically (e.g., the temperature delta goes slightly above body
temp at points). This effect appears to be non-physical and is
simply a limit of the approximate model employed. The same appears
true of the firing rate going positive.
[0201] The "tips" of the sawtooth waveforms appear to exceed the
maximum change in phasic firing rate of 100 Hz (this is seen in the
square wave as well). This may be because the coefficient of
thermal expansion of the endolymph changes with temperature and was
not corrected in the model above. This would result in an
overestimate of the firing rate for a given temperature in the
plot. Therefore, the firing rate may not, in fact, saturate (i.e.,
will stay below a delta of 100 HZ) at 20 C. The loss of a sense of
improvement reported in Example 3 above for temperatures below
about 17 to 20 degrees Centigrade may be due to the cupula of the
vestibular canal "pegging" (achieving its maximal physical
distortion) and the firing rate saturating.
EXAMPLE 13
Treatment of Chronic Migraines and Refractory Depression
[0202] A female subject was a headache sufferer with a 10-year
history of debilitating, chronic migraines, the last five being
refractory. She had failed all pharmaceutical interventions. The
patient underwent an occipital nerve stimulator implant for
headaches, with good symptom-management for approximately one year,
at which point the device was no longer effective. Co-morbid with
her migraine headaches was depression, which was only partially
responsive to pharmaceutical management. Subject was placed on
disability from her employment.
[0203] The subject was treated using a five-day therapy paradigm
consisting of daily treatments comprising a square waveform pattern
of cooling to 20 degrees Centigrade, at a frequency of one cycle
every ten minutes, fora total duration of ten minutes while the
patient was in a reclined position of thirty degrees above
horizontal. Video images of the subject were captured before,
during and after each treatment session and were used to assess the
effectiveness of the treatment (e.g., by assessing the patient's
mood).
[0204] For all active, in-process migraine episodes, within 5-15
minutes after completion of a treatment, subject experienced pain
attenuation. Chronic headache indication was alleviated on the
4.sup.th day of treatment, with concurrent progressive improvement
in her mood over the course of the five days. The treatment course
peaked at day 5. The subject became pain-free, with complete
resolution of mood symptoms. She remained pain-free for 63 days
after the therapy was completed, at which time her migraine
headaches began to recur, but without return of clinical mood
symptoms.
[0205] The five-day therapy paradigm was repeated. The subject
responded more quickly to this second longitudinal therapy, with
her chronic headaches disappearing on the 3.sup.rd day of
treatment. She remained pain-free for five weeks.
[0206] Later, the patient was treated with a sawtooth waveform
(lower temperature of 20.degree. C.) employing a daily treatment
duration of 10 minutes. By the end of the treatment week, the
patient was pain free (using a 0-3 pain scale where 3 is severe, 2
is moderate, 1 is mild, and zero is no pain). Charted pain scores
(not shown) showed improvement after treatment. All CVS treatments
were to the right ear using cold stimulation. Additionally, after
each treatment week, the patient stayed pain free for times varying
from 2-9 weeks. The patient additionally reported feelings of high
energy and resolution of co-morbid depression.
EXAMPLE 14
Treatment-Associated Dizziness in Migraine Patient
[0207] The same subject described in example 8 had right ear CVS
treatment using a heating, to approximately 42-43 degrees, sawtooth
waveform for 10 minutes, with a contiguous repeat for an additional
10 minutes. The treatment was effective in resolving her acute
migraine pain. Additionally, the treatment had a soporific effect
but also caused slight dizziness. The subject did not note the
feeling of dizziness in example 8 using cold stimulation.
EXAMPLE 15
Treatment of Cluster Headache and Treatment-Associated
Dizziness
[0208] The same subject described in example 1 underwent the same
CVS treatment described in example 14. He too reported a feeling of
slight dizziness that was not apparent during cold CVS
stimulation.
EXAMPLE 16
Vestibular Migraine Treatment in Female Patient
[0209] A female subject in her late 30's had a history of migraine
with associated vertigo (vestibular migraine). The subject has a
history of vestibular dysfunction and slight co-morbid depression.
