John H. Krystal, M.D. - US grants

mental disorder chemotherapy; mental disorders; neurosciences; neurophysiology; psychiatry; mental health facility; biomedical facility; child mental disorders; risperidone; serotonin receptor; NMDA receptors; schizophrenia; psychopharmacology; genetic registry /resource /referral center; molecular genetics; Tourette's syndrome; neurochemistry; behavioral genetics; anxiety disorders; major depression; obsessive compulsive disorder; psychosis; clinical research; linkage mapping; adolescence (12-20); child (0-11); electrophysiology; human subject; human genetic material tag;

neurochemistry; developmental neurobiology; mental health facility; biomedical facility; child mental disorders; psychopharmacology; psychobiology; neuropeptides; neurotransmitter metabolism; Tourette's syndrome; attention deficit disorder; brain metabolism; child physical development; developmental genetics; neuroendocrine system; gel electrophoresis; electrochemistry; clinical chemistry; immunocytochemistry; human subject; high performance liquid chromatography; in situ hybridization;

DESCRIPTION (provided by applicant): The past 5 years has been the most productive epoch in my career. I supported my salary with an NIAAA Independent Investigator (KO2) Award that markedly reduced my clinical and administrative responsibilities. Consequently, since 1998, I published 128 research papers and reviews including the multicenter VA naltrexone alcohol dependence study, characterization of NMDA receptor function alterations with alcohol dependence and the familial risk for alcoholism, completion of studies exploring roles for glutamate receptor antagonist or glutamate release inhibiting drugs for treating alcohol dependent patients, and completion of an initial characterization of time-dependent changes in the regulation of GABA systems in patients using concurrent measurements of cortical GABA levels with 1H-magnetic resonance spectroscopy (MRS) and GABAA receptor regulation with single photon emission computerized tomography (SPECT). For this work, I received several awards including the Joel Elkes Award (ACNP) and the Hans-Jonas Weitbrecht Scientific Award (Bayer). During this period, I renewed our VA Alcohol Research Center, led the establishment of the NIAAA Center for the Translational Neuroscience of Alcoholism (CTNA), and received funding for two RO 1 grants and a VA Merit Review Grant. I also participated in several national and international committees, served on the Editorial Boards of several journals, and mentored several highly accomplished trainees. Over the next five years, I propose to advance the scientific theme of my KO2 Award: to further characterize alterations in amino acid neurotransmission associated with alcohol dependence. The principal new conceptual and educational focus of this application is to unite psychopharmacologic and neuroimaging techniques that were my focus for the past five years with molecular genetic (candidate gene) and molecular neuroscientific (mRNA expression arrays) techniques that may help to add significant explanatory power to the proposed studies. I also propose to characterize the specificity of alterations in glutamatergic and GABAergic alterations associated with the vulnerability to alcohol dependence by comparing ethanol, sodium pentothal (barbiturate), and ketamine (NMDA receptor antagonist) responses in healthy individuals with and without family histories of ethanol dependence.

[unreadable] DESCRIPTION (provided by applicant): Accomplishments: With the initial support (RO1 AA11321-01A1), we pioneered the concurrent application of magnetic resonance imaging (MRI), magnetic resonance spectroscopy at (MRS), and 1231-iomazenil single photon emission computerized tomography (SPECT) to characterize parallel changes in cortical GABA levels and GABA-A receptors during recovery from alcohol dependence (healthy subjects; patients at 1 week, 1 month, and 6 months of sobriety). Our SPECT data describe increased ligand binding to GABA-A receptors over the first week of sobriety that recovers during the next 3 weeks. These data could reflect a deficit in GABA-A receptor function normalizes with sobriety. Our MRS data indicate that cortical GABA deficts are not present in acute withdrawal, but levels declined over the first month of sobriety as ligand binding to GABA-A receptors dropped. We hypothesize that these shifts reflect a restoration of GABA-A receptor function that is mediated by changes in GABA-A receptor subunit composition. Comorbid smoking blocked the withdrawal-related changes in cortical GABA levels and GABA-A receptors. Thus, GABA systems may mediate a facet of the comorbidity of smoking and drinking. This renewal application would enable us to: 1) demonstrate that rapid time-dependent change in GABA-A receptors with sobriety occur within subjects, 2) replicate the reduction in GABA levels with sobriety using higher field (4.0 T) human MRS, and 3) replicate the protective impact of smoking. Analyses will control for tissue atrophy and GABA- related genotypes. Because GABA-A receptor subunit substitutions may contribute to changes in GABA-A receptor binding, we will relate SPECT binding data to changes in the GABA-related gene expression, including receptor subunits, using gene expression arrays applied to monocytes extracted from subjects at each imaging session. [unreadable] [unreadable] [unreadable]

