U.S. patent application number 14/527295 was filed with the patent office on 2015-02-19 for methods, systems, and devices for treating tinnitus with vns pairing.
The applicant listed for this patent is The Board of Regents, The University of Texas System, MicroTransponder, Inc.. Invention is credited to Navzer ENGINEER, Michael P. KILGARD, David Michael PIERCE.
Application Number | 20150051657 14/527295 |
Document ID | / |
Family ID | 48535941 |
Filed Date | 2015-02-19 |
United States Patent
Application |
20150051657 |
Kind Code |
A1 |
KILGARD; Michael P. ; et
al. |
February 19, 2015 |
METHODS, SYSTEMS, AND DEVICES FOR TREATING TINNITUS WITH VNS
PAIRING
Abstract
A method of treating tinnitus comprising measuring a patient's
hearing, determining the patient's hearing loss and the patient's
tinnitus frequency using the measurements of the patient's hearing,
programming a clinical controller with the measurements of the
patient's hearing, selecting a plurality of therapeutic tones,
where the therapeutic tones are selected to be at least a
half-octave above or below of the patient's tinnitus frequency,
setting an appropriate volume for each of the plurality of tones,
repetitively playing each of the plurality of therapeutic tones,
and pairing a vagus nerve stimulation pulse train with each playing
of a therapeutic tone, thereby reducing the patient's perception of
tinnitus.
Inventors: |
KILGARD; Michael P.;
(Richardson, TX) ; ENGINEER; Navzer; (Plano,
TX) ; PIERCE; David Michael; (Plano, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MicroTransponder, Inc.
The Board of Regents, The University of Texas System |
Austin
Austin |
TX
TX |
US
US |
|
|
Family ID: |
48535941 |
Appl. No.: |
14/527295 |
Filed: |
October 29, 2014 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13934893 |
Jul 3, 2013 |
|
|
|
14527295 |
|
|
|
|
13673764 |
Nov 9, 2012 |
8666501 |
|
|
13934893 |
|
|
|
|
13095570 |
Apr 27, 2011 |
|
|
|
13673764 |
|
|
|
|
12485040 |
Jun 15, 2009 |
|
|
|
13095570 |
|
|
|
|
61699470 |
Sep 11, 2012 |
|
|
|
61614369 |
Mar 22, 2012 |
|
|
|
61598185 |
Feb 13, 2012 |
|
|
|
61558287 |
Nov 10, 2011 |
|
|
|
61328621 |
Apr 27, 2010 |
|
|
|
61077648 |
Jul 2, 2008 |
|
|
|
61078954 |
Jul 8, 2008 |
|
|
|
61086116 |
Aug 4, 2008 |
|
|
|
61149387 |
Feb 3, 2009 |
|
|
|
Current U.S.
Class: |
607/3 |
Current CPC
Class: |
A61N 1/361 20130101;
A61N 1/37247 20130101; A61N 1/36132 20130101; G09B 23/28 20130101;
A61F 11/00 20130101; A61N 1/36092 20130101; A61N 1/36167 20130101;
H04R 25/75 20130101; A61N 1/36171 20130101; A61N 1/0551 20130101;
A61N 1/36053 20130101; A61N 1/36178 20130101; A61N 1/37235
20130101; A61B 5/128 20130101 |
Class at
Publication: |
607/3 |
International
Class: |
A61F 11/00 20060101
A61F011/00; A61N 1/36 20060101 A61N001/36 |
Claims
1. A method, comprising: treating tinnitus via the actions of:
exposing a patient to a plurality of therapeutic sounds; and
applying a plurality of vagus nerve stimulation pulse trains to the
patient, respective trains of the plurality of trains being in
temporal proximity to respective therapeutic sounds of the
plurality of therapeutic sounds exposed to the patient to reduce
the patient's perception of tinnitus.
2. The method of claim 1, wherein: the respective trains of the
plurality of trains occur during the respective therapeutic sounds
of the plurality of therapeutic sounds exposed to the patient.
3. The method of claim 2, wherein: the respective therapeutic
sounds of the plurality of therapeutic sounds exposed to the
patient begin before the respective trains of the plurality of
trains.
4. The method of claim 2, wherein: the respective therapeutic
sounds of the plurality of therapeutic sounds exposed to the
patient begin after the respective trains of the plurality of
trains.
5. The method of claim 1, wherein: the respective therapeutic
sounds of the plurality of therapeutic sounds exposed to the
patient begin before the respective trains of the plurality of
trains.
6. The method of claim 1, wherein: the respective therapeutic
sounds of the plurality of therapeutic sounds exposed to the
patient begin after the respective trains of the plurality of
trains.
7. The method of claim 1, wherein: respective sounds of the
plurality of therapeutic sounds are pure tones.
8. The method of claim 7, wherein: respective frequencies making up
the sounds of the plurality of therapeutic sounds are at least a
half-octave above or below the patient's tinnitus frequency.
9. A method, comprising: treating tinnitus via the actions of:
selecting a plurality of therapeutic tones; repetitively playing
the plurality of therapeutic tones; and pairing a respective vagus
nerve stimulation pulse train with a respective therapeutic tone of
the played plurality of therapeutic tones, thereby reducing the
patient's perception of tinnitus.
10. The method of claim 9, wherein: the playing of the plurality of
therapeutic tones is temporally random,
11. The method of claim 9, further comprising: randomly selecting
the frequencies of the played therapeutic tones.
12. The method of claim 9, wherein: frequencies of the therapeutic
tones are at least a half-octave above or below the patient's
tinnitus frequency.
13. The method of claim 9, wherein: the respective therapeutic
tones of the plurality of therapeutic tones exposed to the patient
begin before the respective trains of the plurality of trains.
14. The method of claim 9, wherein: the respective therapeutic
tones of the plurality of therapeutic tones exposed to the patient
begin after the respective trains of the plurality of trains.
15. The method of claim 9, wherein: the respective trains of the
plurality of trains occur during the respective therapeutic tones
of the plurality of therapeutic sounds exposed to the patient.
16. The method of claim 15, wherein: the respective therapeutic
tones of the plurality of therapeutic tones exposed to the patient
begin before the respective trains of the plurality of trains.
17. The method of claim 15, wherein: the respective therapeutic
tones of the plurality of therapeutic tones exposed to the patient
begin after the respective trains of the plurality of trains.
15. A method, comprising: treating tinnitus via the actions of:
selecting a plurality of therapeutic tones; repetitively exposing
the patient to the plurality of therapeutic tones; and applying a
plurality of vagus nerve stimulation pulse trains to the patient,
respective trains of the plurality of trains being in temporal
proximity to respective therapeutic tones exposed to the patient to
reduce the patient's perception of tinnitus.
16. The method of claim 15, wherein: the tones of the plurality of
tones are at least a half-octave above or below the patient's
tinnitus frequency.
17. The method of claim 15, wherein: the tones of the plurality of
tones are at least a half-octave above the patient's tinnitus
frequency.
18. The method of claim 15, wherein: the tones of the plurality of
tones are at least a half-octave below the patient's tinnitus
frequency.
