Godfrey Pearlson - US grants

DESCRIPTION (provided by applicant): Driving while intoxicated (DWI) with alcohol is a major public health problem. Despite this, there is relatively little documentation of the inter-relationship of alcohol's effects on a). brain function, b). driving behavior c). the hierarchy of cognitive operations mediating driving performance and d. the dose-relatedness of these effects. Driving is a complex 'whole' behavior that is best studied both directly, in a "top-down" fashion and "bottom up" by examining simpler, cognitive component tasks. Simulated driving offers a direct, reproducible, quantitative in-lab means to assess normal and impaired driving, that can be used with functional magnetic resonance imaging (fMRI) to quantify associated brain changes. The proposed research will address all these aspects in a multidisciplinary project based on Groeger's (2000) cognitive model of driving. We have collected a significant amount of relevant pilot data. We will focus on characterizing alcohol's acute effects on behavior and brain function in a series of controlled, within-subject, human studies of persons admitted to an inpatient CRC for 5 days. We will evaluate double-blind dose-responses of several alcohol doses vs placebo on: 1) behavioral performance during tasks of visual working memory, divided visual attention and simulated driving, 2) profiles of subjective intoxication and impairment and (3) task-related fMRI brain patterns. To examine their interrelationships, the different outcome measures will be assessed in close temporal proximity. Different experiments will examine 1) dose-response effects of alcohol and 2) their effects in the presence vs absence of alcohol tolerance. These studies will provide valuable information about 1) cerebral activation patterns and mechanisms of neurocognitive performance on driving and related tasks, 2) effects of alcohol on this cerebral activation, 3) the effects of alcohol on behavior observed during several neurocognitive tasks, including simulated driving, and 4) inter-relationships among localized brain function, neurocognitive task demands, and pharmacology as determinants of alcohol -produced driving impairments. To conduct this research, we have assembled a unique team with expertise in experimental drug abuse paradigms, cognitive neuroscience, quantitative fMRI and behavior assessment. The PI's laboratory has developed novel fMRI analysis paradigms and driving simulation software. Together, these allow dissection of alcohol's effects on the multiple overlapping neural circuits associated with performance of complex, driving-related cognitive tasks.

[unreadable] DESCRIPTION (provided by applicant): Evidence suggests that two major factors predisposing individuals to initiate and maintain substance abuse are abnormal responses to rewards and punishments and impaired ability to inhibit prepotent responses. These factors may act, in part, through synaptic pathology in the ventral striatum, amygdala, frontal cortex and related "motivation" circuitry to predispose vulnerable individuals to persistent substance abuse. From a cognitive/behavioral neuroscience perspective, evidence supports the first part of this vulnerability as being expressed, in part, as general impairments in the normal ability to engage motivational circuitry by delayed rewards and punishments, biasing individuals toward immediate rewards (exemplified by cocaine), and impulsive behaviors. A specific part of this vulnerability is hypothesized to involve problems in the brain circuitry for reward and punishment expectation - a "Reward Deficit Hypothesis." The second aspect of vulnerability is hypothesized to involve a diminished ability to inhibit prepotent responses and thus act impulsively. Little prior research has examined the relationship between these two factors at a behavioral or brain level in healthy controls or substance abusers. We will study 80 per group of adult subjects (50% male) who either are currently cocaine dependent, formerly cocaine dependent but currently abstinent or matched controls. The 240 subjects will be characterized on scales and interviews assessing aspects of impulsivity and several computer tasks measuring behavioral impulsivity: (delay discounting, risk/reward decision-making, inhibition of prepotent response), and also assessed on potential covariates including psychopathy/antisocial personality, ADHD and lifetime substance use. With functional MRI we will use two distinct but complementary behavioral tasks to examine reward deficit and a third to examine response inhibition, to dissect the underlying functional anatomy of the relevant circuits. The first two tasks quantify responses in motivational circuitry to situations involving both expectation of and receipt of rewards and punishments and the propensity to take risks on one of the tasks, The paradigms are a Monetary Incentive Delay Task that assesses anticipation of reward