DESCRIPTION: (Adapted from the Investigator's Abstract) The capacity of ethanol to block N-methyl-D-aspartate (NMDA) glutamate receptors contributes to its behavioral effects in animals and humans. Recent preclinical data indicate that NMDA receptors and u opiate receptors are co-localized and have opposing actions in several brain regions involved in reward, such as the nucleus accumbens, the amygdala, and the raphe nucleus. These finds lead to the prediction that the mu receptor antagonist, naltrexone, would block the rewarding effects of NMDA antagonists, such as ketamine and ethanol. The capacity of naltrexone to attenuate the rewarding effects of ethanol contributes to its capacity to prevent episodes of drinking from becoming relapses to alcohol abuse. Similarly, our pilot data suggest that naltrexone reduces the euphoric and ethanol-like effects of subperceptual doses of ketamine. However, the mechanisms underlying the interactions of ethanol and naltrexone are not well understood. It is timely to explore the interactions of human opiate and glutamate receptor systems. Acamprostate, another promising pharmacotherapy for alcoholism, may act, in part, via glutamate receptor systems. The NIAAA multicenter study, Project COMBINE, will test the interactive effects of naltrexone and acamprostate. Better understanding of the interactions of opiate and glutamate systems may provide insights into findings from this study. In this application, we test the hypothesis that naltrexone attenuates the euphoric and ethanol-like effects of the NMDA antagonist, ketamine. We propose to examine the interactive effects of naltrexone and ketamine in 36 healthy human subjects using a randomized, balanced, placebo-controlled, within subjects design. The primary outcome measures include the visual analog scale measuring similarity to ethanol and the visual analog scale measuring "high." In our previous studies, we found that the rewarding effects of ketamine were remarkably resistant to antagonism by pretreatment with haloperidol or facilitation by pretreatment with lorazepam or amphetamine. We hypothesize that ketamine may mimic some aspects of the actions of ethanol at the NMDA receptor. Thus, the blockade of the rewarding effects of ketamine by naltrexone may provide insight into an important mechanism underlying the psychopharmacology of ethanol and the treatment of alcoholism.

CTNA Overall John Krystal, M.D. Abstract The gap between basic research advances and new clinical insights and treatments remains a critical obstacle to progress in the field of alcoholism research. This translational neuroscience mission is the enduring focus of the Center for the Translational Neuroscience of Alcoholism (CTNA). CTNA conducts groundbreaking molecular neuroscience, molecular genetics, functional and chemical neuroimaging, and psychopharmacology studies in the service of providing new insights to bridge the gap between basic and clinical research. This renewal application will study how inhibition of mGluR5 might normalize disturbances in cortico-striatal glutamate signaling arising from upregulation of NMDA-R and, in so doing, attenuate both goal- oriented (model-based learning) and habitual (model-free learning) alcohol consumption in animals and reduce alcohol consumption in human heavy drinkers. In so doing, we propose the first translational neuroscience evaluation of the therapeutic potential of mGluR5 NAM?s, a mechanism that has received intensive preclinical study. Building upon its prior achievements, The CTNA will facilitate transdisciplinary research within projects and across projects and with other alcohol focused initiatives nationally. It will also continue its highly productive Pilot Projects Core that provides an open competitive mechanism to enable the Center to rapidly encompass innovative new research and to engage outstanding investigators new to alcoholism research. CTNA will continue to expand its educational mission, building on the success of the the International Conference on the Applications of Neuroimaging to Alcoholism.