The subject was treated on a near daily basis, between 20-40
minutes per day, with cold stimulation (down to 20.degree. C.) CVS
before switching to warm CVS, with a maximum temperature of
48.degree. C. All CVS treatments used a sawtooth pattern with
left-ear stimulation due to more severe vestibular dysfunction in
the right ear. This subject did not note dizziness as a side effect
of the warm CVS treatment, suggesting that her vestibular system,
due to dysfunction, is more immune to CVS (and thus she must treat
more aggressively to gain benefit). A parent of the subject
commented on a change in the subject's speech and "spirit" during
phone conversations while using cold CVS. The switch to warm CVS
resulted in additional mood and motivational elements. Colleagues
commented on enhanced interpersonal interactions and an increased
sense of confidence. The subject stated: "for the last couple of
year I've felt as if my brain has burnt out, it feels so much
better since the warm treatments."
EXAMPLE 17
Vestibular Migraine Treatment in Male Patient
[0210] A male in his 40's developed sudden onset migraine with
vestibular dysfunction that led to effective disability and
inability to go to work. The subject was not helped by medications
and sought the advice of multiple physicians at two prominent
academic research hospitals. The subject was treated on a near
daily basis for 10-20 minutes a day with cold CVS (down to
20.degree. C.) CVS before switching to warm CVS, with a maximum
temperature of 42.degree. C. The subject, like the subject in
example 16, did not experience dizziness with the introduction of
warm CVS treatments, possibly associated with the vestibular
dysfunction accompanying his migraines. CVS treatments are
soporific for this patient. The subject's wife notes a pronounced
change since CVS treatments were started. Whereas prior to CVS
treatment the subject was loath to get out of bed, since CVS
treatment the subject has returned to part-time work with his
employer.
EXAMPLE 18
Treatment of Diabetic Patient with Warm Sawtooth Stimulation
[0211] The same subject described in example 9 switched from cold
CVS to warm CVS for the control of his type II diabetes. He treated
with a sawtooth waveform that oscillated between 34 and 43.degree.
C. The average heating slew rate was typically above 40.degree.
C./min and the average cooling slew rate was typically greater than
10.degree. C./min. Since commencing CVS therapy, the subject has
stopped taking medications, which were previously necessary to
maintain serum glucose near a normal range. At the time of
diagnosis, the subject's A1c value was 9.8. At the time shown at
the end of the chart below, that value was reduced to 5.6 (again,
with no medications). Al c is viewed as a better long-term marker
of diabetes control than serum glucose (it doesn't fluctuate). The
normal range is about 4-6. For diabetics, the recommendation is
that anything below 7 is a good target. A record of the subject's
serum glucose readings (not shown) indicated possible additional
improvement realized with the switch from cold to warm CVS in terms
of reduced variability. The subject also had a gingival abscess
during the period shown and such infections can lead to oxidative
stress and impaired glucose control (see generally J. Southerland
et al., Diabetes and Periodontal Infection: Making the Connection,
Clinical Diabetes 23, 171-178 (2005)). The infection did not
disrupt the subject's glucose maintenance.
[0212] Glucose readings taken at 7 AM and 10 PM; CVS treatment in
evening. Treatment 1:34 to 17 degree C. sawtooth waveform, 20
minute duration. Treatment 2:34 to 43 degree C. sawtooth waveform,
two 20 minute treatment per day. Glucose levels are more controlled
with treatment 2. No other diabetes medications were in use during
the testing period.
[0213] The subject reported that the warm sawtooth CVS differed
slightly from the cold sawtooth CVS in that it appeared to have
increased potency as noted by the feeling of increased dizziness
and mild nausea, which appear consistently with each treatment.
Glucose levels tend to drop 10-30 points approximately 60 minutes
or more after the treatment. The subject reported that combining
exercise in proximity to the TNM therapy appeared to cause a
glucose decrease of 30 to 50 points.
