International Conference on Applications of Neuroimaging to Alcoholism
International Conference on
Applications of
Neuroimaging to Alcoholism
ICANA
January 17-19, 2004
The Anlyan Building
300 Cedar Street, New Haven, CT
Sponsored by:
National Institute on Alcohol Abuse and Alcoholism
and
Yale University School of Medicine
Department of Psychiatry
NIAA Center for the Translational Neuroscience of Alcoholism
CTNA
International Conference on Applications of Neuroimaging to Alcoholism
ICANA Organizing Committee
ICANA Chairman: John H. Krystal, M.D.
Director, NIAAA Center for the Translational Neuroscience of Alcoholism
Robert L. Mc Neil Professor & Deputy Chairman for Research
Department of Psychiatry, Yale University School of Medicine
Connecticut Mental Health Center
VA Connecticut Healthcare System
34 Park Street
New Haven, CT 06519
Tel: 203-937-4790
Email: john.krystal@yale.edu
Anissa Abi-Dargham, M.D.
Professor of Clinical Psychiatry and Radiology
Department of Psychiatry
Columbia University
New York State Psychiatric Institute
1051 Riverside Dr Unit 31
New York NY 10032
Tel: 212 –543-5066
Email aa324@columbia.edu
Graeme F. Mason, Ph.D.
Departments of Psychiatry and Radiology
Yale University School of Medicine
N-141 TAC-MRRC
Yale University School of Medicine
300 Cedar St.
New Haven, CT. 06520-8043
Tel: 203-737-1478
Email: graeme.mason@yale.edu
Raymond F. Anton, M.D.
Charleston Alcohol Research Center
Medical University of South Carolina
67 President St.
PO Box 250861
Charleston, SC 29425
Tel: 843-792-1226
Email: antonr@musc.edu
Daniel Mathalon, M.D., Ph.D.
Department of Psychiatry
Yale University School of Medicine
VA Connecticut Healthcare System
950 Campbell Avenue (116A)
West Haven, CT 06516
Tel: 203- 932-5711, ext. 5539
Email: daniel.mathalon@yale.edu
Joyce A. Cramer, B.S.
Associate Research Scientist
Administrative Director, CTNA
Department of Psychiatry
Yale University School of Medicine
950 Campbell Avenue (G7E)
West Haven, CT. 06516-2770
Tel: 203-937-3894
Email: joyce.cramer@yale.edu
Stephanie O'Malley, Ph.D.
Professor of Psychiatry
Yale University School of Medicine
Connecticut Mental Health Center - SAC 202
34 Park Street
New Haven, CT 06519
Tel: 203-974-7590
Email: stephanie.omalley@yale.edu
Andreas Heinz, M.D.
Director and Chair
Dept. of Psychiatry of the Charite, CCM
Schumannstr.20-21
10117 Berlin, Germany
Tel: 49-30-450517001
Email: andreas.heinz@charite.de
Julie Staley, Ph.D.
Yale University and VACHS
Department of Psychiatry
Yale University and VACHS 116A2
950 Campbell Ave.
West Haven, CT. 06516
Tel: 203-932-5711
Email:Julie.Staley@yale.edu
International Conference on Applications of Neuroimaging to Alcoholism
GENETIC AND ENVIRONMENTAL INFLUENCES ON ALCOHOL DRINKING BEHAVIOR
Ting-Kai Li, M.D.
Director, NIAAA
Alcohol abuse and alcoholism are common, complex health and social problems. They
affect 14 million people in the U.S. and are among the top 10 risk factors for loss of healthy life
years worldwide. Risky patterns of drinking (e.g., too much and too fast), lead to a host of
complex outcomes that affect the drinker, family, friends, and society. Environmental and
cultural factors contribute heavily to alcohol abuse, along with personality and temperament, for
which there is a substantial genetic component of variance. On the other hand, alcoholism or
alcohol dependence, is a common, complex disease wherein a persistent and progressive
pattern of abnormally intense alcohol-seeking behavior that, over time, results in the loss of
control over drinking, a preoccupation with drinking, and the development of tolerance and
dependence. As a common, complex disease (as are also hypertension and diabetes mellitus,
for example) alcohol dependence is influenced by multiple genes of different effect sizes and in
different combinations, by gene-gene interactions and gene-environmental interactions. Genes
that influence alcohol dependence vulnerability include those that are unique to alcoholism and
those that also underlie other drugs of abuse and risk-taking behaviors. Examples of the former
include functional polymorphisms of alcohol and aldehyde dehydrogenase and perhaps genes
for serotonin transport and catechol-o-methyl transferase. There now also exist excellent
alcohol-drinking animal models. These provide candidate genes for a variety of alcohol-related
phenotypes important in the development of alcohol dependence, and offer the means for
preclinical testing of compounds in medication development. Extant and new Neuroimaging
technologies offer outstanding modalities for the study of genetic risk, biological mechanisms of
tolerance, dependence and organ damage, and for translational research between human and
experimental animal models.