DESCRIPTION (provided by applicant): This first symposium devoted to alcoholism will be a seminal event in drawing imaging researchers toward research on alcoholism in hopes of advancing knowledge about this disorder. Established investigators who work in other areas of brain imaging as well as those already working in alcoholism-related areas will be convened to share methodological applications to alcoholism and foster collaboration across modalities. Methods: The program will include an international roster of speakers in a two and a half-day symposium. The audience is expected to include 150-250 researchers from around the world. The proposed meeting dates are September 12-14, 2003. The proposed agenda will include 4 main topics: Magnetic resonance imaging (MRI) - Diffusion tensor imaging (DTI); Functional magnetic resonance imaging (fMRI); Magnetic resonance spectroscopy (MRS); Positron emission tomography (PET)-Single photon emission computed tomography (SPECT) neuroreceptor imaging. A general outline for the two and a half day meeting is: Plenary Presentations What do we need to know about alcoholism?. How does imaging help us learn more about key problem area? Review of neurocircuitry related to alcoholism. Plenary Sessions on each of the 4 modalities: Teaching talk (45") followed by brief presentations on current research (15 min each), concluding with open discussion. MRI-DTI, fMRI, MRS, PET-SPECT New Directions and Applications to Treatment: Talks on clinical applications, transition from basic research to pharmaceutical industry. COMMENTS: Topics will include predictors of diagnosis and treatment success; markers for treatment; neurocircuitry; intracellular targets; MEG; gene expression, etc. A call for abstracts also will bring forward names and ideas from other groups that might be added to the main program. Young Investigator travel scholarships will be considered.

DESCRIPTION (provided by applicant): This is a resubmission of an R21 proposal. This pilot study will compare the effectiveness of the lamotrigine and memantine to standard treatment of acute alcohol withdrawal and abstinence initiation in alcohol dependent patients, and the effect of these drugs on NDMA neurotransmission. A. Specific Aim 1: Are Memantine and Lamotrigine safe and effective detoxification strategies from alcohol in alcohol dependent individuals? 1. Do Lamotrigine and Memantine effectively treat the symptoms of alcohol withdrawal? 2. Do Lamotrigine and Memantine treat the emotional distress and depression associated with alcohol withdrawal in these patients? B. Specific Aim 2: Are Memantine and/or Lamotrigine effective in abstinence initiation and relapse prevention in the post-withdrawal (protracted withdrawal) phase in these individuals? 1. Are Memantine and/or Lamotrigine more effective than placebo in ameliorating depression, anxiety, and craving for alcohol in these patients? 2. Do Memantine and/or Lamotrigine prevent relapse to alcohol use more effectively than placebo in patients in the post-withdrawal (protracted withdrawal) phase ? Patients will be randomized to receive either memantine, lamotrigine, or a control strategy (Symptom Triggered Detoxification) (30 per group). All subjects will be recruited from the Leningrad Regional Center of Addictions affiliated with the St. Petersburg State PavIov Medical University (Russia). Only data analyses will be performed locally in New Haven. This pilot study will compare each active agent to placebo individually in order to evaluate these agents for a larger study. The primary outcomes are the number of patients successfully detoxified without additional benzodiazepine administered, Penn Alcohol Withdrawal Symptoms Checklist (PAWSC) and Clinical Institute Withdrawal Assessment Scale - Revised (CIWA-R) scores.

Administrative Core John Krystal, M.D. Abstract The Center for the Translational Neuroscience of Alcoholism (CTNA) places a high priority on maintaining an efficient flow of information to promote the safe and successful completion of proposed studies, to support the initiation of novel pilot studies, to facilitate the career development of trainees and junior faculty affiliated with the Center, and to promote the dissemination of research advances. However, the CTNA views its mission as translational in that it places a high priority on the interplay between basic and clinical neuroscience. Thus, its administrative, monitoring, and educational components include representation from basic and clinical neuroscience, and an essential charge of these is to preserve the integrity of the translational mission. The Administrative Core provides for the centralized organizational functions of the Center for the Translational Neuroscience of Alcoholism (CTNA). These functions include 1) the central executive function of the Center (Director, Executive Committee), 2) financial oversight, 3) data safety monitoring (Data Safety Monitoring Board), 4) educational functions (Education Committee), 5) and external ongoing review of the scientific merit of CTNA activities (Scientific Advisory Board).