EXAMPLE 19
Treatment of PTSD Patient
[0214] A male in his mid 60's was wounded three times as a Medic in
Vietnam and had a history of post-traumatic stress disorder. His
manner is described as introverted and his mood depressive. After
the commencement of cold CVS treatments, the subject's wife
reported that he started becoming more extroverted. She reported
that "she did not know who this person was speaking to her this
morning"; that he was planning getting together with friends; that
usually he would only do this if forced; that he expressed interest
in going to Africa for a photo safari; that she started thinking
"where is my husband?" After a second treatment, the subject
reported continuous sleep throughout the night (usually he would
usually wake up 3-4 times). He commented that "insomniacs should
use this." The subject reported feeling energized. The subject was
usually unable to recall dreams, but awoke with visual flashback of
events in Vietnam, not unpleasant just old visual memories, and
returned to sleep. The subject traditionally avoided driving but
now is driving with substantially less hesitation. The subject is a
serious amateur painter and both the subject and his spouse report
significant positive developments in his painting style and
productivity since commencement of his CVS. Upon interruption of
CVS therapy, PTSD symptoms gradually returned almost to baseline
one week after CVS stopped.
EXAMPLE 20
Treatment of Diabetes in a PTSD Patient
[0215] The patient of example 19 has type II diabetes. After the
commencement of CVS therapy he became much more responsive to oral
hypoglycemics, has had to cut dose significantly (data not
shown).
EXAMPLE 21
Alternative Waveforms in Treatment of Diabetes and Cluster
Headaches
[0216] The patient described in example 18 above was administered
three different waveform CVS stimuli, as follows:
[0217] A: Cooling, by approximately 22-23 degrees, with a spike
waveform for 10 minutes with a contiguous repeat for an additional
10 minutes.
[0218] B: Heating, to approximately 42-43 degrees, with a spike
waveform for 10 with a contiguous repeat for an additional 10
minutes.
[0219] C: Cooling, to approximately 22-23 degrees, with a spike
waveform for 10 minutes as illustrated in connection with A above,
followed immediately by heating, to approximately 42-43 degrees,
with a spike waveform for 10 minutes as illustrated in connection
with "B" above.
[0220] The treatments seemed to have a bimodal pattern of efficacy
based upon cooling or heat cycles. Both modes seem to induce a
sense of motion and mild nausea associated with enhanced
therapeutic efficacy for the treatment of cluster headaches and the
stabilization of type II diabetes in this subject. Pattern A
appeared to be the most efficacious. Increasing cycle times to
thirty minutes does not appear to confer an additional benefit.
EXAMPLE 22
Induction of Prolonged Nystagmus by Waveform CVS
[0221] Nystagmus is the name given to involuntary eye movements
enabled by the so-called vestibulo-ocular reflex (VOR). CVS
provides an artificial means to activate the VOR. By tilting the
head (.about.20 degrees above the horizontal), the horizontal SCC
is placed in a vertical orientation. Creating a differential
temperature across this canal results in convection currents that
act to displace the cupula. Warm CVS leads to cupular displacement
such that the phasic firing rate increases whereas cold CVS leads
to a decrease in the firing rate. Further, warm CVS results in
nystagmus that is manifested by a rapid movement of the eyes
towards the simulated ear. Cold CVS results in the rapid phase of
nystamus away from the stimulated ear. Therefore, by noting the
existence and the direction of nystagmus, one may determine that
the VOR is being activated and whether the phasic firing rate is
greater than or less than the tonic firing rate.
[0222] The use of continuous CVS irrigation or stimulation at a
constant temperature will induce nystagmus, but after a time on the
order of 2-3 minutes (e.g, Bock et al., Vestibular adaptation to
long-term stimuli, Biol. Cybernetics 33, 77-79 (1979)), the cupula
will adapt to its new, displaced position and the phasic firing
rate will return to the tonic rate. Thus nystagmus will effectively
cease and the vestibular nerve afferents will no longer be
stimulated.
[0223] It is an aspect of the current invention that the use of
time-varying thermal waveforms enables the persistent stimulation
of the vestibular nerve afferents, beyond the time period at which
adaptation to a constant thermal stimulus occurs. In this example,
the present invention has been used to generate nystagmus over a 12
minute period as measured by videonystagmography and by
electronystagmography. A sawtooth cooling waveform going between
temperatures of 34 to 20.degree. C. was applied to the right ear of
a subject who was reclined such that his head was .about.20 degrees
above the horizontal. Electronystagmography was used to measure the
movement of his eyes, and demonstrated the existence of nystagmus
both early in a 12 minute period and near the end of the 12 minute
period (data not shown).
EXAMPLE 23
Effect of CVS on Regional Cerebral Blood Flow (rCBF)
[0224] The purpose of this Example is to find a robust marker of
successful CVS induction of relevance to neurological treatments.
