Full Text PA-96-054
NIH GUIDE, Volume 25, Number 15, May 10, 1996
PA NUMBER:  PA-96-054
P.T. 34

  Medical/Diagnostic Imaging 

National Institute on Alcohol Abuse and Alcoholism
With the rapid advances in noninvasive imaging technology (e.g.,
ligand PET and SPECT scanning, functional magnetic resonance imaging,
magnetic resonance spectroscopy, magnetoencephalography), it is now
possible to directly correlate functional biologic activity in the
brain with the performance of cognitive tasks.  To capitalize on the
advances in neuroimaging, the National Institute on Alcohol Abuse and
Alcoholism (NIAAA) is seeking applications that apply functional
imaging technology to identify the neuronal systems involved in the
reinforcing properties of alcohol which lead to and maintain
addictive alcohol-seeking behavior.  Studies that use noninvasive
functional imaging technologies to measure alcohol's actions on mood,
emotional states, self-administration, tolerance or cognition while
simultaneously assessing metabolic, physiologic, and receptor
function in the brain provide a means of detecting neuronal systems
involved in the initiation of alcohol-seeking behavior in humans.  In
addition, measurement of subjective experiences and corresponding
brain function during withdrawal and abstinence from alcohol could
elucidate neural mechanisms underlying alcohol craving and relapse.
Initiatives that apply functional imaging technology to the study of
the neuroanatomical and neurochemical mechanisms underlying the
motivational/drive aspects of the alcohol addiction process will
eventually lead to new treatments for alcoholism.
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This program
announcement, Functional Imaging and Alcohol-Motivated Behavior, is
related to the priority areas of alcohol abuse reduction and
alcoholism treatment.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0 or
Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-512-1800).
Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) Awards (R29).  Research project grant
(R01) applications from foreign institutions are limited to three
Research support may be obtained through applications for a regular
research project grant (R01) or FIRST (R29) Award.  Applicants may
also submit Investigator-Initiated Interactive Research Project
Grants (IRPG) under this program announcement.  Interactive Research
Project Grants require the coordinated submission of related regular
research project grant applications and, to a limited extent, FIRST
Award applications from investigators who wish to collaborate on
research, but do not require extensive shared physical resources.
Further information on the IRPG mechanism is available in program
announcement PA-96-001, NIH Guide for Grants and Contracts, Vol. 24,
No. 35, October 6, 1995.  Program Project Grants applications (P01)
will not be accepted under this program announcement.
In order to develop new pharmacotherapies for alcohol abuse and
alcoholism, it is critical to understand the neuroanatomical and
neurochemical circuits that control the emotional, cognitive,
motivational, and reinforcing effects of alcohol.  Functional imaging
techniques that allow simultaneous measurement of brain functional
activity and behavior in humans may provide more sensitive tools for
understanding brain regions and biochemical pathways underlying
craving for alcohol and impaired control over drinking.
To date, the majority of noninvasive imaging studies in the alcohol
field have used structural magnetic resonance imaging (MRI) to
investigate structural brain changes produced by chronic alcoholism.
These studies have yielded important findings about quantitative
changes in tissue volume of grey and white matter that occur as a
result of chronic alcohol ingestion, the interactive effects of aging
and alcoholism, and the reversal of these structural changes
following abstinence (Pfefferbaum and Rosenbloom, 1993; Jernigan,
1991a,b). However, structural MRI studies have failed to demonstrate
a consistent relationship between the degree of cognitive deficits
associated with chronic alcoholism, particularly memory impairment,
and the extent of damage to structures thought to subserve memory
functions, e.g., the hippocampus and mammillary bodies (Sullivan, et
al., 1995; Davila, et al., 1994; Jernigan, et al., 1991b; DiSclafani,
et al., 1995), possibly because these structural changes do not
accurately reflect changes in cellular function.
In contrast, functional imaging technologies that measure brain
metabolism and blood flow (such as PET and SPECT), have found more
consistent correlations between performance on tests of frontal lobe
function (i.e., higher order reasoning, concept formation and
abstraction) and cerebral metabolism in subdivisions of the frontal
lobes of older alcoholic patients (Adams, et al., 1993; Adams, et
al., 1995).  These studies indicate that functional imaging may be
more sensitive than structural imaging in demonstrating relationships
between alcohol-induced behavioral impairments and alterations in
underlying neural substrates.  Furthermore, in these studies,
cerebral metabolic activity and cognitive performance were measured
in separate sessions. With the use of radioactive isotopes for PET
that have short half-lives (e.g., 15-oxygen) or functional magnetic
resonance imaging (fMRI) techniques, it is possible to measure
simultaneously cerebral activity and behavior in the same individual
under a variety of conditions.  For example, the same subject can be
studied in a resting state or while performing a task (cognitive
activation).  Multiple studies in the same subject improve resolution
and permit subtraction of the resting state condition or a matched
control task, leaving only those areas that are directly involved in
the task of interest.  The use of these "activation" techniques in
chronic alcoholics will elucidate the entire neuroanatomical circuit
involved in a particular cognitive task and allow comparison of
functional activity in alcoholic subjects with controls.  More
importantly, the functional neuroanatomy or neurochemistry of
alcohol's subjective effects, including mood, emotional changes, and
craving could be studied in PET, SPECT, or functional magnetic
resonance imaging (fMRI) activation paradigms.