and punishment, separating anticipatory (motivational) from outcome (consummatory) components of reward processing. The other, the Domino Task involves decision making under conditions of uncertainty, anticipation to outcome, response to outcome, risk taking behavior, and a social interaction context. The response inhibition task is a Go/No Go paradigm. Subjective responses evinced during task performance will be quantified as important dependent measures. We will separate out effects of recent versus past chronic cocaine use on task-related brain activation patterns. Overall, we thus plan to elucidate the inter-relationship between two important substance abuse-related factors at both a behavioral and a neural circuit level. [unreadable] [unreadable] [unreadable]

21+ years old; 3,4-Dihydroxyphenethylamine; 4-(2-Aminoethyl)-1,2-benzenediol; Adult; Affect; Alcohol Drinking; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholic; Alcoholism; Alcohols; Attitude; Behavior; Behavioral; Boozer; Brain; Brain region; Characteristics; Chemical Class, Alcohol; Cognitive; Complement; Complement Proteins; Corpus Striatum; Corpus striatum structure; Data; Dependent drinker; Dopamine; Encephalon; Encephalons; Epidemiology, Family Medical History; EtOH drinking; Ethanol dependence; Event; FLR; Failure (biologic function); Family; Family Medical History; Family history of; Female; Functional Magnetic Resonance Imaging; Genes; Genetic; Glutamates; Hereditary; Human, Adult; Hydroxytyramine; Impairment; Impulsive Behavior; Impulsivity; Incentives; Individual; Inherited; Interview; L-Glutamate; Link; MRI, Functional; Magnetic Resonance Imaging, Functional; Measures; Methods; Motivation; N-Methyl-D-Aspartate Receptors; NMDA Receptor-Ionophore Complex; NMDA Receptors; Nervous System, Brain; Neurobiology; Neurosciences; Numbers; Outcome; Parents; Pathology; Pattern; Personality; Phase; Phosphonofluoridic acid, methyl-, 1-methylethyl ester; Punishment; Questionnaires; Receptors, N-Methylaspartate; Recruitment Activity; Rewards; Risk; Risk Factors; Risk-Taking; Running; Sampling; Sarin; Scanning; Social Interaction; Specificity; Striate Body; Striatum; Striatum, Ventral; Synapses; Synaptic; System; System, LOINC Axis 4; Task Performances; Testing; Uncertainty; Variant; Variation; Ventral Striatum; addiction; adult human (21+); alcohol addiction; alcohol dependency; alcohol effect; alcohol ingestion; alcohol intake; alcohol problem; alcohol product use; alcohol use; alcohol-dependent; alcoholic beverage consumption; alcoholic drink intake; anti social; antisocial; base; clinical relevance; clinically relevant; design; designing; doubt; ethanol abuse; ethanol addiction; ethanol consumption; ethanol dependency; ethanol drinking; ethanol effect; ethanol ingestion; ethanol intake; ethanol product use; ethanol use; ethanol-dependent; etoh use; expectation; fMRI; failure; hazardous alcohol use; hemodynamics; incentive; independent component analysis; inducement; insight; male; neurobiological; o-Isopropylmethyl Phosphonofluoridate; ortho-Isopropylmethyl Phosphonofluoridate; problem drinker; problem drinking; psychopharmacologic; psychopharmacological; receptor function; recruit; response; reward circuitry; reward processing; striatal; trait

DESCRIPTION (provided by applicant): Recent studies provide considerable evidence that schizophrenia (SZ) and psychotic bipolar disorder (BP) may share overlapping etiologic determinants. Identifying disease-related genetic effects is a major focus in SZ and BP research, with enormous implications for diagnosis and treatment for these two disorders. Efforts have been multifaceted, with the ultimate goal of describing causal paths from specific genetic variants, to changes in neuronal functioning, to altered brain anatomy, to behavioral and functional impairments. Parallel efforts have identified and refined several alternative endophenotypes that are stable, heritable, have (partly) known biological substrates, and are associated with psychosis liability. Although many such endophenotypes have been individually studied in SZ, and to a lesser extent in BP, no study has comprehensively assessed a broad panel of these markers in the two disorders with parallel recruitment, and the extent to which they mark independent aspects of psychosis risk, or their overlap in the two disorders. This line of investigation will potentially impact our conceptualization of psychotic disorders, help us make critical strides to identify the pathophysiology of psychosis, and guide development of new specific treatments targeting particular deficits. The overall goal of the proposed research is to examine a broad panel of putative endophenotypes in affected individuals with schizophrenia and bipolar and their unaffected relatives in order to: 1) characterize the degree of familial phenotypic overlap between SZ and psychotic BP;2) identify patterns of endophenotypes unique to the two disorders, and 3) contrast the