The study is being performed on rats using a modified version of a
dual ear CVS unit. Specifically, ear bars that are connected to
TEC's are placed in the ear canals of rats that have been
anesthetized. The device has dual ear stimulation capability.
Methods and Results: Single ear CVS: Rat #9 received a sawtooth
waveform in the right ear that oscillated between 36 and 14.degree.
C. for 60 minutes (not shown). The rat was anesthetized with
isoflurane. It should be noted that anesthesia may lessen the
effects of CVS to a degree. The rat was oriented horizontally,
which places the horizontal semicircular canal in the vestibular
bodies at a roughly 30 degree tilt upwards on the anterior side.
After the end of the 60 minute right ear stimulation, the same
caloric waveform was then applied to the left ear. The response of
the regional cerebral blood flow was measured on the right parietal
region of the skull via a laser Doppler probe affixed to the skull.
Roughly 30 minutes after the start of right ear CVS, the
oscillation in blood flow became pronounced. The period of the
sawtooth temperature waveform is 1.9 minutes. As observed (using
nearest neighbor averaging), the period of the modulation in blood
flow is longer, by about 30 seconds on average (data not shown).
This suggests that the driving force (the CVS) leads to modulation
of the blood flow via a mechanism that stays in a non-equilibrium
state. That is, the rat's response does not simply match the period
of the CVS waveform and is instead adapting to it dynamically. At
the end of right ear CVS, the oscillations stop. Roughly 35-40
minutes after the start of left ear CVS, clear oscillations once
again appear, though diminished in amplitude relative to right ear
stimulation. This is presumably due to the fact that left ear
stimulation has a weaker effect on blood flow in the right portion
of the brain. Serrador et al. (BMC Neuroscience 10, 119 (2009))
note that "connections have been found between the vestibular
nuclei and the fastigial nucleus . . . followed by vasodilatory
connections to the cerebral vessels."
[0225] Control run: The CVS device was placed on the rat, but was
not activated. No oscillations in rCBF were seen (the downward
drift in the flow data is due to a slight shift in the baseline of
the probe).
[0226] Dual ear, same waveform: Rat # 12 had CVS delivered to both
right and left ears simultaneously (not shown). The waveforms were
not tied in phase and tended to become out of phase during the bulk
of the 60 minute treatment period. No modulations in rCBF were
manifested (data not shown).
[0227] The dual ear stimulation data suggest that the application
of the same waveform to both ears simultaneously acted to cancel
out any net modulatory effect on rCBF. However, it is still the
case that the same stimulation was given to the vestibular nuclei
as when only single ear CVS was used. Nystagmus, would also not
appear if the same CVS stimulation were applied to both ears since
the phenomenon, mediated by the vestibulo-ocular reflex (VOR),
requires a differential input to the two horizontal SCC's. Thus the
absence of rCBF modulation does not mean that the fastigial nuclei
(both nuclei for dual ear CVS) are not being stimulated. Rather,
their combined activation yields no net effect on rCBF. Since
modulation of rCBF is not a necessary aspect of CVS induced
neuroprotection (it is a marker of CVS induction), CVS therapy may
actually be as or more effective with dual ear stimulation.
[0228] Dual ear, different waveforms: Run 17 simultaneously applied
a 34 to 44 C sawtooth waveform to the right ear (period of
.about.40 seconds) and a 34 to 13 C sawtooth (period .about.1.7
min.) to the left ear (not shown). In this case, flow modulations
were seen and they persisted well past the end of the CVS treatment
period (not shown). In this case the flow effect, with different
temperatures applied, not only was present but continued to
oscillate after the end of the active CVS treatment.
[0229] Summary: The vestibular systems of all mammals act in the
same way. Therefore, the results of the rat study discussed above
has implications for human CVS therapy as well. The conclusion from
the study is that the most likely cause of the modulation seen in
rCBF is that CVS does stimulate the fastigial nucleus in the
cerebellum.
EXAMPLE 24
EEG in Rats as a Metric of CVS Efficacy
[0230] EEG is useful in identifying cortical activation associated
with CVS. Therefore, EEG is useful as a non-invasive means to
titrate CVS therapy. This report summarizes EEG data acquired in a
rat study.