Most PET and SPECT studies in humans and animals to date have
investigated the acute and chronic effects of alcohol on local
cerebral glucose metabolism (LCGU) or regional cerebral blood flow
(RCBF) to establish detailed patterns of changes in functional
activity throughout the brain.  Both human and animal studies have
shown that dose, route and/or method of administration, time of
measurement after alcohol administration (i.e., at different points
on the ascending or descending limb of the blood alcohol curve), and
individual experience with ethanol determine alcohol's effects on
functional activity in specific regions of the brain (Eckardt, et
al., 1988, 1992; for reviews see Volkow, et al., 1995a; Lyons and
Porrino, 1995).  Since alcohol's acute effects are biphasic,
carefully controlled research is needed in humans and animals,
particularly with respect to dose and pharmacokinetics, to yield more
consistent data on the regional and temporal pattern of brain
metabolic activity following acute alcohol administration.
Longitudinal studies following chronic ingestion are needed to
distinguish withdrawal-related changes in brain metabolism from
irreversible changes, and to determine the effects of abstinence on
recovery of brain metabolic function. Coupled with behavioral
measures, these latter studies could reveal neural circuits
associated with craving or cognitive deficits, the reversibility of
cognitive deficits relative to brain functional metabolic deficits,
and could shed light on how cognitive changes contribute to excessive
drinking and relapse.
Knowledge of the functional effects of alcohol, i.e., which neuronal
structures are altered and how they are altered (stimulated or
inhibited) is important for the development of pharmacotherapies.
However, where PET and SPECT show the most promise for the alcohol
field is in bridging the gap between brain chemistry and behavior.
Although many of the amine and polypeptide receptor ligands have been
labeled with radioactive tracers, only a few studies using PET or
SPECT have measured alcohol's effects on neurotransmission.  The
NIAAA has supported research using PET and
2-deoxy-2-[F18]fluoro-D-glucose (FDG) to evaluate whether the
function of the GABA system differs between alcoholics and
nonalcoholics.  A challenge dose of the benzodiazepine lorazepam,
which exerts its effect by facilitating GABA activity, resulted in a
reduced cerebral metabolic response (blunted response) in the
thalamus, basal ganglia, and orbitofrontal cortex in alcoholics
(Volkow, et al., 1993). A similar blunted metabolic responses to
lorazepam challenge was observed in the cerebellum of individuals
with a positive family history of alcoholism (Volkow, et al., 1995b).
These findings suggest that disrupted activity of the
benzodiazepine-GABA receptors may be both a consequence of chronic
alcoholism and a potential marker for alcoholism risk.
With the availability of receptor ligands for many neurotransmitter
systems, more direct mechanistic studies of receptor function can be
performed in animals and humans.  For example, many aspects of
dopamine biochemistry, a neurotransmitter that is associated with the
reinforcing properties of alcohol, can be examined in the human
brain.  D2-dopamine receptors can be imaged and quantified with the
tracer [11C]N-methyl spiperone.  Dopamine release can be measured by
its competitive inhibition of tracers that bind to dopamine
receptors.  The availability of both presynaptic and postsynaptic
receptors, including the presynaptic dopamine transporter can be
assessed.  A few alcohol researchers have begun to use functional
imaging techniques to study neurotransmitter function, such as
quantifying D2 receptors in alcoholics. Much more research is needed
combining functional imaging, neurochemistry, and behavior to
eventually understand the mechanisms underlying the
reinforcing/motivational aspects of alcoholism and to use this
information to develop new treatments and pharmacotherapies.
Magnetic resonance spectroscopy (MRS) and magnetoencephalography
(MEG) are functional imaging techniques that have had relatively
little application to neurobiological mechanisms of alcoholism.  MRS
detects signals of compounds that participate in energy metabolism
and phospholipid metabolism, such as adenosine triphosphate (ATP, a
cofactor in energy metabolism), creatine (an energy metabolite),
phosphomonoesters and phosphodiesters (products of membrane
phospholipids), and N-acetyl aspartate (an amino acid localized in
neurons).  The chronic effects of alcohol consumption on cerebral
phosphorous metabolites and neuronal loss have been investigated
using MRS techniques (Fein, et al., 1994; Meyerhoff, et al., 1995).