19. The method of claim 15, wherein: the therapeutic tones have a
duration of about 500 milliseconds.
20. The method of claim 15, wherein: the therapeutic tones are
shaped by a ramp function.
21. The method of claim 15, wherein: the respective therapeutic
tones of the plurality of therapeutic tones exposed to the patient
begin before the respective trains of the plurality of trains.
22. The method of claim 15, wherein: the respective therapeutic
tones of the plurality of therapeutic tones exposed to the patient
begin after the respective trains of the plurality of trains.
23. The method of claim 15, wherein: the respective trains of the
plurality of trains occur during the respective therapeutic tones
of the plurality of therapeutic sounds exposed to the patient.
24. The method of claim 23, wherein: the respective therapeutic
tones of the plurality of therapeutic tones exposed to the patient
begin before the respective trains of the plurality of trains.
25. The method of claim 23, wherein: the respective therapeutic
tones of the plurality of therapeutic tones exposed to the patient
begin after the respective trains of the plurality of trains.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. patent application
Ser. No. 13/934,893, filed Jul. 3, 2013, which claims priority to
U.S. patent application Ser. No. 13/673,764, filed Nov. 9, 2014,
which claims the benefit of U.S. Provisional Patent Application No.
61/699,470, filed Sep. 11, 2012, U.S. Provisional Patent
Application No. 61/614,369, filed Mar. 22, 2012, U.S. Provisional
Patent Application No. 61/598,185, filed Feb. 13, 2012, and U.S.
Provisional Patent Application No. 61/558,287, filed Nov. 10, 2011.
This application is also a Continuation-In-Part of U.S. patent
application Ser. No. 13/095,570, filed Apr. 27, 2011, which claims
the benefit of U.S. Provisional Patent Application No. 61/328,621,
filed Apr. 27, 2010 and which is a Continuation-In-Part of U.S.
patent application Ser. No. 12/485,040, filed Jun. 15, 2009, which
claims the benefit of: U.S. Provisional Patent Application No.
61/077,648, filed Jul. 2, 2008; U.S. Provisional Patent Application
No. 61/078,954, filed Jul. 8, 2008; U.S. Provisional Patent
Application No. 61/086,116, filed Aug. 4, 2008; and U.S.
Provisional Patent Application No. 61/149,387, filed Feb. 3, 2009.
All of these applications are incorporated herein by reference as
if reproduced in their entirety.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not applicable.
REFERENCE TO A MICROFICHE APPENDIX
[0003] Not applicable.
BACKGROUND
[0004] Tinnitus is characterized by an auditory sensation in the
absence of external sound. Approximately 12 million individuals in
the United States have some degree of tinnitus. About 5 million of
these sufferers have severe tinnitus that interferes with their
daily activities and their quality of life. In fact, severe
tinnitus can lead to depression and other mental health challenges
that severely affect the patient and the patient's family members.
Therapies such as masking, sound therapy, electrical stimulation,
and drugs have shown some benefit. Unfortunately, these treatments
are non-specific and are insufficient to reverse the brain changes
that cause tinnitus. Therefore, treatment of tinnitus remains a
significant unmet need.
[0005] Numerous therapies have been used to treat or alleviate the
symptoms of tinnitus. For example, pharmaceutical therapies such as
antidepressants, anti-anxiety medications, as well as other
medicinal compounds have been attempted. Neurostimulation
techniques including transcranial magnetic stimulation and cortical
stimulation have been used to alleviate symptoms. Sound has been
used in several ways, including masking therapy auditory exposure
and frequency discrimination training.
[0006] U.S. Patent Application Publication 2007/0027504 (Barrett)
describes a system for treating tinnitus using vagus nerve
stimulation. A patient's vagus nerve was stimulated as the patient
experienced tinnitus symptoms to temporarily alleviate the
symptoms. No audible tones are specifically presented or paired in
Barrett's therapy.
[0007] U.S. Pat. No. 6,990,377 (Gliner) describes a therapy to
treat visual impairments. The therapy includes presenting various
types of visual stimuli in conjunction with stimulation of the
visual cortex. The therapy described in Gliner does not control the
timing relationship of the stimuli and the stimulation.
[0008] U.S. Patent Application Publication 2007/1079534 (Firlik)
describes a therapy having patient interactive cortical stimulation
and/or drug therapy. The therapy has patients performing tasks,
detecting patient characteristics, and modifying the stimulation
depending on the detected patient characteristics. The therapy
described in Firlik does not control the timing relationship
between the tasks and the cortical stimulation.
[0009] It is common in the prior art to suggest that stimulation of
the cortex, the deep brain, the cranial nerves, and the peripheral
nerves are somehow equivalent or interchangeable to produce
therapeutic effects. Despite these blanket statements, stimulation
at different parts of the nervous system is not equivalent. It is
generally understood that the vagus nerve is a nerve that performs
unique functions through the release of a wide array of
neuromodulators throughout the brain. To generate certain kinds of
plasticity, the timing of the stimulation of the vagus nerve is
critical in producing specific therapeutic effects.
[0010] U.S. Pat. No. 6,104,956 (Naritoku) is representative of work
done using vagus nerve stimulation (VNS) to treat a variety of
disorders, including epilepsy, traumatic brain injury, and memory
impairment. The VNS is delivered without any other therapy. To
improve memory consolidation, VNS 1s delivered several minutes
after a learning experience. Memory consolidation is unrelated to
the present therapy for treating tinnitus.
SUMMARY
[0011] For purposes of summarizing the disclosure, certain aspects,
advantages, and novel features of the disclosure have been
described herein. It is to be understood that not necessarily all
such advantages may be achieved in accordance with any particular
embodiment of the disclosure. Thus, the disclosure may be embodied
or carried out in a manner that achieves or optimizes one advantage
or group of advantages as taught herein without necessarily
achieving other advantages as may be taught or suggested
herein.
[0012] In an embodiment the disclosure includes a method of
treating tinnitus comprising measuring a patient's hearing,
determining the patient's hearing loss and the patient's tinnitus
frequency using the measurements of the patient's hearing,
programming a clinical controller with the measurements of the
patient's hearing, selecting a plurality of therapeutic tones,
where the therapeutic tones are selected to be at least a
half-octave above or below of the patient's tinnitus frequency,
setting an appropriate volume for each of the plurality of tones,
repetitively playing each of the plurality of therapeutic tones,
and pairing a vagus nerve stimulation pulse train with each playing
of a therapeutic tone, thereby reducing the patient's perception of
tinnitus.
[0013] In another embodiment the disclosure includes a system for
treating tinnitus comprising a clinical controller executing
tinnitus therapy software, a VNS implantable pulse generator (IPG)
in communication with the clinical controller and receiving
stimulation signals from the clinical controller, a VNS lead
connected to the VNS IPG, a VNS electrode connected to the VNS lead
and receiving stimulation signals through the VNS lead from the VNS
IPG, and headphones connected to the clinical controller, wherein
the clinical controller plays selected sound files through the
headphones while sending stimulation signals to the VNS IPG such
that the sound files may be heard by a patient while a stimulation
pulse train at the VNS electrode causes the patient's vagus nerve
to be stimulated.