heritability of endophenotypes across the disorders. To achieve these goals, we will recruit 500 SZ and 500 BP I (with psychosis) probands, ~1700-2000 1st degree relatives of these probands, and 500 unrelated non-psychiatric controls from five centers. We will obtain measures of neurophysiology (e.g., eye tracking, P50 gating, PPI, and P300), neurocognition (e.g., attention/vigilance, episodic and working memory), and brain structure (e.g., volumes of gray and white matter in specified brain regions). We will collect blood for future genetic studies. We will assess the degree of familial aggregation of endophenotypes in SZ and BP relatives. Establishing similarities and differences in the endophenotypic signatures within SZ and BP families will provide important insights for future genetic studies, and clarify concepts about common and distinct aspects of pathophysiology, potentially meaningful heterogeneity within disorders, and the clinical boundaries of the two commonest psychotic disorders in adult psychiatry. This research will be conducted by 5 experienced research groups, with a long history of close and productive collaboration. Public Health Relevance: This multisite project will identify endophenotypes (or liability markers) that are shared and different in schizophrenia and bipolar disorder. Findings from these studies will provide important insights for future genetic studies, and clarify concepts about common and distinct aspects of pathophysiology, potentially meaningful heterogeneity within disorders, and the clinical boundaries of the two commonest psychotic disorders in adult psychiatry.

DESCRIPTION (provided by applicant): Adolescents, especially college students, are at high risk for problem drinking, but the resulting long term consequences on brain development and function are not well studied. In this 5-year proposal, the investigators will recruit a total of 2000 18-21 year old first-year students (50% male) from 2 demographically distinct local colleges in CT; Central Connecticut State University and Trinity College. All students will be characterized at baseline at their respective campuses on a comprehensive battery of cognitive tasks, some assessing risk for problem drinking in the context of an integrative risk model and others previously identified as being sensitive to effects of alcohol abuse in adolescents. All participants will also be assessed on instruments measuring amount and patterns of current and past alcohol and drug use, consequences of use (eg mood alteration, DWI), and family history of substance use. Academic grades and SAT/ACT scores will be recorded. The sample will be stratified by alcohol use patterns and a total of 300 representative members derived from use quartiles (over-represented from the heaviest quartile, especially binge-pattern users) will undergo additional detailed assessment at the Olin Neuropsychiatry Research Center on 4 functional MRI (fMRI) paradigms assessing a. hippocampal integrity (a virtual maze spatial memory task), b. working memory circuitry (a modified Sternberg paradigm), c. reward anticipation (a monetary incentive delay task) and d. ability to inhibit a pre-potent stimulus (a Go/No-Go task), plus structural MRI and urine toxicology testing. Monthly, all participants will complete web-based ratings of alcohol and drug use amounts and patterns, mood, life events, stress and adverse consequences of use. Two years post initial testing, all available participants (~90%) will repeat the initial cognitive test battery (using alternate test forms) and detailed substance use measures. Of the 300 initial fMRI participants, the ~85% available and willing will repeat the imaging paradigms. The 3 overarching aims are to identify initial predictors of persisting alcohol and drug abuse, to detect early evidence of alcohol and drug-related impairment of brain function & cognitive problems and to determine whether particular patterns of drinking, especially binging, are most associated with cognitive decline over the 2 yrs of assessment. As part of the project we will test a theoretical model of how brain structure and function explain key relationships between risk and alcohol/substance use outcome, incorporating highly novel measures using data fusion, in order to better accomplish the overall goals. The PI and his collaborators have extensive experience with the tasks and procedures used in this Project, including web-based tracking of alcohol use. PUBLIC HEALTH RELEVANCE: US college students are at high risk for problem drinking. This project will recruit and test cognitively 2000 first-year students from local colleges in Connecticut, fMRI scan a representative sub-sample and assess alcohol and drug use by web-based reporting over 2 years, when all students will be retested/rescanned. Findings from this study will provide important insights on risk factors for problem drinking and how alcohol use impacts the developing adolescent brain.