DESCRIPTION (provided by applicant): The gap between basic research advances and new clinical insights and treatments remains a critical obstacle to progress in the field of alcoholism research. This translational neuroscience mission is the enduring focus of the Center for the Translational Neuroscience of Alcoholism (CTNA). The CTNA conducts groundbreaking psychopharmacology, neuroimaging, molecular neuroscience, and molecular genetic studies in the service of providing new insights to bridge the gap between basic and clinical research. This renewal application will study mechanisms through which disturbances in glutamate and dopamine neurotransmission within cortico-limbic circuitry contribute to the vulnerability to persistent heavy drinking and alcohol dependence. Building on these insights, it will explore a novel approach to the pharmacotherapy of alcohol dependence that emerges directly from mechanistic CTNA research. The CTNA will facilitate transdisciplinary research within projects and between projects within the Center and will facilitate additional external collaborations. It will also continue its highly productive Pilot Projects Core that provides for an open competitive mechanism that supports innovative research and talented investigators new to the field of alcoholism research. The CTNA will continue and expand its career development mission, building on the success of its new NIAAA Research Fellowship Program. It will also continue its program of community based educational programs for lay audiences. Further it will continue to promote translational research through sponsorship of educational programs, such as the NIAAA-supported International Conference on the Applications of Neuroimaging to Alcoholism.

DESCRIPTION (provided by applicant): Schizophrenia and cocaine dependence produce disability, in part, by impairing executive cognitive function. Also, schizophrenic patients are at increased risk for developing cocaine dependence. When abstinent from cocaine, comorbid patients show reduced symptoms, but poorer executive cognitive function than other schizophrenic patients. This proposal probes the interactive cognitive neuroscience of schizophrenia and cocaine dependence. It builds on the work of our late colleague, Patricia Goldman-Rakic, who showed in monkeys that prefrontal cortex (PFC) activity during the maintenance phase of working memory (WM) was dependent upon dopamine D1 receptor function, while PFC activity during the response selection phase of WM was dependent upon D2 receptor function. We propose to use functional magnetic resonance imaging (fMRI) to compare PFC activity associated with WM and cortical functional connectivity in four groups of subjects: healthy individuals, abstinent cocaine dependent individuals, schizophrenia patients, and abstinent cocaine dependent schizophrenic patients. Our pilot data suggest that the comorbid group shows greater PFC activity deficits in the maintenance phase of WM than either single diagnosis group, perhaps related to greater deficits in PFC D1 receptor function. However, the comorbid group shows greater response phase activity than either single diagnosis group or healthy subjects, suggestive of a cocaine use-related enhancement of PFC D2 receptor function. By highlighting novel circuit adaptations that contribute to cognitive dysfunction associated with the interplay of schizophrenia and cocaine dependence, this application may shed new light on PFC mechanisms that contribute to poorer cognitive outcomes associated with schizophrenia, cocaine dependence, and their comorbidity. PUBLIC HEALTH RELEVANCE This project may help us to understand how schizophrenia and cocaine abuse affect prefrontal function how these factors interact in those who are co-morbid for schizophrenia and cocaine dependence. Such knowledge may help us to develop better treatments for those who are comorbid for schizophrenia and cocaine dependence.

The Pilot Projects Core provides a mechanism to provide a limited amount of funding to investigators to collect pilot data for innovative research projects. These projects serve the CTNA by 1) testing hypotheses or addressing methodologic issues central to the CTNA, 2) bringing new investigators into the CTNA and the field of alcoholism research, 3) generating new alcoholism RO1's, 4) enabling CTNA to rapidly adapt to advances in the field, and 5) guiding the next iteration of the CTNA. Pilot Project Proposals are solicited through an open and public solicitation process. Proposal are developed in collaboration with the CTNA Cores (Data Management and Biostatistics, Clinical, Genetics) and refined with feedback from the Executive Committee. The following four studies are proposed for the first two years of CTNA funding: 1) Dana Small, Ph.D. will lead the first human functional neuroimaging (fMRI) study to describe the neural circuitry underlying alcohol-related habit formation. 2) Philip Corlett, Ph.D. will initially conduct a behavior/electrophysiology study and then, building on this, conduct an fMRI study to explore neural mechanisms related to the impact of alcohol-related learning upon attention. 3) Anissa Abi-Dargham, M.D. will conduct the first evaluation of alterations in cortical dopamine release associated with alcohol dependence, using the new radiotracer [11C]FLB457 and positron emission tomorgraphy (PET). We also briefly describe additional outstanding proposals under consideration for the outlying years (3-5) of CTNA.