[0014] In yet another embodiment the disclosure includes a method
of treating tinnitus comprising measuring a patient's hearing,
determining the patient's hearing loss and the patient's tinnitus
frequency using the measurements of the patient's hearing,
programming a clinical controller with the measurements of the
patient's hearing, selecting a plurality of therapeutic tones where
the therapeutic tones are selected to be at least a half-octave
above or below of the patient's tinnitus frequency, generating
sound files by shaping the selected therapeutic tones using a ramp
function, modulating the sound files with phase information that
simulates a sound source location, setting an appropriate volume
for each of the plurality of tones, repetitively playing each of
the plurality of therapeutic tones, and pairing a vagus nerve
stimulation pulse train with each playing of a therapeutic tone,
thereby reducing the patient's perception of tinnitus.
[0015] These and other features will be more clearly understood
from the following detailed description taken in conjunction with
the accompanying drawings and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] For a more complete understanding of this disclosure,
reference is now made to the following following brief description,
taken in connection with the accompanying drawings and detailed
description, wherein like reference numerals represent like
parts.
[0017] FIGS. 1A, 1B, and 1C are graphs depicting aspects of a
patient's hearing;
[0018] FIG. 2 depicts a pure tone;
[0019] FIG. 3A depicts an up ramp tone;
[0020] FIG. 3B depicts a down ramp tone;
[0021] FIG. 4 depicts location encoded sounds;
[0022] FIGS. 5A, 5B, and 5C are graphs of stimulation timing
relationships;
[0023] FIG. 6 depicts an implantable vagus nerve stimulation
system;
[0024] FIG. 7 depicts a paired VNS tinnitus therapy system;
[0025] FIG. 8 is a flowchart depicting a patient therapy initiation
routine;
[0026] FIG. 9 is a flowchart depicting a tone selection
routine;
[0027] FIG. 10 is a flowchart depicting a patient therapy
routine;
[0028] FIG. 11 is a flowchart depicting a patient home therapy
routine;
[0029] FIG. 12 is a flowchart depicting a sound file generation
routine;
[0030] FIG. 13 is a screen shot of the paired VNS tinnitus therapy
software menu;
[0031] FIG. 14 is a screen shot of an audiogram input screen;
[0032] FIG. 15 is a screen shot of an audiogram input screen with
sample data input;
[0033] FIG. 16 is a screen shot of interpolated audiogram data;
[0034] FIG. 17 is a screen shot of therapeutic tone selection;
[0035] FIG. 18 is a screen shot of therapeutic tone selection with
a tinnitus frequency notch;
[0036] FIG. 19 is a screen shot of therapeutic tone selection with
multiple tinnitus frequency notches;
[0037] FIG. 20 is a screen shot of therapeutic tone selection with
two tinnitus frequency notches;
[0038] FIG. 21 is a screen shot of therapeutic tone volume
setting;
[0039] FIG. 22 is a screen shot of therapeutic tone selection with
additional notches;
[0040] FIG. 23 is a screen shot of stimulation parameter setting;
and
[0041] FIG. 24 is a screen shot of therapy delivery.
DETAILED DESCRIPTION
[0042] It should be understood at the outset that although an
illustrative implementation of one or more embodiments are provided
below, the disclosed systems and/or methods may be implemented
using any number of techniques, whether currently known or in
existence. The disclosure should in no way be limited to the
illustrative implementations, drawings, and techniques illustrated
below, including the exemplary designs and implementations
illustrated and described herein, but may be modified within the
scope of the appended claims along with their full scope of
equivalents. The present application describes several embodiments,
and none of the statements below should be taken as limiting the
claims generally.
[0043] Where block diagrams have been used to illustrate the
embodiments, it should be recognized that the physical location
where described functions are performed are not necessarily
represented by the blocks. Part of a function may be performed in
one location while another part of the same function is performed
at a distinct location. Multiple functions may be performed at the
same location. In a functional block diagram, a single line may
represent a connection, in general, or a communicable connection,
particularly in the presence of a double line, which may represent
a power connection. In either case, a connection may be tangible,
as in a wire, or radiated, as in near-field communication. An arrow
may typically represent the direction of communication or power
although should not be taken as limiting the direction of connected
flow.
[0044] Repeatedly pairing a range of non-tinnitus frequency sounds
with VNS reduces the perception of tinnitus sounds in a patient
with tinnitus. No one ever before recognized that playing repeated
VNS paired sounds could reduce symptoms of tinnitus.
[0045] A common cause of hearing loss that leads to tinnitus is
cochlear damage from noise trauma. Elevated synchronous spontaneous
activity in the central auditory system may account for the
tinnitus percept that arises following hearing loss. As a result,
some neurons in the auditory cortex no longer receive their normal
input. These neurons start responding to adjacent frequencies, and
therefore a population of neurons starts firing spontaneously and
synchronously. This pathological activity is thought to give rise
to the tinnitus sensation. Based on these considerations, we
developed an approach to reduce the tinnitus percept by
redistributing the frequencies along the auditory tonotopic axis,
thus reducing the responsiveness of neurons that had too much
input. Our approach pairs selected tone presentations other than
the tinnitus frequency with simultaneous stimulation of the vagus
nerve to induce a redistribution of the distorted auditory cortical
frequency map observed in tinnitus. This approach seems to
alleviate the presumed behavioral and neurophysiological
correlations of tinnitus in a rat model of the disease.
[0046] The mechanism of our therapy may be referred to as repeated
paired training A repeated paired training is defined as
follows:
[0047] A "training" may be defined as a discrete event in time that
has a starting point and a stopping point. In the case of tinnitus
therapy, a training may be a brief sound, such as a tone with a
distinct frequency.
[0048] A training may be defined as "paired" when a discrete vagus
nerve stimulation pulse train, having a starting point and a
stopping point, occurs during a training This requires that the
training and VNS start and stop in a manner that links the two
together in time. When both the training and VNS have stopped,
there may follow a period when there is neither training nor VNS.
This non-training period allows the brain to perceive the next
event as a separate discrete event. The mechanism of therapy takes
advantage of the fact that the brain can distinguish between two
discrete events close together in time.
[0049] A "repeated paired training" may be defined as a recurring
sequence of paired trainings The mechanism of our therapy is the
cumulative effect of repeated paired trainings.
[0050] The vagus nerve is composed of somatic and visceral
afferents (e.g., inward conducting nerve fibers which convey
impulses toward a nerve center such as the brain or spinal cord)
and efferents (e.g., outward conducting nerve fibers which convey
impulses to an effector to stimulate it and produce activity). 80%
of the fibers in the vagus nerve are afferent fibers; the rest are
efferent. The vast majority of vagal nerve fibers are C fibers,
with the majority being visceral afferents having cell bodies lying
in masses or ganglia in the skull. The central projections
terminate largely in the nucleus of the solitary tract which sends
fibers to various regions of the brain (e.g., the hypothalamus,
thalamus, locus ceruleus, and amygdala); others continue to the
medial reticular formation of the medulla, the cerebellum, the
nucleus cuneatus, and other regions. Afferents activate both
ascending and descending pathways.