DESCRIPTION (provided by applicant): "Genetic architecture of alcohol misuse candidate endophenotypes" Research Area This application addresses broad Challenge Area 03) Biomarker Discovery and Validation;specific Challenge Topic 03-AA-101,Identification of Intermediate Phenotypic Markers of Alcohol Use Disorders. The strategy of this study to explore the genetic underpinnings of a novel fMRI-based putative endophenotype for high-risk drinking in college students, by expanding the type and amount of data being collected in two existing, funded NIAAA grants, to yield a sample of 450 individuals, sufficiently powered to perform a genome-wide association study (GWAS). Dysfunctional drinking in college students significantly raises the odds for their experiencing not only alcohol-related problems in college but is also a significant risk factor for alcohol abuse and dependence a decade later. Risk markers for individuals rather than populations are lacking however. In one of the current proposals, 130 of 750 total college students assessed per year undergo structural and fMRI imaging. The current proposal has an additional 140 students per year for two years, complete an abbreviated imaging protocol, consisting of a structural sequence and fMRI during a Monetary Incentive Delay Task (MIDT) that measures the brain's response to reward and whose activation patterns we have shown are associated with alcoholism risk. We will also obtain an auditory oddball P300 event related potential assessment in all subjects undergoing imaging and derive event-related oscillation (ERO) measures from this to examine a recently published second alcohol endophenotype. Both questionnaire- and laboratory-based impulsivity measures are currently collected on all subjects;we have determined that these fall into 5 factor domains, two of which are significantly correlated with the MIDT fMRI activation patterns. Finally, DNA collection and genotyping for GWAS will be added for all study subjects. We will enrich the sample for individuals at higher risk for alcohol use disorders by choosing 30% of our subjects with a positive family history of alcohol abuse in father and at least 1 other close relative. High-risk drinking patterns, previously shown to predict later- life harmful drinking will be quantified based on several elements, derived from 6-month data on subjects'existing monthly self-reports of drinking behavior on a secure website. These include currently collected measures of quantity and frequency of drinking, plus self- reports of response to alcohol, adverse alcohol-related consequences and objective measures of college grades. Endophenotypes will be derived from the best combination of BOLD activation during the MIDT and ERO measures. Parallel independent component analysis of the fMRI and SNP data will be used to extract relations between patterns of fMRI components and SNP associations purely based on an analysis incorporating higher order statistics. The method allows for broader associations of genotypes with phenotypes than traditional hypothesis-driven univariate correlational analyses. Traditional methods requiring greater subject numbers will be used in addition. Thus, the major goal of the proposed research is to characterize the genetic architecture of two alcohol use disorder candidate endophenotypes, one novel based on abnormal responses on an fMRI monetary incentive delay task, one known and based on ERO measures, to compare these two measures to each other and to validate them against ongoing longitudinal measures the dysfunctional alcohol use. Why is a Challenge grant mechanism ideal for the proposed research? 1. Our goal of using innovative approaches to identify candidate intermediate phenotypic markers (endophenotypes) for alcoholism that are suitable for subsequent validation efforts matches the goals of this RFA and represents a new direction in the field. There are currently no reliable biomarkers for alcoholism so that the proposed search for such intermediate phenotypes that can predict disease risk is of high impact. 2. A two-year grant award is ideal for the proposed work. We can base subject recruitment for the proposed study on an ongoing large-scale NIAAA-funded research project that is already identifying subjects and characterizing them in detail for another purpose, in a manner that allows us to identify suitable individuals and obtain relevant longitudinal information, without having to build a new infrastructure to do so. We have assembled a team of investigators with unique expertise and an excellent record of effective past collaborations to pursue these studies. 3. We plan to hire and train new personnel including postdoctoral students and to employ unique genome- wide technology using US-based companies such as Illumina Inc. that will have the added benefit of stimulating the economy. The goal of this Challenge grant application is to identify a novel functional MRI-based endophenotype of alcohol misuse in subjects who are chosen from a large ongoing study of drinking in college students, to compare it with an existing electrophysiologically-based endophenotype and to determine the genetic underpinnings of these endophenotypes using a genome wide association study design. The identification of such biological markers will not only increase our knowledge of the pathophysiology of alcohol misuse, but more importantly identify individuals at high risk for the disorder.