DESCRIPTION (provided by applicant): The purpose of this conference is to convene the next NIAAA Center Directors meeting to be held at Yale University. This conference is designed to allow Center Directors and NIAAA to review critical aspects of Center operation, logistics and outline plans for the future. To this end, the conference will feature a half-day series of busines meetings to facilitate interaction between the NIAAA and the Center Directors and invited designees. In addition to the logisitical aspect of the conference, the purpose of the Directors Meeting is to facilitate scientific exchange and interaction centered on key problems and state-of-the-art developments in the field of alcohol research. In the past, the Directors Meeting conferences provided a common theme with broad appeal to facilitate presentation of multi-disciplinary research across national Centers. The proposed theme for the conference will center around the construct of vulnerability. Specifically, the focus will be placed on the followig integrative topics related to vulnerability across levels of inquiry: 1) Vulnerability due to Alterations in Learning Mechanisms; 2) Role of Stress and Cognitive Control in Vulnerability; 3) Vulnerability Alterations due to Altered Alcohol Response Patterns; 4) Social and Community Vulnerability Factors, Prevention and Treatment; We are confident the proposed program will provide a fertile platform for discussions and exchange with the aim of advancing knowledge about this disorder and its underlying neurobiology. The progam will generally parallel prior iterations of the NIAAA Directors Meeting. The audience is expected to include ~100 researchers from NIAAA Centers, invited designees as well as local Yale researchers. The proposed meeting dates are April 29-30th, 2013.

DESCRIPTION (provided by applicant): Background: Cognitive impairments, for which there are no effective treatments, contribute significantly to functional disability in schizophrenia. Th goal of this application is to use a translational neuroscience approach to develop a treatment for the cognitive impairments associated with schizophrenia (CIAS). Deficits in NMDA receptor (NMDAR) function contribute to the CIAS and therefore, facilitation of NMDA-R function is one potential treatment approach for CIAS. Glycine transporter inhibitors (GlyT1Is) can enhance NMDAR related plasticity by raising synaptic glycine levels and stimulating the GlycineB co-agonist site of NMDARs. Preclinical data support the potential of GlyT1Is as treatments for the CIAS. PF-03463275 is a Glyt1I inhibitor that has not been tested for treatment of the CIAS. Higher doses of Glyt1Is including PF-03463275 may have a plateauing and/or worsening of effects suggestive of an inverted 'U' dose response. Therefore, it is critical for the optimal therapeutic dose range of GlyT1Is. UH2: The goal of the UH2 is to determine the best dose of PF-03463275. We will use positron emission tomography (PET) imaging to determine the dose-related occupancy of F-03463275 in order to determine whether it reaches its intended target and produces sufficient occupancy to be effective. In parallel, we will use fMRI as an assay of the dose-related GlyT1I facilitation of NMDAR function; we will determine whether PF-03463275 produces dose-related attenuation of the ketamine-induced disruption in prefrontal cortical BOLD activation related to working memory. UH2 Approach: 24 healthy subjects will receive placebo or two active doses of PF-03463275 BID for one week each during each of which, they will undergo a PET scan, long-term potentiation (LTP) session and a Ketamine-fMRI challenge study. UH3: In this phase (UH3), we will test the efficacy of PF-03463275 for CIAS in a novel proof of concept, double-blind, placebo-controlled, between-group study. Pharmacological enhancement of plasticity may not be sufficient to remediate long-standing cognitive dysfunction in the presence of the typical impoverished cognitive environment that patients live in. Therefore, just as physical exercise might optimize the effects of anabolic steroids, this trial wil combine cognitive remediation with PF-03463275 treatment. UH3 Approach: Schizophrenia subjects (n=76) taking risperidone or aripiprazole will be randomized to receive either placebo or active PF-03463275 BID in addition to cognitive remediation. Change in CAIS will be assessed using the Matrics Consensus Cognitive Battery composite score. We will also use visual Long Term Potentiation (LTP), an in vivo measure of NMDA-R-dependent synaptic plasticity, as a novel biomarker of the mechanism of action of PF-03463275. Using this approach, we propose to identify PF-03463275 effects on plasticity as indexed by LTP and to evaluate the capacity of PF- 03463275 to restore this form of neuroplasticity in schizophrenia patients, in whom it is deficient.