[0051] The vagus nerve may be contacted at any point along its
length or one of its branches. For instance, stimulating or sensing
electrodes may be located directly on, or close to, the left and/or
right vagus nerve(s) in a cervical location. Alternatively, the
vagus nerve could be stimulated at a near-diaphragmatic location
(e.g., supra-diaphragmatic or sub-diaphragmatic).
[0052] Stimulation of the vagus nerve may beneficially activate one
or more of the gustatory pathways, olfactory pathways,
pro-inflammatory or anti-inflammatory pathways, respiratory
pathways, cardiac pathways, baroreceptor pathways, and the
somatosensory pathways, causing a response of neural activity in
various areas of the brain. Vagus nerve stimulation may also affect
neurotransmitter pathways such as noradrenergic, serotoninergic,
dopaminergic catecholaminergic, GABAergic, opioidergic and
cholinergic pathways similarly. Neural activating circuits may
include the circuit of Papez, the mesolimbic pathway, the
mesocortical pathway or the nigrostriatal pathway. The effect of
such responsive effect on the brain tissue may be excitatory or
inhibitory and may potentiate acute and/or long-term changes in
neuronal activity.
[0053] The afferent vagus nerve feeds in the Nucleus Tractus
Solitarius which in tum feeds into several deep brain nuclei
including nucleus basalis and locus ceruleus. Each activation of
the vagus nerve results in a release of acetylcholine from the
nucleus basalis and norepinephrine from the amygdala and locus
ceruleus. These neurotransmitters influence the cortex and other
parts of the brain. The context of this release of neuromodulators
defines the effects.
[0054] The release of the neuromodulators resulting from activation
of the vagus nerve during a paired sensory event generates
plasticity in the cortex that is specific to the sensory event. The
pairing effectively tells the brain what to learn. Activation of
the vagus nerve during a sensory event such as a sound or sound
sequence generates plasticity in the auditory cortex that is
specific to the sound or sound sequence because the perception of
the sound coincides with the release of neuromodulators in the
auditory cortex. Activation of the vagus nerve during a motion
generates specific plasticity in the motor cortex, again because
the action and released neuromodulators coincide in the motor
cortex. The conjunction of these simultaneous activations generates
specific plasticity with a very brief window, less than eight
seconds for tinnitus.
[0055] Until our experiments, the synergy of these activations was
unappreciated. Presenting a sensory event at the same time as
activation of the vagus nerve has an effect on the area of the
cortex related to the sensory event. Timing a sensory event with
vagus nerve stimulation activates the appropriate parts of the
brain. The described tinnitus therapy has been developed using
these principles and tested clinically.
[0056] The tinnitus therapy includes a controlled-timing vagus
nerve stimulation. The vagus nerve may be stimulated using
effective methods, such as direct electrical stimulation. Direct
electrical stimulation of the vagus nerve may be performed using an
implantable vagus nerve stimulator or a percutaneous vagus nerve
stimulator to provide electrical pulses to an electrode close to
the vagus nerve tissue. Other methods of stimulating the vagus
nerve could be used as appropriate, as long as the timing of the
vagus nerve stimulation can be controlled. In accordance with an
embodiment of the therapy, an implantable vagus nerve stimulation
device may be implanted in the patient. Alternatively, a
percutaneous lead could be attached to an electrode at the vagus
nerve through the patient's skin to provide stimulation of the
vagus nerve. The necessary surgery may be performed in advance of
the actual therapy, so the tissue has time to heal.
[0057] When the therapy is ready to begin, the patient's hearing
and tinnitus symptoms are assessed. An audiogram may be generated
by an audiologist to characterize the patient's hearing loss.
Tinnitus pitch matching may be done to measure one or more
frequencies at which the patient is experiencing tinnitus. One
patient's hearing is depicted in FIG. 1A, and the patient's
tinnitus symptoms is depicted in FIG. 1B. A range of therapeutic
tones for the patient is depicted in FIG. 1C. Because the hearing
and symptoms of every patient is individual and unique, the hearing
loss, tinnitus symptoms, and range of therapeutic tones may differ
from those shown.
[0058] Using the knowledge of the patient's hearing loss and the
frequency or frequencies that characterize a patient's tinnitus
symptoms, the clinician selects a set of therapeutic tones at
frequencies the patient can hear, not including the patient's
tinnitus frequencies. The clinician may select tones at frequencies
ranging from 170 hertz (Hz) to 16 kilohertz (kHz) and adjust the
intensity accordingly. In accordance with an embodiment, 25
therapeutic frequencies may be selected. The distribution of
frequencies may be based on Mel scales.
[0059] In accordance with an embodiment, therapeutic tones may be
generated using pure sine wave tones with a sampling rate of 44,100
Hz. This relatively high sampling rate ensures the tones are pure.
The sampling rate should be at least twice as high as the highest
frequency being used as a tone.
[0060] Using the data generated by the audiogram, a set of sound
files may be generated for the therapy. A therapeutic tone may be a
pure tone, as shown in FIG. 2. A pure tone may be defined as a
presentation of a single frequency that exhibits no harmonic
distortions. For the purpose of this therapy, a tone may be said to
be pure when the ratio of the single frequency to any other
frequency (harmonics, ambient nOlse, etc.) is 20:1 or greater. A
tone may be sufficiently pure when only the single frequency can be
discerned by a patient.
[0061] Because a pure tone as a sine wave has an abrupt start and
stop, the presentation of a pure tone can seem to include
unpleasant pops at the beginning and end of the tone. To prevent
this phenomenon, a 4-10 millisecond ramp can be introduced to
modulate the start and stop. A ramp up, as shown in FIG. 3A, may be
used at the start of the tone and a ramp down, as shown in FIG. 3B,
may be used before the stop.
[0062] The brain may struggle when presented with a stereo
in-phase, equal amplitude pure tone, because the lack of location
information in this simple tone makes it impossible for the mind to
place the source of the sound in space. To make the tone
presentation more natural, to give the sound an apparent location
in space both in terms of direction and distance, the therapy may
include phase and amplitude adjustments between the left and right
headphone speakers, so that a tone is heard by the patient as
existing at a specific location in space.
[0063] Encoding multiple locations which are applied randomly to
the tones may be important, because training an association between
a specific tone and a specific location may have adverse
consequences. We do not want to train the patient to pay attention
to only one location or tone, but rather have the VNS occur at
random locations and frequencies.
[0064] A variety of models can be used to encode locations and
environments. In accordance with one embodiment, a rectangular
room, with a drop ceiling, carpet, four walls, and microphones at
specific locations provides the model environment. The model
environment simulates the echoes, delays, and absorption at the
microphone. Output is determined at seventeen locations in each of
the two rooms. A second environment may be one where all walls
completely absorb sound, which is effectively the same as being
outdoors.
[0065] For the 34 locations in the two rooms, a set of impulse
functions is generated. Each of these impulse functions is
multiplied with a sine wave of a selected frequency to create a
complex tone waveform for that location, distance, room, and tone,
as shown in FIG. 4. To create the sense of a tone coming from a
specific location in space, the sound for the right ear is given an
intensity IR and the sound for the left ear is given an intensity
II and the left and right sounds are separated with a time delay
(.PHI.). By changing the intensity values and the time delay, the
sounds will seem to be coming from different locations in space, in
different environments.