[0231] Methods and results: The report on regional cerebral blood
flow changes in a rat during various CVS treatments has been
generated. In this summary, EEG electrodes were placed in the scalp
of the rat, differential pairs being applied on either side of the
midline of the skull. (data not shown).
[0232] Discussion The activity observed in the theta band was
markedly different between the 3 states. For the low flow state,
activity was depressed. The high flow peaks were shifted to lower
frequencies as compared to the baseline (pre-CVS). In the 0-40 Hz
plot, the high and low flow peaks in the low-30 Hz range overlap
whereas the baseline peak is shifted (this is likely due to a
difference in somatosensory perception during CVS versus pre-CVS).
The sensitivity of EEG spectra to the details of CVS delivery
suggest that EEG is an effective tool for evaluating the difference
between CVS waveforms and for titrating them.
EXAMPLE 25
Heart rate variability (HRV) as a Metric of CVS Efficacy
[0233] Heart rate variability seems to be a significant marker of
health and systems for measuring it non-invasively are becoming
common. This report describes the use of the ithlete, a commercial
HRV measurement instrument that runs as an smartphone software
program, or "app."
[0234] Methods and results: The subject is a 40-45 year old male
diagnosed with seasonal cluster headaches. The device used to
measure HRV is the ithlete (HRV Fit Ltd., Hants UK)) which uses an
iPhone as the recording/readout device and a chest strap with
sensors that monitor heart rate. The HRV parameter is calculated
via a proprietary algorithm that takes the raw heart rate data as
input. Note: of course there are many devices that will measure HRV
and the ithlete was chosen only as a low cost and convenient
system. Proper HRV is used as a metric of proper cardiac health
(good health implies adequately high HRV; e.g. Malik, "Heart rate
variability: standards of measurement, physiological
interpretation, and clinical use," Eur. Heart Journal, vol. 17, pg.
354, 1996). For example, Gujjar et al. have linked HRV and outcomes
after acute severe stroke ("Heart rate variability and outcome in
acute severe stroke," Neurocritical Care, vol. 1, pg. 347,
2004).
[0235] The CVS treatment was a 42.degree. C. sawtooth wave applied
to the left ear and a 17.degree. C. sawtooth applied to the right
ear. The treatment lasted for 10 minutes. HRV data were recorded
immediately after the end of the treatment. HRV is a dimensionless
measure. During the October 24.sup.th test, average HRV dropped by
30% and on October 28.sup.th by 27% (data not shown).
[0236] Discussion: HRV is proposed as a marker of effective CVS
induction and could thus be used as a tool for titrating CVS
dosing. Pathological conditions (such as cluster headaches
discussed here) can lead to elevated HRV levels. Other pathological
conditions, e.g. cardiac insufficiencies, are often associated with
abnormally low HRV values (for that individual).
EXAMPLE 26
Treatment of Fibromyalgia
[0237] A subject (also female, age 50-55) was diagnosed with
fibromyalgia 3 years ago. Multiple allopathic and homeopathic
interventions provided no substantive relief. The subject has
co-morbid migraine headaches.
[0238] Methods and results: The subject underwent CVS treatment in
the right ear, with a 17 degree C. sawtooth waveform.
[0239] From Sep 13-19 the subject stopped CVS treatment due to
significant pain and inability to function. On Sep 20 the subject
began treatments twice per day, sometimes using a 3.sup.rd daily
treatment using the CVS parameters listed above. She realized an
improvement in both migraine pain and pain from fibromyalgia. In
the Sep 28-30 timeframe thunderstorms seemed to trigger additional
migraine pain, but this abated over the following days until her
pain level was barely noticeable.
[0240] The subject commented upon starting twice-a-day treatments:
"I'm writing to report excellent results using 2 treatments. Last
night I tried 2 consecutive treatments, and I felt great! Like I'd
been to a spa and had a relaxing massage and soak in the hot
tub."
[0241] The subject reported on September 26.sup.th: "This weekend I
was able to work with [husband] getting 14 new bushes in the yard
and picking out new paint at Lowe's to repaint the shutters on the
house. I'm so very hopeful and happy. Gardening is a shared passion
for us, and the first two years here, I wasn't able to even water
the plants, so the ones left are real survivors! I feel like you
are giving me my life back, and giving [husband] his wife
back."