? DESCRIPTION (provided by applicant): The gap between basic research advances and new clinical insights and treatments remains a critical obstacle to progress in the field of alcoholism research. This translational neuroscience mission is the enduring focus of the Center for the Translational Neuroscience of Alcoholism (CTNA). CTNA conducts groundbreaking molecular neuroscience, molecular genetics, functional and chemical neuroimaging, and psychopharmacology studies in the service of providing new insights to bridge the gap between basic and clinical research. This renewal application will study mechanisms through which disturbances in glutamate and dopamine neurotransmission within cortico-limbic circuitry promote the development of pathological drinking. Building on this perspective and its prior achievements, CTNA will conduct the first translational neuroscience initiative in alcoholism research focusing on a signaling mechanism linking dopamine and glutamate neurotransmission, and test its implications for the treatment of alcoholism. It will facilitate transdisciplinary research within projects and across projects. It will also continue its highly productive Pilot Projects Core that provides an open competitive mechanism to enable the Center to rapidly encompass innovative new research and to engage outstanding investigators new to alcoholism research. CTNA will continue to expand its educational mission, building on the success of the NIAAA Research Fellowship and the International Conference on the Applications of Neuroimaging to Alcoholism.

Pilot Project Core John Krystal, M.D. Abstract The Pilot Projects Core provides a mechanism to provide a limited amount of funding to investigators to collect pilot data for innovative research projects. These projects serve the CTNA by 1) testing hypotheses or addressing methodologic issues central to the CTNA, 2) bringing new investigators into the CTNA and the field of alcoholism research, 3) generating new alcoholism R01's, 4) enabling CTNA to rapidly adapt to advances in the field, and 5) guiding the next iteration of the CTNA. Pilot Project Proposals are solicited through an open and public solicitation process. Proposal are developed in collaboration with the CTNA Cores (Data Management and Biostatistics, Clinical, Genetics) and refined with feedback from the Executive Committee. The following four studies are proposed for the first two years of CTNA funding: 1) Anissa Abi-Dargham, M.D. will conduct the first test of whether dopamine D2/D3 receptor regulation (PET-[11C]PHNO) is linked to NMDA glutamate receptor regulation and functions of the striatal direct and indirect pathway in humans, 2) Godfrey Pearlson, M.D. will test the capacity of an mGluR5 NAM to normalize cortico-striatal reward circuit function in healthy people with alcoholism family histories, 3) Suchitra Krishnan-Sarin, Ph.D. will test whether this mGluR5 NAM will reduce alcohol consumption in heavy drinkers, and 4) Kelly Cosgrove, Ph.D. will conduct the first evaluation of mGluR5 density alterations in alcohol dependence and recovery in humans using PET and [18F]FPEB. We also briefly describe additional outstanding proposals under consideration for the outlying years (3-5) of CTNA.

Project Summary/Abstract The Yale School of Medicine has a long tradition and record of accomplishments in the training of medical students for careers in academic medicine and research. This application is a resubmission requesting NIAAA support for medical students (NIAAA Short-Term Training: Students in Health Professional Schools) to carry out research primarily with NIAAA funded investigators. The purpose of the grant application is to provide intensive short-term training in research for selected pre-doctoral medical students in the most outstanding laboratories and training sites in the Yale School of Medicine. The specific research experiences will include social, behavioral, biological, and mathematical sciences as related to alcohol abuse and alcoholism. The initial application received an impact score of 41. The program is designed to attract the most highly qualified Yale medical students into careers as physician-scientists in the biomedical sciences. An extensive follow-up documents a high level of subsequent research training, research productivity, and faculty appointments (40.2%) among previously supported students. Trainees will be chosen upon application of pre-doctoral medical students who have completed in good standing one year of the curriculum of the Yale School of Medicine. Eight (8) students per year will be selected competitively for this short-term training support on the basis of the quality of a formal written proposal of the planned research and the quality of the mentor and the training environment. The participating departments and sections will include: psychiatry, cell biology, cellular and molecular physiology, genetics, molecular biophysics and biochemistry, pharmacology and related interdisciplinary centers.