In CTNA-2, we showed that in a Monetary Incentive Delay (MID) task, FH+ subjects, relative to FH-individuals, had increased engagement of cortico striatal networks when the opportunity for reward presented itself (reward prospect), but reduced activation of this same network when rewards/punishments were delayed (reward anticipation) or when the reward was presented (consummatory reward phase) (see P3). Striatal abnormalities were also seen in FH+ during a Go/No-Go (GNG) task. In CTNA-3, we face the challenge of directly linking the altered cortical-striatal function in FH+ to its underlying neurobiology. Aim #1: The first aim of this project is to determine whether increased NMDA-R function contributes to alterations in cortico-striatal activity associated with FH+ status. Preliminary data (see full project) support the Aim #1's hypothesis by suggesting that memantine 40 mg. p.o. normalizes the deficits in ventral striatal (VS) activation associated with reward anticipation in FH+ individuals but has only modest effects on VS activation in FHN. Aim#2: This aim explores memantine effects on activation of VS and anterior cingulate during GNG. Aim #3: The third project aim is critical to linking the pattern of cortico-striatal functional alterations associated with FH+ to the initial step in the addiction process, Pavlovian Conditioning. To that end, FH+ individuals who complete Aim #1 also will complete alcohol cue reactivity testing during fMRI imaging. Aim #4: This exploratory aim examines a modification of the MID by inclusion of PIT-related stimuli in FH+ compared to FH- subjects. Lastly, these subjects will be college students who will enter a prospective 2-year follow-up supported by a separate NIAAA grant (the "BARCS" study). This follow-up period will enable CTNA to explore the possibility that reward-related activation (MIDT), alcohol Pavlovian conditioning (cue reactivity), and alcohol PIT (assessed via the Core Battery) predict the intensity of drinking over time. DNA will be collected on all study subjects and the impact of polymorphisms in the genes coding for the proteins in figure 6 will be explored via the Genetics Core.

DESCRIPTION (provided by applicant): Recent studies provide considerable evidence that schizophrenia (SZ) and psychotic bipolar disorder (BP) may share overlapping etiologic determinants. Identifying disease-related genetic effects is a major focus in SZ and BP research, with enormous implications for diagnosis and treatment for these two disorders. Efforts have been multifaceted, with the ultimate goal of describing causal paths from specific genetic variants, to changes in neuronal functioning, to altered brain anatomy, to behavioral and functional impairments. Parallel efforts have identified and refined several alternative endophenotypes that are stable, heritable, have (partly) known biological substrates, and are associated with psychosis liability. Although many such endophenotypes have been individually studied in SZ, and to a lesser extent in BP, no study has comprehensively assessed a broad panel of these markers in the two disorders with parallel recruitment, and the extent to which they mark independent aspects of psychosis risk, or their overlap in the two disorders. This line of investigation will potentially impact our conceptualization of psychotic disorders, help us make critical strides to identify the pathophysiology of psychosis, and guide development of new specific treatments targeting particular deficits. The overall goal of the proposed research is to examine a broad panel of putative endophenotypes in affected individuals with schizophrenia and bipolar and their unaffected relatives in order to: 1) characterize the degree of familial phenotypic overlap between SZ and psychotic BP; 2) identify patterns of endophenotypes unique to the two disorders, and 3) contrast the heritability of endophenotypes across the disorders. To achieve these goals, we will recruit 500 SZ and 500 BP I (with psychosis) probands, ~1700-2000 1st degree relatives of these probands, and 500 unrelated non-psychiatric controls from five centers. We will obtain measures of neurophysiology (e.g., eye tracking, P50 gating, PPI, and P300), neurocognition (e.g., attention/vigilance, episodic and working memory), and brain structure (e.g., volumes of gray and white matter in specified brain regions). We will collect blood for future genetic studies. We will assess the degree of familial aggregation of endophenotypes in SZ and BP relatives. Establishing similarities and differences in the endophenotypic signatures within SZ and BP families will provide important insights for future genetic studies, and clarify concepts about common and distinct aspects of pathophysiology, potentially meaningful heterogeneity within disorders, and the clinical boundaries of the two commonest psychotic disorders in adult psychiatry. This research will be conducted by 5 experienced research groups, with a long history of close and productive collaboration. Public Health Relevance: This multisite project will identify endophenotypes (or liability markers) that are shared and different in schizophrenia and bipolar disorder. Findings from these studies will provide important insights for future genetic studies, and clarify concepts about common and distinct aspects of pathophysiology, potentially meaningful heterogeneity within disorders, and the clinical boundaries of the two commonest psychotic disorders in adult psychiatry.

