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REQUEST FOR APPLICATIONS FOR A
GRANT-IN-AID
Subject: Behavioral Neurobiology of Tinnitus:
Mechanisms of or Sites Associated with the Percept
of or Reactions to Tinnitus
Source: Tinnitus Research Consortium
Letter of Intent Receipt Date: December 15,
2008
Application Receipt Date: February 2, 2009
PURPOSE
The Tinnitus Research Consortium, supported by
private philanthropy, invites
applications for the support of research in
animal models or human subjects (1) to study the
mechanisms responsible for the percept of
behaviorally verified tinnitus or the reactions to
it or (2) to identify the site(s) of initiation,
generation or perpetuation of the percept of or the
reactions to behaviorally verified tinnitus. The
goal of this request for applications is to
elucidate the structural and functional bases of
the production of tinnitus or the reactions to it
and locate the site(s) in which these phenomena
occur.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic (US)
for-profit and non-profit organizations, such as
universities, colleges, hospitals, clinics,
laboratories and units of state and local
governments.
SUPPORT
The total project period for an application
submitted in response to this request may not
exceed three years. There are no plans for
continuation of the project beyond three years.
Responsibility for planning, direction and
execution of the proposed project will rest solely
with the applicant. The total funds planned for
support of the successful response to this request
for applications are $300,000. An award of up to
$100,000 per year may be made for direct costs of
the research. Grants-in-aid made through the
Tinnitus Research Consortium do not provide
overhead expenses. An award made pursuant to this
request for applications is contingent upon the
availability of funds for this purpose. The award
will be made on or about June 1, 2009, and the
starting date should be July 1, 2009 or later.
RESEARCH OBJECTIVES
Background
Tinnitus is the perception of a sound in the
absence of an environmental acoustic stimulus.
Approximately 30 million people in the United
States experience tinnitus, and probably three
million of these individuals suffer from tinnitus
to the extent that it interferes substantially with
the activities of daily living including sleep.
Tinnitus is a symptom that is associated with
virtually all diseases and disorders affecting the
auditory system and can arise from a lesion in any
part of the auditory system. Since tinnitus occurs
without a physical sound source, it has been called
a phantom sensation. There are many analogies
between phantom limb pain and tinnitus. The
site(s) of generation of the sound percept may be
in the central nervous system even if the initial
lesion is in the end organ of the auditory system.
The most common percept of tinnitus is thought to
result from anomalous activity in and perhaps
reorganization of parts of the central auditory
pathways after injury to the peripheral part of the
auditory system. Many of the causes of tinnitus
are well known, but the mechanisms of its
production and its site(s) of generation are not
fully understood. Recent advances in the knowledge
of the structure and function of the auditory
system and of the mechanisms responsible for
allodynia (condition in which ordinarily
non-hurtful stimuli evoke pain) may provide new
insights into the mechanisms producing tinnitus and
help determine the site(s) in which these phenomena
occur. New findings on the role of microglia in
chronic pain may suggest novel approaches to
uncovering mechanisms responsible for tinnitus. Of
particular interest is the recently found
relationship of glial shortage of interleukin-4,
interleukin-10 or other anti-inflammatory cytokines
to pain. Another attractive approach to
understanding the mechanisms of tinnitus and their
sites is the modulation of the various
neurotransmitter systems that may be involved in
the initiation, generation and perpetuation of the
percept of tinnitus.
Animal perceptual models of tinnitus developed
over the last 20 years are based on the assumption
that animals trained to respond in a particular way
during silent intervals will respond differently
when they perceive some sound in the place of
silence. If such differences in patterns of
responding are observed following interventions
expected to produce tinnitus, the assumption is
made that the change in responding is the result of
the tinnitus. Subsequently developed animal models
of tinnitus, relying, e.g., on active avoidance,
identification of the direction of the perceived
source of tinnitus or poorer detection of silent
gaps in noise, are rapid and less labor intensive
and lend themselves to the verification of chronic
as well as acute tinnitus.
From studies in animal models of tinnitus, there
is increasing evidence that a neural correlate of
tinnitus is a change in the pattern of spontaneous
activity in the centers of the central auditory
pathway. Similarly, imaging studies in humans have
suggested sites of neural activity related to
tinnitus that include the dorsal cochlear nucleus,
inferior colliculus, thalamus and auditory cortex.