Working memory has traditionally been characterized as providing temporary memory storage and guidance of ongoing behavior and depending on recurrent excitation of prefrontal neurons. It is hypothesized that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists interfere with working memory. The NMDAR antagonist, ketamine, can produce in healthy humans temporary deficits in working memory performance and accompanying prefrontal activation. Theories and preclinical research link these phenomena to cortical disinhibition. However, these theories have not been tested in humans because no imaging modality could appropriately quantify both the deficits in working memory related activation and performance and putative changes in baseline cortical metabolism. Recently, a technique called calibrated functional magnetic resonance imaging has become available for use in humans. We propose to use this technique in healthy persons to measure baseline cortical oxidative metabolism. This method will be combined with conventional functional magnetic resonance imaging and a spatial working memory paradigm to measure working memory deficits during infusion with the NMDAR antagonist ketamine. We will test three key hypotheses: 1) that the NMDAR antagonist ketamine increases prefrontal cortical oxidative metabolism as measured with calibrated fMRI; 2) that increases in prefrontal cortical oxidative metabolism are related to decreases in working- memory related activation measured with conventional functional magnetic resonance imaging; and 3) that increases in prefrontal cortical oxidative metabolism are related to reductions in working memory accuracy. The results of this study would increase understanding of working memory deficits and could be helpful in developing and testing novel therapeutics for working memory dysfunction. They may be particularly important in schizophrenia because there is strong evidence of glutamatergic dysfunction in the disorder and working memory function predicts functional recovery.

SUMMARY We propose holding the fourth iteration of the International Conference on Applications of Neuroimaging to Alcoholism (ICANA-4). Each of the prior three ICANA Conferences, held in New Haven, CT in 2004, 2008, and 2013, drew over 100 leading investigators from around the globe to focus on techniques, conceptual issues, and findings related to application of a dynamically evolving set of neuroimaging tools and approaches to the study of alcohol use and alcohol dependence. Our ICANA conferences have drawn broad attention, including publications in the Journal of the American Medical Association (JAMA) and Alcoholism: Clinical and Experimental Research. The proposed conference would be another seminal event that would draw leading imaging experts together to advance our knowledge about the neurological effects, development, and treatment of alcoholism and alcohol use. Established investigators who work in other areas of brain imaging, as well as those already working in alcoholism-related areas, will be convened to share methodological applications to alcoholism and foster collaboration across modalities. Special efforts will be made to support the attendance and participation of research trainees, fellows, and new investigators. The proposed program would utilize the format of the earlier conferences and include an international roster of speakers in a two-and-one-half day conference. The audience is expected to include 100-150 researchers from around the world. The interest level in this fourth meeting is already quite high, as indicated by our speaker commitments and by the agreement of Dr. George Koob, Director of NIAAA, to give the opening plenary presentation of the conference. The proposed meetings dates are July 19-21, 2019. The proposed agenda includes 5 main topics. Each topic will include discussion of the diversity of imaging techniques used to study the specific topical area: (1) Reward Learning and Habit; (2) Stress and Craving of Alcoholism; (3) Inflammation and Alcohol; (4) Structural and Functional Connectivity in Alcohol Use Disorder; and (5) Pharmacoimaging. The conference will include plenary presentations, sessions discussing the variety of imaging techniques (fMRI, MRS, PET/SPECT) used to study alcohol use, neuroimaging in preclinical and clinical studies, and the applications of neuroimaging to the development of treatments for alcohol dependence.

Contact PD/PI: Sherwin, Robert S. 1. Overall Project Summary- The Yale Center for Clinical Investigation (YCCI) was created in 2005 to strengthen Yale's infrastructure for clinical and translational research, based on the recommendation of a Medical School strategic planning committee. Soon afterwards, when NIH launched its new program of Clinical & Translational Science Awards, YCCI applied and became the home of the Yale CTSA. Since then, one of its major priorities has been to support the education and career development of the next generation of clinical and translational investigators. As described in the present application, this initiative has met with great success, underscored by the fact that graduates of YCCI's K-Scholar program have received 47 individual NIH K Awards, 43 NIH RO1 awards, and 65 Foundation grants, published >1,800 papers, and obtained >$240 million in independent research funding. Remarkably, 98% of the program's graduates have stayed in academic medicine or pursued research careers in the biotech or pharmaceutical industries. YCCI has also made substantial progress in its push to accelerate the translation of disease-related discoveries into the clinic. As will be described, it provides Yale investigators with key assistance in areas including biostatistics and bioinformatics, study design, protocol development, regulatory approval, patient recruitment, access to inpatient and outpatient research facilities, and budgeting support, and gives them ready access to pilot grants and state-of-the-art research cores. The result has been a significant upsurge in the number and scope of clinical research projects throughout the Medical Center. In the next grant cycle, YCCI will build upon these achievements with an emphasis on team-based T1 to T4 research, including studies across the lifespan. YCCI will also pursue new partnerships with the Yale School of Engineering & Applied Science to develop an innovative technology transfer program called the Center for Biological and Innovative Technology (CBIT) and with the School of Organization & Management to offer a novel program of leadership training for clinicians and physician-scientists. In addition, YCCI will take active advantage of the recent expansion of clinical services by Yale-New Haven Hospital (YNHH), which now has 1,540 beds and more than 1 million outpatients visits per year, and the growth of the Yale Medical Group (YMG), which has a network of >1,200 practicing physicians in >100 clinical specialties. The resulting clinical volume (~4 million patient records) gives Yale researchers access to a large, diverse patient base for outcomes studies and clinical trials. Overall, YCCI will leverage Yale's outstanding scientific and clinical environment and work with other CTSA hubs to foster the growth of multidisciplinary team science, to develop innovative strategies for disease prevention, diagnostics, and therapeutics, and to implement results for the benefit of the health care system and the population as a whole. Project Summary/Abstract Page 220 Contact PD/PI: Sherwin, Robert S. Program Narrative Yale Center for Clinical Investigation (YCCI) is a leader in team-based T1 to T4 research, including studies across the lifespan. YCCI will leverage Yale University's outstanding scientific and clinical environment and work with other CTSA hubs to foster the growth of multidisciplinary team science, to develop innovative strategies for disease prevention, diagnostics, and therapeutics, and to implement results for the benefit of the health care system and the population as a whole.

