Full Text PA-96-054 FUNCTIONAL IMAGING AND ALCOHOL-MOTIVATED BEHAVIOR NIH GUIDE, Volume 25, Number 15, May 10, 1996 PA NUMBER: PA-96-054 P.T. 34 Keywords: Medical/Diagnostic Imaging Alcohol/Alcoholism National Institute on Alcohol Abuse and Alcoholism PURPOSE 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. HEALTHY PEOPLE 2000 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). ELIGIBILITY 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 years. MECHANISM OF SUPPORT 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. RESEARCH OBJECTIVES 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. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS 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. APPLICATION PROCEDURES 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: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817-7710 (for express/courier service) REVIEW CONSIDERATIONS 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 following: 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. AWARD CRITERIA 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 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 AUTHORITY AND REGULATIONS 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. References 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, 8:433-44. 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. 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Jernigan, T., Butters, N., DiTraglia, G., Schafer,K., Smith, T., Irwin, M., Grant, I., Schuckit, M., and Cermak, L. (1991b) Reduced cerebral grey matter observed in alcoholics using magnetic resonance imaging. Alcoholism: Clinical and Experimental Research, 15(3):418-27. Lyons, D. and Porrino, L. Visualizing neural pathways affected by alcohol in animals. (1995) Alcohol, Health and Research World, 19(4): 300-05. McLaughlin, A., Pekar, J., Ligeti, L., Ruttner, Z., Lyon, R., Sinnwell, T., van Gelderen, P., Fiat, D., and Moonen, C. In vivo measurement of cerebral blood flow and oxygen consumption using 17O magnetic resonance imaging. (1992) In: NIAAA Research Monograph 21: Imaging in Alcohol Research, Zakhari, S. and Witt, E. (eds.), DHHS Pub. No. (ADM)92-1890, Rockville, MD, pp. 273-86. Mendelson, j., Woods, B., Chiu, T., Mello, N., Luckas, S., Teoh, S., Sintavanarong, P., Cochin, J., Hopkins, M., and Dobrosielski, M. 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(1993) In: NIAAA Research Monograph 22: Alcohol induced brain damage, Hunt, W.A. and Nixon S.J. (eds.), NIH Pub. No. 93-3549, Rockville, MD, pp. 71-88. Shulman, R., Behar, L., Rothman, D., and Mason, G. NMR studies of cerebral metabolism. (1992) In: NIAAA Research Monography 21: Imaging in Alcohol Research, Zakhari, S. and Witt, E. (eds.), DHHS Pub. No. (ADM)92-1890, Rockville, MD, pp. 195-200. Shulman, R., Rothman, D., and Blamire, A. NMR studies of human brain function. (1994) Trends in Biochemical Sciences, 19:522-26. Sullivan, E., Marsh, L., Mathalon, D., Lim, K., and Pfefferbaum, A. (1995) Anterior hippocampal volume deficits without explicit memory impairment in chronic alcoholics. Alcoholism: Clinical and Experimental Research, 19:110-22. Vion-Dury, J., Meyerhoff, D., Cozzone, P., and Weiner, M. What might be the impact on neurology of the analysis of brain metabolism by in vivo magnetic resonance spectroscopy? (1994) Journal of Neurology, 241:354- 71. 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