[0066] The clinician may test the volume setting of the device
before the therapy begins. The volume of the tones should be
audible and comfortable to the patient. Because a pure tone
necessarily has a louder output than a complex tone waveform, pure
tones may be used to check the volume settings.
[0067] In accordance with an embodiment, each of the 36 (34
locations+right and left pure tones) complex tone waveforms are
multiplied with each of the 25 selected therapeutic tones to
provide 900 left and right sound files. These sound files may be
stored on the clinical controller. The clinical controller includes
a soundcard connected to stereo headphones. When the clinical
controller plays a sound file, the soundcard converts the sound
file to an output that is received by the stereo headphones and
converted to audible sound. Because each soundcard and headphone
has a unique frequency response, they may introduce variables that
may need to be compensated. Typically, the therapy is conducted at
80 decibels (dB) or less. Headphones and soundcards may introduce
harmonics and distortions volumes higher than 80 dB. A patient may
need to be able to hear a reasonable number (at least two) of tones
at 80 dB.
[0068] The tinnitus therapy may be summarized as follows: The
patient has an implantable VNS device implanted so that it can
provide stimulation to the patient's vagus nerve on command. An
audiologist generates an audiogram for the patient. The tinnitus
frequency or frequencies are determined. The frequency of each
therapeutic sound or tone is selected by the audiologist or
clinician based on the tinnitus frequency. The apparent location of
each tone is established by the audiologist, clinician, or an
automated process that provides a suitable selection of perceived
tone locations. The tone may be shaped by a ramp. The clinician
goes through a software setup procedure, and a clinical setup is
performed.
[0069] The intensity of each therapeutic tone is set. Typically the
intensity is assigned an initial value. A clinician may check with
the patient to determine if the initial intensity settings are
appropriate and may change the intensity of one or more tones
accordingly. The intensity may be calculated from the audiogram
data. Feedback loops may be incorporated for automatic control of
intensity. From the intensity, the voltage required to produce the
tone is determined. Typically this is performed by software,
automatically.
[0070] An audiogram is generated by an audiologist and provided as
input to the software. The audiogram measures the hearing loss at
each frequency, measured in dB Hearing Loss (HL). The data from the
audiogram is then converted from a hearing loss measure into dB
Sound Pressure Level (SPL). A sound check may be performed. The
tinnitus therapy, once set up by the clinician, may be performed by
the patient at home. The software may give options to the clinician
to set-up the therapy for home use, in particular to allow the
patient to deliver the therapy to themself, at home, while not
allowing the patient to change the parameters of the therapy.
[0071] The software is designed to deliver the therapeutic tones
and the vagus nerve stimulation to the patient at the same time. In
accordance with an embodiment, the therapeutic tones are each about
500 milliseconds in duration and the vagus nerve stimulation pulse
train is about 500 milliseconds. In accordance with an embodiment,
a therapy session may include about 300 therapeutic tones paired
with about 300 vagus nerve stimulations. In accordance with an
embodiment, a therapy regime may include about six weeks of therapy
sessions, provided about five times per week. The tinnitus therapy
includes a number of variables that may be changed, as
appropriate.
[0072] In accordance with an embodiment, the therapeutic tones are
about 500 milliseconds. The duration of the therapeutic tones may
be made longer or shorter. FIG. 5A depicts a relative timing
diagram for the tone and vagus nerve stimulation pulse train. FIG.
5B depicts a relative timing diagram for a plurality of tones and
vagus nerve stimulation pulse trains. FIG. 5C depicts a relative
timing diagram for randomly spaced tones and vagus nerve
stimulation pulse trains.
[0073] In accordance with an embodiment, twenty-five therapeutic
tones are selected by the clinician. The twenty-five tones may be
selected at regular intervals through frequencies that can be heard
by the patient, except the frequencies that characterize the
patient's tinnitus or within a half-octave of the tinnitus
frequencies. More or less tones may be selected as appropriate. The
vagus nerve stimulation pulse trains delivered to the patient are
500 milliseconds in duration. The duration of the vagus nerve
stimulation pulse trains may be longer or shorter as appropriate.
The vagus nerve stimulation pulse trains delivered to the patient
are about 0.8 milliamps. The intensity of the stimulation may be
more or less than 0.8 milliamps, as appropriate. The intensity of
the tones being delivered to the patient should be set to a level
that is comfortable for the patient. Depending on a patient's
hearing loss, the intensity of the tones may be set to a normal
level or a higher level.
[0074] In accordance with an embodiment, the therapeutic tones and
vagus nerve stimulations are delivered at the same time, within a
few milliseconds. It may be appropriate to begin the therapeutic
tones earlier than the vagus nerve stimulation or after the vagus
nerve stimulation. The tones are typically delivered at 30-second
intervals. The intervals may be changed as appropriate. The
clinician may select 25 therapeutic tones. More or less tones may
be selected, as appropriate. The session will typically include 300
therapeutic tones paired with vagus nerve stimulations. More or
less tones may be delivered during a session, as appropriate. The
therapy may include 20 sessions. More or less sessions may be
given, as appropriate. The sessions may be provided daily. Sessions
may be provided more or less often, as appropriate.
[0075] By controlling the phase of the tones in a stereo
environment, the tones may be given the subjective attribute of
apparent location. The locations of one or more tones may be
varied, as appropriate. In accordance with an embodiment, various
randomizations may be introduced. The selection of tones, from the
therapeutic tones, for delivery to the patient, may be randomized.
The timing of the tone delivery may be randomized. In accordance
with an embodiment, the tones have a 50% chance of being delivered
at 15 seconds intervals, so that on average, the tones are
delivered thirty seconds apart. By controlling the phase of the
tones in a stereo environment, the tones may be given the
subjective attribute of apparent location. This location of tones
may be randomized.
[0076] A variety of systems and devices may be used to implement
the tinnitus therapy. A percutaneous lead may be used to stimulate
the vagus nerve. Because of the risk of infection is increased with
a percutaneous lead, the duration of the therapy delivered will
necessarily be shorter (less than six weeks) than is possible with
an implanted lead.
[0077] As shown in FIG. 6, an implant system 100 may include an
electrode 130, typically a cuff electrode. The electrode 130 is
connected by a lead 120 to an implantable pulse generator (IPG)
110. The electrode 130 provides the electrical stimulation pulse
train in close proximity to the vagus nerve. The lead 120 conveys
the electrical current to stimulate the vagus nerve from the IPG
110 to the electrode 130. The IPG 110 includes internal software to
receive commands from a clinical controller 140 as well as
providing safety features. An example of a transcutaneous
electrical stimulation system that could be adapted for use in the
described therapy may be found in U.S. Pat. No. 7,797,042.
Stimulation of the vagus nerve may be done at other sites along the
vagus nerve and branches of the vagus nerve.