PROJECT SUMMARY This UO1 application is a response to the NIMH Program Announcement intended to accelerate the development of a high priority therapeutic agent by establishing its dose-related pharmacodynamic effects on biomarkers designed to inform subse- quent clinical development. Dopamine D1 receptor (D1R) agonism is among the most highly prioritized adjunctive treatment mechanisms for schizophrenia. Currently, all D1R agonists are also D5R agonists. D1R/D5R agonists have pro-cognitive and antipsychotic-like effects in preclinical studies, reflecting their ability to stabilize prefrontal cortical network activity in the face of distractors, and to enhance the precision of spatial working memory (sWM) by enhancing inhibitory tuning of prefrontal cortical (PFC) functional connectivity (FC). Yet, dose-related benefits of D1R/D5R agonism in patients could not be demonstrated in prior pilot studies. This application proposes that the testing of D1R/D5R agonists requires both a more direct translational/computational neuroscience framework (i.e., the most appropriate biomarkers) and a precision medicine strategy (i.e., the appropriate subpopulation of patients). To accelerate the selection of an optimal dose, we propose a multi- center study that densely maps the dose-related effects of the D1R/D5R partial agonist, PF-06412562 immediate release (IR), on three informative translational functional neuroimaging (fMRI) biomarkers as primary outcome measures: i) sWM-related activation; ii) task-based FC; and iii) resting-state FC in early course schizophrenia patients. Primary Aim 1 will apply a mul- tivariate analytic strategy to these three outcome measures (sWM-related activation, task-based FC and resting-state FC) to test if PF-06412562 produces a dose-related effect. This multivariate translational neural marker is designed and powered to inform a clear Go/No-Go decision with regards to proceeding to a full-scale clinical trial. A Go decision will be indicated if there is a significant dose-related drug effect on the neural signal measured via the multivariate combination of task-evoked activation and FC during the sWM task and FC during rest. Conversely, a No-Go decision will be reached if there is an absence of a dose-related effect on the multivariate index. Secondary Aim 2 will quantify dose-related drug effects on sWM precision based on behavioral data collected during fMRI. Exploratory Aim 3 will model the biophysical properties of PF- 06412562 in a cortical circuit model capable of sWM simulations, which will simulate hypothesized molecular mechanisms governing pro-cognitive PF-06412562 effects on sWM. In turn, we will will test if the dose-related pattern of PF-06412562 effects on resting FC in patients maps onto D1R and D5R receptor transcriptomic profiles in humans derived from from Allen Human Brain Atlas. Finally, Exploratory Aim 4 will study potential clinical predictors and moderators of PF-06412562 ef- fects on neuroimaging biomarkers. Collectively, this translational biomarker study informs the highest priority experimental treatment mechanism identified by the NIMH MATRICS Initiative using a precision medicine strategy that targets a specific subpopulation of early course schizophrenia patients who may pro-cognitively respond to D1R/D5R agonism.