Alcohol can also be detected in the brain by proton MRS (Mendelson,
et al., 1990), and this method has been used to study alcohol
tolerance in the human brain (Mendelson, et al., 1992). The amino
acid glutamate and glutamate-related amino acids; such as, glutamine,
aspartate, and gamma- amino-butyric acid (GABA), can be detected by
1H MRS (Vion-Dury, et al., 1994).  Recently, MRS methods have been
developed in animals and humans to measure cerebral blood flow
(McLaughlin, et al., 1992), and cerebral metabolic rates for oxygen
and glucose (Shulman, et al., 1992; 1994). Thus, issues involving
alcohol's effects on brain biochemistry and glucose metabolism could
be addressed using this method.
Finally, MEG noninvasively measures actual electrical activity of the
brain with millisecond temporal resolution. This technique has been
used (most recently in combination with other imaging techniques) to
image selective attention (Aine, et al., 1995), map auditory and
visual cortex, and study memory processes (see Naatanen, et al., 1994
for review). Since alcohol's acute effects are biphasic, MEG could be
used to delineate the temporal sequence of brain changes associated
with acute alcohol-induced cognitive processing deficits.
Areas needing further research include, but are not limited to:
o  Use of functional imaging technologies in combination with
behavioral measures (e.g., craving questionnaires, mood inventories,
cue-reactivity, self-administration paradigms), or drug challenge
paradigms to elucidate the neuroanatomical and biochemical circuits
underling the reinforcing properties of alcohol during initiation
and/or withdrawal from alcohol.
o  Use of functional imaging technologies (PET and SPECT ligands) in
humans and animals to characterize neurochemical processes associated
with alcohol reinforcement and/or craving including neurotransmitter
release, receptor concentrations, neurotransmitter synthesis, and
neurotransmitter transporters.
o  Use of functional imaging technologies to study neural circuits
underlying cognitive deficits associated with acute and chronic
alcohol intake, particularly studies that elucidate how functional
deficits in specific neuranatomical circuits and their related
cognitive deficits may contribute to excessive alcohol intake.
o  Use of functional imaging technologies to study neurobiological
markers of vulnerability to alcohol abuse and alcoholism in children
and/or adolescents, particularly MRS, MEG, or fMRI that do not
involve radioactive tracers.
Applicants planning alcohol challenges to human subjects should
obtain a copy of the "Recommended Council Guidelines on Ethyl Alcohol
Administration in Human Experimentation" (rev. June 1989) from the
program contact listed under INQUIRIES.
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.
Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Grants Information Office, Office of Extramural
Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/710-0267, email: asknih@odrockm1.od.nih.gov.  The title and
number of the program announcement must be typed in section 2 on the
face page of the application.
Applications for the FIRST award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application. FIRST award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
The completed original application and five legible copies must be
sent or delivered to:
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817-7710 (for express/courier service)
Applications that are complete will be evaluated for scientific and
technical merit by an appropriate peer review group convened in
accordance with the standard NIH peer review procedures.  As part of
the initial merit review, all applications will receive a written
critique and undergo a process in which only those applications
deemed to have the highest scientific merit, generally the top half
of the applications under review, will be discussed, assigned a
priority score, and receive a second level review by the appropriate
national advisory council.
Review Criteria
Criteria to be used in the scientific and technical merit review of
applications for research project grants (R01) will include the
1.  The scientific, technical, or medical significance, and
originality of the proposed research.
2.  The appropriateness and adequacy of the research design and
methodology proposed to carry out the research.
3.  The adequacy of the qualifications (including level of education
and training) and relevant research experience of the principal
investigator and key research personnel.
4.  The availability of adequate resources and equipment to conduct
the proposed research.
5.  The appropriateness of budget estimates and duration in relation
to the proposed research.
6.  Adequacy of plans to include both genders and minorities and
their subgroups as appropriate for the scientific goals of the
research. Plans for the recruitment and retention of subjects will
also be evaluated.
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.
The review criteria for FIRST Awards (R29), and IRPGs, are contained
in the relevant program announcements.
Applications recommended for approval will be considered for funding
on the basis of the overall scientific and technical merit of the
application as determined by peer review, programmatic needs and
balance, and the availability of funds.
Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.
Direct general inquiries regarding research issues to:
Ellen Witt, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-6545
FAX:  (301) 594-0673
Email:  ewitt@willco.niaaa.nih.gov
Direct inquiries regarding fiscal matters to:
Linda Hilley
Grants Management Branch
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-0915
FAX:  (301) 443-3891
Email:  lhilley@willco.niaaa.nih.gov
This program is described in the Catalog of Federal Domestic
Assistance, No. 93.273.  Awards are made under the authorization of
the Public Health Service Act, Sections 301 and 464H, and
administered under the PHS policies and Federal Regulations at Title
42 CFR Part 52 and 45 CFR Part 74.  This program is not subject to
the intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency Review.