[0078] The clinical controller 140 is connected to the IPG 110 by
radio frequency communication using a program interface 160. The
Programming Interface (PI) 160 has a cable with a universal serial
bus (USB) connector that plugs into the clinical controller 140 and
converts the information from the clinical controller 140 into a
radio frequency (RF) signal that is transmitted to the IPG 110. The
PI 160 converts the digital signals from the computer and software
into RF signals that can be transmitted through the air and skin to
the device and receives RF signals back from the IPG 110. The IPG
110 then translates the signal and acts on the commands given it
from the clinical controller 140. The PI 160 may have a cable of at
least 6 feet long and may communicate with the IPG 110 at up to 2
meters from the PI 160. The PI 160 is powered via the USB
connection and does not require any additional power source, such
as battery, or additional power connection. Other communication
methods could be implemented as appropriate.
[0079] As shown in FIG. 7, the external controller 140, or clinical
controller, is typically a laptop computer running appropriate
software. The clinical controller 140 is communicably connected to
headphones 150 that are worn by the patient. Similar automated
systems are described in U.S. Pat. Nos. 6,155,971 and 7,024,398,
which are incorporated herein by reference.
[0080] FIG. 8 depicts a flow chart of the patient initialization
and therapy process. An audiogram is generated by an audiologist at
202. The patient's hearing loss and tinnitus frequencies are
identified at 204. Therapeutic tones are selected at 206. The tones
are shaped at 208. The tones are encoded with locations at 210. The
sound files are saved at 212. The intensity of each tone is set and
checked at 214. The therapy parameters are programmed at 216.
Therapy begins at 218.
[0081] When the therapy is delivered, a tone selection process as
shown m FIG. 9 is used. A random tone is selected at 220. A random
location is selected at 222. A playtime is determined at 224. The
stimulation process is initiated at 226 so that the tone is played
and the vagus nerve is stimulated at the same tine at 228. An
end-therapy decision is made at 230. If the therapy continues, a
new random tone is selected at 220. Otherwise, the therapy ends at
232.
[0082] The therapy is outlined in FIG. 10. The clinician logs into
the software at 234. A hardware check is performed at 236. A
patient set up is performed at 238. An audiogram is input at 240.
Therapeutic tones are selected at 242. The intensity of the tones
is set at 244. The stimulation parameters are set at 246. The
session parameters are set at 248. The therapy is delivered at 250.
The therapy data is saved at 252.
[0083] A patient home therapy process is outlined in FIG. 11. A
patient logs into the software at 254. A hardware check is
performed at 256. The therapy begins at 258. The therapy data is
saved at 260.
[0084] A tone preparation process is shown in FIG. 12. A
therapeutic tone is selected at 254. Each tone is encoded with
location files at 256. The tone sound files are saved at 258. The
tone intensity is set at 260.
[0085] Specialized software has been developed to implement the
tinnitus therapy. There are two modes in this software: At Home and
Physician modes. The only mode available unless the Physician Login
has been accessed and the appropriate password input is the At Home
mode. In this mode only the Deliver Tinnitus Therapy option is
enabled. The At Home mode allows patients to initiate a therapy
session--this is the only function allowed by this mode. In order
to access the rest of the program, the Physician Login button must
be selected. This allows the Physician to type in a password which
allows access to the rest of the software.
[0086] To login and access all other TAPS screens, the audiologist
or physician presses the Physician Login button (upper right menu
bar, 4th button from the right--innermost button) and enters the
password. This opens full access to the software and allows all
settings to be established and modified. At this point the program
is "unlocked" and all menus in the program are available, as shown
in FIG. 13. The first option, Audiogram, is used by the
physician/audiologist to enter the audiogram data. The second
option, Therapy Tones Settings, is used by the
physician/audiologist to set the tones. The third option, Program
Implant, is used to set the stimulation settings and allows
impedance checks. The fourth option, Deliver Tinnitus Therapy, is
used only during clinical trials. It allows the physician or
audiologist to set a sham-control group that does not receive
paired VNS, but instead receives tones-only or VNS-only (in
sequences such that the patient receives tones and VNS, but they
are not received simultaneously). This allows blinding to be
maintained in a parallel study design. The "Log Patient File"
option allows a patient's file to be saved. The "VNS" option allows
independent delivery of VNS.
[0087] In order for therapy to be delivered, the tones and
stimulation must be set by the audiologist, physician, or
healthcare worker. The tones must be set first. To set the tones,
the Audiogram and the Therapy Tone Settings tabs must be completed.
The Audiogram is accessed as shown in FIGS. 14-22.
[0088] FIG. 14 is the screen where Audiogram information is added
and interpolated. The information may be loaded from a file that
was previously generated in by the specialized software or entered
manually. Once the audiogram is entered, it can be saved to a file.
In order to manually enter the data, the audiologist or physician
clicks in the appropriate cells of the Audiogram Parameters table
and types the values in as needed for frequency and hearing loss of
both the Left and Right ears, as shown in FIG. 15. The user must
interpolate the audiogram in order to be able to access Therapy
Tone Settings and continue with therapy set up. In order to
interpolate the data into the Therapy Tone Settings, following the
successful entry of all audiogram parameters, the Interpolate
button must be selected, as shown in FIG. 16. The interpolated data
populates the Therapy Tone Parameters table on the Therapy Tone
Settings automatically. This data will not be saved until either
the Save to file . . . button or the Download button is selected.
The Save to file . . . function prompts the user to save the file
in a preferred location (an external USB drive is recommended), and
the Download function saves the data into the IPG. In order to
deliver proper therapy, the Download function must be performed so
that the therapy information is loaded into the IPG's memory.
[0089] As shown in FIG. 17, after the Audiogram parameters are
populated with Audiogram-based data (either manually or from a
file) and subsequently interpolated, the "Therapy Tone Settings"
button can be selected. The Tinnitus Frequencies can now be added.
This is also where the manual testing of the tones occurs and can
be adjusted. Frequencies can be de-selected in order to notch out
frequencies around the Tinnitus frequency or frequencies.
[0090] For example, as shown in FIG. 18, if a patient has tinnitus
in the left ear, around a frequency of 1,100 Hz, the audiologist is
recommended to notch out tones being played in a V2 Octave around
1,100 Hz. To do this, the frequency of 1,100 is input into the drop
down menu under Left and Tinnitus Frequency as shown below (right
middle of screen, FIG. 18). The software will then automatically
select the frequencies of 910, 1121, and 1360 Hz. If necessary, the
audiologist or physician can manually modify this by clicking on a
frequency and selecting or deselecting the frequency.
[0091] As shown in FIG. 19, if the patient also has a tinnitus
frequency of 3500 in the right ear, the audiologist would add
"3500" in the Right-Tinnitus Frequency box, and the software will
again automatically "notch out" frequencies V2 octave around 3,500
Hz. Note that the + box next to the tinnitus frequency can be
clicked, and additional tinnitus frequencies can be added.
[0092] As shown in FIG. 20, two tinnitus frequencies (1,100 Hz and
3,500 Hz) are shown, and any frequency within a V2 octave of those
frequencies are notched out (inactive frequency buttons are
grayed), so that the tinnitus frequencies cannot be selected.