Interest continues to increase not only in the
generation of the percept of tinnitus but also in
the emotional and other reactions to tinnitus. The
negative reactions to tinnitus occur less
frequently than the perception of tinnitus and are
considered to be based at least in part on
cognition. The reactions to tinnitus are thought
to result from changes in the autonomic nervous
system and parts of the limbic system involved in
the evaluation of the emotional content of sensory
experiences. Limited imaging evidence of limbic
system involvement has been found with certain
forms of tinnitus. Emotional distress, depression
and insomnia associated with tinnitus may have a
common basis in some limbic structure such as the
nucleus accumbens.
Stress induction and fear conditioning could
serve as the bases for animal models for the study
of reactions to tinnitus in which a change in
annoyance or suffering is of greater importance
than a change in loudness of tinnitus. Stress, as,
for example, induced by body restraint, has been
measured with blood glucocorticosteroid levels.
Fear conditioning has been induced in animals
principally with sound as the conditioned stimulus.
Animal models of conditioned or contextual fear
may be applicable to research on the reactions to
tinnitus mediated through the amygdala. It may be
possible to modify animal models of tinnitus with
the introduction of stress, conditioned fear to
sound or contextual fear or to modify animal models
of conditioned or contextual fear by the
introduction of tinnitus. Creative combinations of
stress or conditioned or contextual fear and
tinnitus may provide insight to the mechanisms of
or sites associated with the emotional reactions to
tinnitus including anxiety and its related
depression and insomnia.
Research Goals and Scope
There is a need to identify and elucidate
mechanisms of or sites associated with the
generation of the percept of tinnitus with fine
structural, mechanical, electrophysiological,
biochemical, biophysical, imaging, genetic,
immunological, neuropsychological,
neuropharmacological, modeling and molecular
biological approaches. This information is
necessary to develop strategies to interrupt the
initiation, generation or perpetuation of the
percept of tinnitus. Identification of mechanisms
responsible for the percept of tinnitus will permit
systematic experimental manipulations and
introduction of pharmacotherapeutic agents to
modify or extinguish the percept of tinnitus. This
information is needed to formulate rational
therapeutic strategies for the prevention,
amelioration, suppression or elimination of the
various subtypes of tinnitus.
There is also a need to identify mechanisms of
or sites associated with the negative reactions to
tinnitus with fine structural,
electrophysiological, biochemical, biophysical,
imaging, genetic, immunological,
neuropsychological, neuropharmacological, modeling
and molecular biological approaches. This
information is necessary to develop strategies to
relieve the suffering from tinnitus. There is also
a need to develop animal models for the study of
reactions to tinnitus. Identification of
mechanisms responsible for the reactions to
tinnitus will permit systematic experimental
manipulations and introduction of
pharmacotherapeutic agents to modify or extinguish
the reactions to tinnitus even if the percept of
tinnitus cannot be eliminated.
The research to be supported in response to this
request must be clearly relevant to progress in the
scientific problems of tinnitus. Research on
diseases accompanied by tinnitus will not be
considered responsive unless the emphasis is on the
mechanisms responsible for the percept of
behaviorally verified tinnitus or the reactions to
it or the site(s) of initiation, generation or
perpetuation of the percept of behaviorally
verified tinnitus or the reactions to it. Novel
approaches to the study of tinnitus are encouraged.
Studies involving structural or functional
correlates of the perception of or reactions to
tinnitus in humans or animal models are only
compelling when coupled with behavioral
verification of the presence of tinnitus.
A confounding aspect of the experimental
induction of tinnitus is the occurrence of hearing
loss. The experimental manipulation causing the
hearing loss may or may not cause tinnitus. In
animal studies, segregation of the correlates of
tinnitus from the consequences of hearing loss
requires the inclusion of a second control group:
animals that have been subjected to the
manipulation for the induction of tinnitus, e.g.,
intense sound exposure, and show a hearing loss but
do not show behavioral evidence of tinnitus.
Comparison of normal animals, animals with hearing
loss without tinnitus and animals with hearing loss
and tinnitus is required for the interpretation of
the results and for the research to have value.
Clinical research on the mechanisms and sites of
tinnitus or the reactions to it is also confounded
by this problem, and the solution is to include
control subjects matched for hearing loss without
tinnitus.