The PHS strongly encourages all grant recipients to provide a
smoke-free workplace and promote the non-use of all tobacco products.
In addition, Public Law 103-227, the Pro-Children Act of 1994,
prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library, day care, health care or early childhood development
services are provided to children. This is consistent with the PHS
mission to protect and advance the physical and mental health of the
American people.
Adams, K., Gilman, S., Koeppe, R., Kluin, K., Brunberg, J., Dede, D.,
Berent, S., and Kroll,P.  (1993) Neuropsychological deficits are
correlated with frontal hypometabolsim in positron emission
tomography studies of older alcoholics.  Alcoholism:  Clinical and
Experimental Research, 17(2):205-10.
Adams, K., Gilman, S., Koeppe, R., Kluin, K., Junck, L., Lohman, M.,
Johnson-Greene, D., Berent, S., Dede, D., and Kroll,P.  (1995)
Correlation of neuropsychological function with cerebral metabolic
rate in subdivisions of the frontal lobes of older alcoholic patients
measured with [F18]fluorodeoxyglucose and positron emission
tomography. Neuropsychology, 9(3):275-80.
Aine, C., Supek, S., and George, J.  Temporal dynamics of
visual-evoked neuromagnetic sources:  effects of stimulus parameters
and selective attention. (1995) International Journal of
Neuroscience, 80:79-104.
Davila, M., Shear, P., Lane, B., Sullivan, E., and Pfefferbaum, A.
(1994) Mammillary body and cerebellar shrinkage in chronic
alcoholics: An MRI and neuropsychological study.  Neuropsychology,
DiSclafani, V., Ezekiel, F., Meyerhoff, D., MacKay, S., Dillon, W.,
Weiner, M., and Fein, G. (1995) Brain atrophy and cognitive function
in older abstinent alcoholic men.  Alcoholism:  Clinical and
Experimental Research, 19(5):1121-6.
Eckardt, M., Campbell, G., Marietta, C., Majchrowicz, E., and Weight,
F. Acute ethanol administration selectively alters localized cerebral
glucose metabolism.  (1988) Brain Research, 444:53-8.
Eckardt, M. Campbell, G., Marietta, C., Majchrowicz, Rawlings, R.,
and Weight, F.  Ethanol dependence and withdrawal selectively alter
localized cerebral glucose utilization. (1992) Brain Research,
584:244- 50.
Fein, G., Meyerhoff, D., DiSclafani, V., Ezekiel, F., Poole, N.,
MacKay, S., Dillon, W., Constans, J., Weiner, M.  1H magnetic
resonance spectroscopic imaging separates neuronal from glial changes
in alcohol related brain atrophy. (1994)  In: NIAAA Research
Monograph 27:  Alcohol and Glial Cells, Lancaster, F.(ed.), NIH Pub.
No., 94-3742, Bethesda, MD, pp. 227-42.
Jernigan, T. L., Schafer, K., Butters, N., and Cermak, L.  (1991a)
Magnetic resonance imaging of alcoholic Korsakoff patients.
Neuropsychopharmacology, 4:175-86.
Jernigan, T., Butters, N., DiTraglia, G., Schafer,K., Smith, T.,
Irwin, M., Grant, I., Schuckit, M., and Cermak, L.  (1991b) Reduced
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Sinnwell, T., van Gelderen, P., Fiat, D., and Moonen, C. In vivo
measurement of cerebral blood flow and oxygen consumption using 17O
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Mendelson, j., Woods, B., Chiu, T., Mello, N., Luckas, S., Teoh, S.,
Sintavanarong, P., Cochin, J., Hopkins, M., and Dobrosielski, M.
(1990) In vivo proton magnetic resonance spectroscopy of alcohol in
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Mendelson, J.,Chiu, T., Amass, L., Mello, N., Teoh, S., Woods, B.,
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alcohol abuse and HIV infection on brain phosphorus metabolites.
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Naatanen, R., Ilmoniemi, R., and Alho, K.  Magnetoencephalography in
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Pfefferbaum, A. and Rosenbloom, M.  In vivo imaging of morphological
brain alterations associated with alcoholism. (1993)  In:  NIAAA
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Shulman, R., Behar, L., Rothman, D., and Mason, G. NMR studies of
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Shulman, R., Rothman, D., and Blamire, A.  NMR studies of human brain
function. (1994) Trends in Biochemical Sciences, 19:522-26.
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(1995) Anterior hippocampal volume deficits without explicit memory
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(1995b)  Alcoholism:  Clinical and Experimental Research,

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