[0242] When the subject's spouse was asked if the CVS device was
truly helpful he responded: "Nothing in the last 3 years had helped
before this."
[0243] After October 6, the unit was retrieved. The subject has
since returned to baseline.
EXAMPLE 27
Treatment of Peripheral Neuropathy
[0244] A female subject underwent spinal surgery and sustained
damage to the spinal cord. Thereafter she has had intractable
peripheral neuropathy (foot pain) over a roughly 4 month period
that had not responded to analgesics. The subject has obtained
relief using CVS, with the extent and duration of relief depending
on the device used and the waveform details. Methods and results:
The subject underwent CVS treatment with the following
chronology:
[0245] 1. Dual ear CVS unit: L-ear, sawtooth, 34 to 20.degree. C.;
R-ear, sawtooth, 34 to 42.degree. C., 10 min. therapy. The
treatment made her very sleepy (deep sleep for 20 min). Within 30
minutes, she was pain free and stayed so for 3 days, which was
extraordinary for her.
[0246] 2. Single (right) ear CVS unit, sawtooth, 34 to 17.degree.
C., 10 min therapy. She realized about a 50% reduction in pain
level that lasted around 2 hours.
[0247] 3. Single (right) ear CVS unit, long (single rise) square
wave, 34 to 48.degree. C., 10 min She finds that the single ear,
warm treatment is better than single ear, cold treatment. She must
use the device several times a day to achieve pain relief.
[0248] 4. Dual ear CVS unit, L-ear 17.degree. C. square wave, R-ear
44.degree. C. sawtooth, 10 min. Deep sleep for 45 min (at 5 PM).
Foot pain ceased.
[0249] Discussion: The subject received extended (multiple day)
pain relief from one 10 min session using dual ear CVS. Single ear
CVS, using a sawtooth waveform (slower slew rate) and an early
device (basically a single cold/warm square wave), led to partial
pain reduction for a time limited to hours. Therefore, the dual ear
CVS treatment was superior to single ear for pain reduction. This
subject and another have stated that the mixed waveform, dual ear
(e.g., example 4) results in more significant subjective sensations
(deep relaxation/sleep for this subject, increased nausea for the
other). It is unclear with this single case if the mixed waveform
treatment leads to increased pain reduction efficacy (both dual ear
treatments were significant).
EXAMPLE 28
Single ear Treatment of Episodic Migraine
[0250] This Example evaluates the feasibility of using a portable
CVS unit in a home setting over a month or more. The hypothesis was
that daily CVS treatment would reduce the overall pain level and
frequency of headaches.
[0251] Methods and results: The subject is a 50-55 year old female
with a history of 6-8 migraine headache days per month (a month is
taken as 28 days when reporting on migraine frequency). The subject
used a right-ear CVS device and a sawtooth waveform that went from
34.degree. C. to 17.degree. C. with a period of roughly 1.7
minutes. The duration of the treatment was 10 minutes per session
(daily sessions, moving to every other day after about 2 weeks of
treatment). The average slew rate for heating was 40.degree.
C./minute and the average slew rate for cooling was 14.degree.
C./minute.
[0252] The subject experienced a decrease in pain over the first
week of therapy. (pain score data not shown). In the 40 days past
the one week transitionary period, the subject had only one
migraine headache (again, to qualify as a migraine it must be at a
pain level of 6 or more on a scale of zero to ten and last for 4
hours or more). The one headache occurred during unusual stress
associated with a transatlantic trip and disruption of work
schedule upon her return. The subject also noted a subjective
improvement in co-morbid depression over the treatment period.
EXAMPLE 29
Titration of CVS Therapy for Type II Diabetes
[0253] The intent of this report is to show experimental evidence
of the control of glucose levels by adjusting the frequency with
which CVS is used in a subject with type II diabetes.
[0254] Methods and results: The subject is a 40-45 year old male
diagnosed with type II diabetes within the last two years. As
reported earlier, the subject has been able to forego the use of
medications to control serum glucose levels, using CVS therapy
instead. Recently, the subject has started using dual ear CVS, with
a warm time-varying waveform applied to one ear and a cold
time-varying waveform applied to the other. The dual ear therapy
reduced the frequency with which the subject needed to use CVS in
order to control serum glucose levels (data not shown). Dual ear
CVS was used with a 17.degree. C. square wave for the right ear and
a 42.degree. C. sawtooth on the left ear. Each point in the graph
represents a daily measurement (consistent time during each day).