[0093] As shown in FIG. 21, the tone volume for the sound level
that each tone is played at for each frequency is also available
for input. The volume played in the left and right ear is
adjustable--in the example below, it is 170 Hz. Frequency is being
adjusted to 100 dB for both the left and right ears. The Play Left
or Play Right button can be selected to test the tones and volume
levels.
[0094] FIG. 22 shows an additional three frequencies being
notched-out (7278, 8324, and 9506 Hz), as indicated by the gray
deselected buttons near the bottom of the screen.
[0095] The Program Implant menu, as shown in FIG. 23, allows the
user to set the VNS Parameters, check the lead impedance, and then
test and ultimately program the parameters into the IPG. For each
of the settings (Magnet, Train Duration, Amplitude, Train Period,
Frequency, Train Probability, Pulse Width, Tone Time and Therapy
Duration), the box next to the setting is clicked, and all
available parameters are shown in a drop down box. The appropriate
value is selected for each parameter. After all of the parameters
are set, the user may Test or Program the displayed parameters. It
is recommended the user verify that the VNS settings chosen are
tolerable for the patient. Selecting the Test button delivers a
single train of stimulation per the parameters displayed in the
Parameters menu for this purpose. This does not permanently program
the IPG, but only performs a one-time stimulation.
[0096] Once the user is satisfied that the chosen parameters are
appropriate and tolerable, the Program button must be selected in
order to program the IPG with the therapy parameters displayed in
the Parameters menu. The values programmed via the Program function
are input into the IPG and all subsequent therapy sessions will be
performed at these parameters. The user can modify the parameters
at any time by selecting new parameters and programming them into
the IPG. The user may also want to verify the lead impedance. In
the Status portion of the Program Implant menu the lead impedance
can be checked by selecting a Check button. Doing so delivers a
small current pulse through the lead to calculate the lead
impedance. The user shall ensure that the lead impedance check does
not cause discomfort in the patient. After the check button is
selected, the lead impedance value is shown. For any value above
10,000 ohms, a Warning screen above reminds the patient to contact
their physician or audiologist to see if any action needs to be
taken.
[0097] As shown in FIG. 24, the therapy is delivered by selecting
the PLAY button. For home therapy, the patient may be given limited
access to some features in the specialized software. The patient
can administer therapy to themselves, and all the data
corresponding to the session will be recorded for subsequent review
by the clinician. Headphones have been selected to deliver
consistent tone intensity across the full range of frequencies.
Clinical and pre-clinical data has been collected to support the
effectiveness of the formatting.
[0098] The peripheral nervous system, central nervous system
including the brain and spinal cord can all be used as stimulation
locations. The choice of stimulation location largely determines
the behavioral and neurophysiologic outcome. Even though similar
neural populations are activated by input from two different
locations, the manner in which they are activated, for example, the
pattern of activity generated within the neuron population will
depend on the time course of activation, release of one or more
neuromodulators, attention state, etc.
[0099] The neurophysiological consequences therefore are bound to
be different. Given the large (and unknown) number of variables
that can influence the activation of a given neural population, the
mechanisms are likely to be complex and unpredictable. There is no
calculus to determine which locations will produce which effects.
Finding a location that produces a given effect can only be done
experimentally. It is not valid to suggest that stimulation at one
location makes it obvious to stimulate at a different location,
even if the goal is to stimulate the same population of
neurons.
[0100] The same can be said for stimulation parameters. At a given
stimulation location, stimulation according to one set of
parameters will not necessarily produce the same (or similar)
effects as a stimulation according to another set of parameters.
The frequency of stimulation, the current amplitude of stimulation,
the duration of each stimulation, the waveform of stimulation, as
well as other stimulation parameters can change the results of
stimulation.
[0101] Our experiments have shown that the effect generated by VNS
pairing is very short, less than 15 seconds. A first tone at a
first frequency when paired with VNS generated an increase in the
number of neurons that respond to the paired frequency. A second
unpaired tone at a second frequency, played 15 seconds after the
paired VNS did not show a corresponding increase in the number of
neurons that respond to the second frequency. Nothing in the prior
art indicates this kind of precise timing requirement.
[0102] Similarly, we have performed experiments m which multiple
tones at a given frequency were paired with VNS and given 30
seconds apart. This was done in the tinnitus study (Engineer et
al., 2011) in which VNS was paired with each of the randomly
interleaved tones every 30 seconds (e.g., 1.3 kHz+VNS, then wait
for 30 seconds, then give 6.3 kHz+VNS, then wait for 30 seconds,
and so on). The tones were selected such that they surrounded the
tinnitus frequency and the tinnitus frequency itself was excluded.
The idea was to shrink the representation of the tinnitus frequency
thereby restoring the map and synchronous activity back to normal.
When the same tones were presented 8 seconds apart, the effect was
less than if the tones were presented 30 seconds apart, which was
surprising.
[0103] To cite another example, we have performed a series of
experiments where a tone is repeatedly paired with a foot-shock to
establish a conditioned fear response. Subsequently, when the tone
was presented without a foot-shock, the rat would freeze,
anticipating a foot shock. If the tone, without the foot-shock, is
then presented repeatedly, the fear caused by the tone would
eventually be extinguished, undoing the conditioning. By pairing
the tone (without the foot-shock) with VNS, the fear is
extinguished much more quickly. However, presenting the tone by
itself and then giving VNS minutes later, the fear is extinguished
at the normal rate. These results demonstrate that the precise
timing between VNS and the event, as well as the interval
separating the VNS-event pairings appear, to be important for
inducing highly specific plasticity."
[0104] Neurostimulation does not behave in a predictable fashion.
Different stimulation locations produce different results, even
when both locations are cranial nerves. For example,
synchronization in the cerebral cortex is a manifestation of
epilepsy. Stimulating the vagus nerve causes desynchronization of
the cortex neurons, which has been proposed as a potential
mechanism for how vagus stimulation prevents an epileptic seizure.
Stimulation of the trigeminal nerve, another cranial nerve, causes
desynchronization as well. To determine whether the plasticity
induced by VNS is specific to the vagus nerve, we paired
stimulation of the trigeminal nerve with a 19 kHz tone. However,
when we paired trigeminal stimulation with a tone, in the same way
we paired VNS with a tone, we did not observe any plasticity that
was specific to the paired tone. Pairing the trigeminal stimulation
with a tone at a given frequency did not change the response to
that frequency even though it caused desynchronization as in the
previous study. Each stimulation location is unique across the full
range of effects. It appears that VNS may be uniquely suited to
direct cortical plasticity and suggests that the vagus nerve is
likely a key conduit by which the autonomic nervous system informs
the central nervous system of important stimuli.
[0105] The VNS pamng therapy is more than the sum of its
constituent parts. Simply playing a tone at a given frequency,
without VNS, does not result in a change in response to the
frequency. Similarly, VNS by itself did not produce any changes in
response to any frequency. Only by precisely pairing VNS with a
tone at a given frequency induces a change in response to the
frequency.
[0106] Both VNS pairing and nucleus basalis stimulation (NBS)
pairing have been shown to change the number of neurons responding
to a paired frequency. To be effective, the current amplitude
parameter of the stimulation for VNS pairing is more than twice the
current amplitude used for NBS pairing. There is an important
difference between the neuromodulators released by NBS from those
released by VNS, so significant differences between the results of
NBS and VNS are expected.