The application should include, but not be
limited to:
- the description of the strategies to be
followed and the anticipated results;
- the experimental model to be utilized and
why it was selected, including methods for
behaviorally verifying the presence of
tinnitus;
- the control of variables known to influence
the results;
- control experiments to validate the
observations;
- the statistical management of the data; and.
- alternative plans for unanticipated
results.
SPECIAL REQUIREMENTS
The principal investigator must obtain the
approval of his or her Institutional Animal
Care and Use Committee or Institutional Review
Board for the project and provide documentation of
it. (Reference: http://grants2.nih.gov/grants/olaw/tutorial/iacuc.htm,
particularly Sections IV and V, or Code of Federal
Regulations Title 45 Part 46 at http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).
The "National Institutes of Health Guidelines on
the Inclusion of Women and Minorities as Subjects
in Clinical Research" amended October 2001 should
be followed. (Please see http://grants2.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm).
Semiannual progress reports and annual financial
reports are required, and the principal
investigator is expected to meet with the Tinnitus
Research Consortium annually at the discretion of
the Tinnitus Research Consortium to discuss the
progress in the project. Funding for the second
and third years is contingent on evidence of
satisfactory progress in the semiannual progress
reports. A final progress report is required at
the end of the grant period.
LETTER OF INTENT
Prospective applicants are requested to submit
by December 15, 2008 a letter of intent containing
the title of the proposed research, the name,
address and telephone number of the principal
investigator, the names of other key personnel and
the participating institution(s). This information
allows the Tinnitus Research Consortium to plan for
the review and avoid conflicts of interest. The
letter of intent is not required, is not binding
and is not considered in the subsequent review.
The letter of intent should be sent to: James B.
Snow, Jr., M.D., Tinnitus Research Consortium, 327
Greenbriar Lane, West Grove, PA 19390-9490 or
e-mail jandssnow@comcast.net.
APPLICATION PROCEDURES
The application and a list of the members of the
Tinnitus Research Consortium may be obtained from
James B. Snow, Jr., M.D., Tinnitus Research
Consortium, 327 Greenbriar Lane, West Grove, PA
19390-9490, telephone and fax 610-345-0085 and
e-mail jandssnow@comcast.net.
Please submit the application in electronic format
in a single Word file on a CD and a signed printed
version and three signed copies to James B. Snow,
Jr., M.D., Tinnitus Research Consortium, 327
Greenbriar Lane, West Grove, PA 19390-9490 by
February 2, 2009.
REVIEW CONSIDERATIONS
Applications will be evaluated for scientific
and technical merit by experts in the subject
matter of the application selected by the Tinnitus
Research Consortium and receive an evaluation
score. A second level of review will be provided
by the Tinnitus Research Consortium, which will
make funding recommendations to the sponsor.
Evaluation Criteria
A carefully designed and feasible study that
attempts to identify the mechanisms responsible for
the percept of behaviorally verified tinnitus or
the reactions to it or to identify the site(s) of
initiation, generation or perpetuation of or
reactions to behaviorally verified tinnitus will be
considered responsive to this request for
applications.
Additional evaluation criteria include:
- scientific and technical significance and
originality of the proposed research;
- appropriateness and adequacy of the design
of the study and the methods to be employed in
the research; in particular, the design of the
study should permit differentiation between the
effects of tinnitus and the effects of hearing
loss and other consequences of the experimental
manipulations;
- ability to correlate individual subject data
as well as group data with tinnitus assessment
variables;
- availability of pilot data of the procedures
to be used;
- qualifications and research experience of
the principal investigator and key staff in the
area of proposed research;
- availability of laboratory, clinical and/or
animal facilities necessary to perform the
research;
- rationale for selection of the experimental
model to be studied;
- provisions for the protection of the welfare
of the animal or human subjects and safety of
the research environment;
- appropriateness of the plan for the
statistical management of the data; and
- appropriateness of the budget and the
duration of the proposed research project.
Special consideration will be given to
applicants who are successful in obtaining partial
support for the research project from other
sources.
INQUIRIES
Postal mail, telephone or e-mail inquiries
regarding this request for applications are
encouraged. The opportunity to clarify any issues
for potential applicants is welcomed.
Direct inquiries to James B. Snow, Jr., M.D.,
Tinnitus Research Consortium, 327 Greenbriar Lane,
West Grove, PA 19390-9490, telephone and fax
610-345-0085 and e-mail jandssnow@comcast.net.
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