The red lines show when CVS was used. As the glucose levels were
tracked, they would tend to move up in between CVS treatments, thus
signaling when another treatment should be applied. This feedback
method should be able to be extended to other patients, using their
specific glucose levels to titrate frequency and intensity of CVS
treatments. This subject remains off any other medications to
control glucose levels.
[0255] Discussion: This is an update report to supplement accounts
from this subject already included in the Examples above, and
further shows that serum glucose is a useful metric for CVS
titration.
EXAMPLE 30
CVS Intensity for Different Waveforms
[0256] As the CVS treatment device has evolved, we have moved from
single to dual ear stimulation and have increased the slew rate to
allow waveforms to be played out at a higher frequency. This report
lists subjective metrics that can be used to assess the strength of
CVS stimulation for a given subject.
[0257] Methods and results: The subject is a 40-45 year old male
using CVS therapy chronically for type II diabetes and seasonal
cluster headaches. He ranks the level of intensity of the CVS
experience as follows: [0258] single ear: [0259] daily treatments
were required to control cluster headaches and serum glucose levels
[0260] typical treatment is a cold sawtooth wave going between 34
and 17.degree. C. [0261] dual ear, same waveform shape, warm and
cold: [0262] only 1-3 treatments per week are needed to control
cluster headaches and serum glucose [0263] typical waveform is a
sawtooth going from 34 to 42-44.degree. C. in one ear and 34 to
17.degree. C. in the other ear. [0264] Not much subjective
difference compared with single ear during treatment [0265] More
pronounced dizziness upon standing [0266] Nausea more persistent
[0267] Faster, more complete responses for increased pain level
[0268] Blurred vision for 3-5 minutes (possibly nystagmus) [0269]
dual ear, different waveform shape, warm and cold: [0270] only 1-3
treatments per week are needed to control cluster headaches and
serum glucose [0271] typical waveform is a sawtooth going from 34
to 42-44.degree. C. in one ear and a square wave in the other ear
going from 34 to 17-20.degree. C. [0272] most potent of all types
tried in terms of pain mitigation and positive mood effects (side
effects do not outweigh additional benefits) [0273] sleep inducing
[0274] nausea while in horizontal position [0275] significant
nausea and brief period of poor postural control upon standing
[0276] persistent feeling of head fullness
[0277] Discussion: The most significant metrics for CVS therapy for
pain patients is its effects on pain level and relative side
effects. This report recounts observations by one subject that can
serve as a paradigm for how other patients can be assessed in the
clinic. The right titration will involve an on-going assessment of
effects on symptoms (e.g., pain) and minimization of unwanted,
lasting side effects (for clarity, the side effects reported above
are transient). There are tradeoffs that patients can make between
efficacy with more intense side effects balanced against less
frequent need to treat.
[0278] The following parameters can be varied in a dual ear system:
[0279] 1. temperature (magnitude and sign with respect to body
temperature) [0280] 2. waveform shape [0281] 3. frequency of
waveform(s); if they are different frequencies, they could be
commensurate and beat frequencies could be established. [0282] 4.
relative phase of waveforms (e.g., in phase or some degree of being
out of phase if they have the same frequency) [0283] 5. variable
frequency during the course of a treatment (each side)
[0284] The CVS device can be programmed, in principal, to play out
a different combination every day, thus frustrating any tendency of
the VS of the patient to adapt to a given therapeutic waveform.
This is a principal advantage of dual ear over single ear CVS.
EXAMPLE 31
Treatment of Sleep Disorders/Insomnia with CVS
[0285] A common report from users of the CVS device is that they
have beneficial effects in terms of sleeping soundly. It is known
(e.g., Horii et al., J. Neurophysiol, 70, 1822, (1993)) that CVS
does activate the hypothalamus. The hypothalamus in turn controls
the sleep/wake cycle in mammals.