[0107] Another experiment demonstrated that pairing a single tone
at a specified frequency with VNS increased the number of neurons
responding not only to that frequency but to close frequencies,
e.g., increased the bandwidth compared to control rats. For NBS
pairing, the bandwidth was not significantly different from control
rats. Unlike VNS pairing, NBS pairing is highly invasive and may be
unsuitable to provide a practical therapeutic benefit. Similar
results in one circumstance cannot be extended to predict similar
results in another, even slightly different, circumstance.
Different stimulation parameters have to be used for effective VNS
pairing and NBS pairing.
[0108] We observed that 30 seconds of VNS at 30 Hz and 0.8
milliamps (mA) transiently decreased the blood oxygen saturation
level (Sp02) in 3 rats. The standard 0.5 second VNS used in this
study had no measurable effect on either heart rate or oxygen
saturation (data not shown). These results are consistent with
visual observations that brief VNS causes no noticeable behavioral
response. For example, rats did not stop grooming or awaken when
brief VNS was delivered.
[0109] Our observations that brief VNS (1) caused no behavioral
response, (2) caused no change in heart rate, and (3) caused no
change in blood oxygen saturation, suggest that VNS induced
plasticity is not equivalent to pairing tones with a painful or
irritating stimulus (as in footshock or air puff).
[0110] Three weeks after the end of therapy, neural recordings were
obtained from 13 of the 18 noise exposed rats. We continued to
follow 4 rats (2 therapy and 2 sham rats) for an additional two
months. Consistent with previous reports, the untreated rats
continued to exhibit impaired gap detection 3.5 months after the
noise exposure. Signs of impairment of gap detection did not return
in either of the rats that received the VNS-multiple tone therapy.
These results confirm that the VNS-multiple tone therapy causes a
long lasting reversal of noise induced perceptual hearing
abnormalities in rats.
[0111] In an effort to document changes in cortical synchronization
in unanesthetized rats, we looked for systematic effects of
VNS-multiple tone pairing on Electroencephalography (EEG) in noise
exposed rats (7 VNS paired and 4 VNS alone rats). Although the data
is variable because the animal's behavioral state was uncontrolled
and the EEG electrode was located at the vertex and not over
auditory cortex, we nevertheless observed statistically more gamma
power relative to alpha in treated rats compared to untreated rats
during the last week of therapy (p<0.05), but no difference
between the EEG of therapy and VNS alone rats during the first
week. These results are consistent with animal studies that
tinnitus can be associated with abnormal cortical synchronization
and clinical reports of reduced alpha and increased gamma in
tinnitus patients. As in our anesthetized recordings, the degree of
EEG change was not significantly correlated with gap impairment in
individual rats.
[0112] The pairing as it relates to tinnitus is notably unique. We
are not pairing just random sounds. We are not doing some kind of
auditory training or improving perception of one sound over
another. The key is that we are deliberately pairing the
non-tinnitus frequency. The reason is that pairing the non-tinnitus
frequency results in a decrease in the area of the brain responding
to the tinnitus frequency and decrease the synchronous firing of
neurons. By reducing the response to the tinnitus frequency and
decreasing synchrony, we are able to reduce tinnitus symptoms. No
one has before shown that the symptoms of tinnitus can be improved
by excluding specific sounds and including specific sounds. A drug
cannot work selectively in this way, nor can cortical stimulation.
VNS has the specificity to do this.
[0113] None of the description in the present application should be
read as implying that any particular element, step, or function is
an essential element that must be included in the claim scope: the
scope of patented subject matter is defined only by the allowed
claims. Moreover, none of these claims is intended to invoke
paragraph six of 35 USC section 112 unless the exact words "means
for" are followed by a participle. The claims as filed are intended
to be as comprehensive as possible, and no subject matter is
intentionally relinquished, dedicated, or abandoned.
[0114] At least one embodiment is disclosed and variations,
combinations, and/or modifications of the embodiment(s) and/or
features of the embodiment(s) made by a person having ordinary
skill in the art are within the scope of the disclosure.
Alternative embodiments that result from combining, integrating,
and/or omitting features of the embodiment(s) are also within the
scope of the disclosure. Where numerical ranges or limitations are
expressly stated, such express ranges or limitations should be
understood to include iterative ranges or limitations of like
magnitude falling within the expressly stated ranges or limitations
(e.g., from about 1 to about 10 includes, 2, 5, 4, etc.; greater
than 0.10 includes 0.11, 0.12, 0.15, etc.). For example, whenever a
numerical range with a lower limit, Ri, and an upper limit, Ru, is
disclosed, any number falling within the range is specifically
disclosed. In particular, the following numbers within the range
are specifically disclosed: R=R.sub.1+k*(R.sub.u-R.sub.1), wherein
k is a variable ranging from 1 percent to 100 percent with a 1
percent increment, i.e., k is 1 percent, 2 percent, 5 percent, 4
percent, 5 percent, . . . , 50 percent, 51 percent, 52 percent, . .
. , 75 percent, 76 percent, 77 percent, 78 percent, 77 percent, or
100 percent. Moreover, any numerical range defined by two R numbers
as defined in the above is also specifically disclosed. The use of
the term "about" means .+-.10 percent of the subsequent number
unless otherwise defined. Use of the term "optionally" with respect
to any element of a claim means that the element is required, or
alternatively, the element is not required, both alternatives being
within the scope of the claim. Use of broader terms such as
comprises, includes, and having should be understood to provide
support for narrower terms such as consisting of, consisting
essentially of, and comprised substantially of. Accordingly, the
scope of protection is not limited by the description set out above
but is defined by the claims that follow, that scope including all
equivalents of the subject matter of the claims. Each and every
claim is incorporated as further disclosure into the specification
and the claims are embodiment(s) of the present disclosure. The
discussion of a reference in the disclosure is not an admission
that it is prior art, especially any reference that has a
publication date after the priority date of this application. The
disclosure of all patents, patent applications, and publications
cited in the disclosure are hereby incorporated by reference, to
the extent that they provide exemplary, procedural, or other
details supplementary to the disclosure.
[0115] While several embodiments have been provided in the present
disclosure, it should be understood that the disclosed systems and
methods might be embodied in many other specific forms without
departing from the spirit or scope of the present disclosure. The
present examples are to be considered as illustrative and not
restrictive, and the intention is not to be limited to the details
given herein. For example, the various elements or components may
be combined or integrated in another system or certain features may
be omitted, or not implemented.
[0116] In addition, techniques, systems, subsystems, and methods
described and illustrated in the various embodiments as discrete or
separate may be combined or integrated with other systems, modules,
techniques, or methods without departing from the scope of the
present disclosure. Other items shown or discussed as coupled or
directly coupled or communicating with each other may be indirectly
coupled or communicating through some interface, device, or
intermediate component whether electrically, mechanically, or
otherwise. Other examples of changes, substitutions, and
alterations are ascertainable by one skilled in the art and could
be made without departing from the spirit and scope disclosed
herein.
* * * * *