International Conference on Applications of Neuroimaging to Alcoholism
Keynote Address
SYNTHESIS OF NEUROIMAGING APPLICATION IN ALCOHOLISM
Adolf Pfefferbaum
Unabated alcohol abuse results in high incidence of morbidity and mortality. Sequelae of
chronic alcoholism include transient and enduring changes to the brain’s morphology,
microstructure, biochemistry, metabolism, and function. Identifying the role of alcohol-induced
insult to the brain in continued harmful drinking, despite its untoward physical, psychological,
and social consequences, is an essential step toward developing successful regimes for
prevention and treatment. Alterations in brain constituents themselves are likely factors
perpetuating the disease. Discovery of brain mechanisms underlying these alterations is
enabled by a vast array of in vivo neuroimaging approaches, targeting structural, biochemical,
metabolic, and molecular properties of brain tissue. Magnetic resonance imaging (MRI)
provides multiple modalities for identifying the locus, nature, and extent of alcohol's deleterious
effects on the brain. As noninvasive in vivo tools, MRI enables tracking alcoholism's dynamic
course through relapse and recovery. MRI modalities include high resolution anatomical
imaging of brain macrostructure, diffusion tensor imaging (DTI) of white microstructural integrity,
and blood-oxygen-level dependent MRI (fMRI) of regional activation associated with specific
brain functions. MR spectroscopy (MRS) permits examination of brain biochemical moieties
relevant to neuronal integrity, cell membrane metabolism, degenerative processes, and ethanol
presence and metabolism. Positron emission tomography (PET) and single proton emission
computed tomography (SPECT) are methods to quantify regional brain metabolism and when
performed with selective neurotransmitter ligands, the regional distribution and dynamics of
neurotransmitter function can be examined. Taken together, these brain imaging modalities
provide a powerful armamentarium of quantitative approaches to track the dynamic course of
the disease of alcoholism. The potential of these human studies is substantially enhanced
when coupled with analogous studies performed longitudinally in animal models of alcoholism,
permitting control over critical factors—including age of onset, duration of dependence, temporal
course and amount drunk, individual variation in alcohol metabolism, and genetic disposition—
modulating alcoholism but uncontrollable in human study. Bidirectional translational research
based on neuroimaging methods will provide not simply a snap shot but rather a movie of brain
mechanisms defining the development and resolution of the alcohol dependence syndrome.
Supported by NIAAA: AA05965, AA12388, AA12999, AA13521, AA10723
International Conference on Applications of Neuroimaging to Alcoholism
IMAGING GENETICS AND BRAIN FUNCTION
David Goldman
With: M.A. Enoch, K. Xu, M. M. Heitzeg, Y.R. Smith, J. A. Bueller, Y. Xu, R.A. Koeppe, C.
S. Stohler, J. Zubieta
Imaging genetics utilizes brain structural and functional intermediate phenotypes to
identify roles of genes in behavior and to understand the causal relationships of functional
alleles in behavior. Imaging genetics is a relatively new approach which has already yielded
decisive information on allele function in brain, presumably because of the precision of the
methods and their ability to directly access phenotypes which are ordinarily obscured by other
sources of variance, i.e. the environment. Linkages of COMT Val158Met, BNDF Val66Met and
HTTLPR to behaviors were achieved by a multilevel approach incorporating imaging measures.
fMRI, PET and SPECT techniques captured information on gene expression, neurotransmitter
binding and release and regional brain metabolic response to cognitive challenges.
An example of the application of functional neuroimaging in psychiatric genetics is the
iIdentification of counterbalancing roles of COMT Val158Met in the behavioral domains of
cognition and anxiety/stress response. The power of imaging genetics is illustrated by a
synthesis of recent findings on the role of COMT Val158Met in behavior. This functional locus
has been linked to complex psychiatric diseases including schizophrenia, alcoholism, and OCD.
Val158 and Met158 exert opposing effects on two intermediate phenotypes, potentially
explaining the high abundance of the two alleles in various populations. Executive cognition is
enhanced in individuals with Met158 genotypes predicted to elevate frontal dopamine levels.
We have identified an opposing effect of Met158 genotypes to elevate trait anxiety levels and
pain/stress responses. Dimensionally measured anxiety was assessed in Bethesda [N=149]
and American Indian [N=252] population samples using the TPQ. The Met158 allele associated
with higher levels of anxiety, in women only and in both samples, consistent with estrogen
regulation of COMT. A pain-stress challenge was used in combination with opioid receptor
imaging to measure the influence of Val158Met on capacity to modulate responses to painstress. µ-opioid receptor binding was measured in 30 healthy volunteers with the selective
radiotracer [11C]carfentanil before and after pain-stress induced by infusion of hypertonic saline
into the masseter muscle. Displacement of opioid binding reflects opioid activation and predicts
resilience to pain/stress. The Met158 allele predicts diminished regional µ-opioid system
activation as well as higher ratings of sensory and affective qualities of the pain, and a more
negative internal affective state during the stimulus. These data demonstrate that COMT
Val158Met influences the experience of pain, and may underlie interindividual differences in the
adaptation and responses to pain and other salient and stressful stimuli.