[0286] Methods and results: The reports of the soporific effects of
CVS with subjects is variable and subjective. Listing the claims by
subjects in order of frequency:
[0287] 1. a relaxed feeling right after the completion of a CVS
treatment
[0288] 2. report of having an exceptionally complete sleep cycle on
the night following a CVS treatment
[0289] 3. A very powerful soporific effect that resulted in the
subject falling asleep during a 10-20 minute CVS treatment and
staying asleep for up to several hours.
[0290] Examples of each of the observations listed above:
[0291] 1. A small pilot clinical trial was performed at a private
headache clinic on patients who were being treated for migraine
headache. The CVS waveform used was a sawtooth, right ear only,
with the temperature oscillating between 34 and 17.degree. C. None
of the subjects fell asleep during the 10 minute CVS treatment, but
commonly reported being relaxed in a way that was greater than what
they would feel when lying down, in a similar position, for the
same amount of time.
[0292] 2. A male, age 50-55 acting as a normal test subject used
single ear (right) CVS, sawtooth waveform oscillating between 34
and 17.degree. C. He reported pleasant drowsiness after the 10
minute therapy session and then reported that he'd slept
exceptionally soundly that night.
[0293] 3. A subject using CVS for foot pain (see previous Example
on this subject) used a dual ear CVS device: L-ear, sawtooth, 34 to
20.degree. C.; R-ear, sawtooth, 34 to 42.degree. C., 10 min.
therapy. The treatment made her very sleepy (deep sleep for 20
min). Then again: dual ear, L-ear 17.degree. C. square wave, R-ear
44.degree. C. sawtooth, 10 min. Deep sleep for 45 min (at 5 PM) and
had to be awakened.
[0294] In all cases, subjects reported restful sleep versus
"forced" sleep and they reported no ill side effects.
EXAMPLE 32
Single Ear CVS treatment of Pediatric Epilepsy
[0295] The intent with this study was to evaluate using the Gen 2.0
CVS unit (left ear only, same earpiece but different (less
powerful) TEC (thermoelectric cooler or Peltier cooler) than will
be used in Gen 3 device) in a single session to observe any effects
on spike activity in epileptic patients as monitored by EEG.
[0296] Methods and results: The subjects were treated with a
sawtooth waveform that went from 34.degree. C. to 17.degree. C.
(left ear only). Note that the actual temperature profile was not
the same for all patients. For patient 3, the average slew rate on
heating was around 14-15.degree. C./min and the cooling rate
dropped from about 5.8.degree. C./min to 4.5.degree. C./min (not
shown). It can be seen that more time was required to in the second
"dip" to get to 17.degree. C. This is due to insufficient power in
the Gen 2.0 CVS device.
[0297] For patient 4, the inadequate power of the unit is even more
apparent. The average heating slew rate was about the same as with
patient 3, but the cooling rate started at 4.2.degree. C./min and
dropped to 3.6 /min (not shown). The device failed to reach the
17.degree. C. target temperature.
[0298] The spike rate was measured by continuous EEG before CVS
treatment and after CVS treatment (data not shown). The decrease in
spike rate lasted from 1-2 hours for each of the four patients. The
reduction in spiking ranges from 21-32%.
[0299] Discussion: despite the underperformance of the Gen 2.0
model, primarily caused by an older, less powerful TEC and the lack
of a cooling fan on the heat sink, demonstrable effects were seen
in all 4 patients in terms of a reduction in spike activity that
persisted past the end of the CVS treatment session. At this time,
we don't have the ability to try a more advanced device (e.g., Gen
2.5) with these patients. A logical course would be to treat the
patients longitudinally to see if the effects of CVS could be made
more lasting. Despite the challenge of performing CVS on this
population (age range from 6-10 years old), it was accomplished and
there were no side effects of the treatment.
[0300] The foregoing is illustrative of the present invention and
is not to be construed as limiting thereof. Although a few
exemplary embodiments of this invention have been described, those
skilled in the art will readily appreciate that many modifications
are possible in the exemplary embodiments without materially
departing from the novel teachings and advantages of this
invention. Accordingly, all such modifications are intended to be
included within the scope of this invention as defined in the
claims. Therefore, it is to be understood that the foregoing is
illustrative of the present invention and is not to be construed as
limited to the specific embodiments disclosed, and that
modifications to the disclosed embodiments, as well as other
embodiments, are intended to be included within the scope of the
appended claims. The invention is defined by the following claims,
with equivalents of the claims to be included therein.
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