DESCRIPTION (provided by applicant): Psychotic symptoms are present in a significant subset of individuals with Bipolar Disorder (BD) and carry devastating personal and clinical implications. Most biomedical research on BD has ignored the variable presentation of psychosis possibly overlooking biologically significant heterogeneity in BD; such heterogeneity may cause inconsistencies in the literature by treating BD as a homogenous category 7,18. The expression of psychosis in some BD patients (BD-P) and absence in others (BD-NP) may indicate divergent disease processes of critical nosological and clinical relevance. PARDIP leverages a large sample of BD, a comprehensive battery, and sophisticated analytic tools to establish whether BD-P and BD-NP represent a difference in degree or a difference in kind. Long-term goals: This work will critically impact how BD is classified and studied, provide robust targets for effective future etiological studies, and clarify the utility of available biomarkers o major psychiatric disturbance. PARDIP represents a step toward mechanistically based classification of psychiatric disorders. Specific Aims: PARDIP will (i) identify the patterns of bo-cognitive disruptions which mark psychosis (BD-P`BD-NP) or mood instability in general (BD`healthy comparisons), (ii) explore how these biomarkers relate to one another and to other dimensions of psychopathology present in BD, and (iii) utilize latent class and cluster analyses of the multivariate dataset to verify taxonicity within BD with regard to psychosis and uncover latent psychiatric subgroups of interest for future genotyping and etiological research. Methods: The three-year PARDIP project will recruit 135 psychotic BD, 135 non-psychotic BD, and 135 psychiatrically healthy comparison subjects (all new recruits), administering a comprehensive battery focused on the psychosis and mania domains of psychopathology. We will obtain measures of neurophysiology, (smooth pursuit eye movements, antisaccades, auditory ERPs), cognition (cognitive battery, response inhibition, spatial working memory), neuroanatomy (structural magnetic resonance imaging [MRI]), emotional processing (ERPs to emotional pictures), intrinsic brain state (resting functional MRI connectivity), and circadian function (Actigraphy). We will compare biomarkers between BD-P, BD-NP, and H groups to determine which track with psychosis and which track with affective disturbance. We will identify common sources of variance among measures with joint-ICA and PCA approaches, and examine how biomarkers and biomarker composites relate to other aspects of clinical heterogeneity. Taxometric procedures (MAXCOV- HITMAX and its multivariate extension MAXEIG-HITMAX and k-means clustering) will be carried out with the multivariate dataset to empirically identify distinct subgroups of subjects. PARDIP will be conducted by 4 experienced research groups (across 3 collection sites) with a long history of close and productive collaboration.

? DESCRIPTION (provided by applicant): Driving while intoxicated on cannabis is a major and growing public health problem. Driving safety is an important issue in the United States as more than 3 million persons are reported injured and >40,000 die annually in motor vehicle crashes. Traffic accidents are the greatest single cause of death in 5-32 year-olds; many are due to intoxicated drivers. Cannabis (CNB) is a commonly abused drug whose use cuts across social class, is linked to cognitive impairment, is a major contributor to intoxication-related accidents either alone or with alcohol. However, CNB intoxication is little studied in relation to driving compared to alcohol. Not only does the current NHTSA Strategic Plan for Behavioral Research prioritize understanding how drugs other than alcohol contribute to traffic crashes, it has recentl become more pressing to understand the effects of CNB because of increasing rates of legalized medical and/or recreational use, that will likely result in more CNB intoxicated drivers. Social and legal policy will be unable to effectively address the many concerns about driving safety raised by more frequent and widespread use of CNB without new research to better determine the parameters within which CNB use does, or does not, increase automobile accident risk. Our purpose is to better describe specific, driving-related cognitive impairments caused by acute CNB intoxication, their persistence over time, underlying functional brain anatomy, and relationship to performance on a state-of the art validated simulated driving task in which we have prior experience. In a randomized, counterbalanced, double-blinded fashion, we will administer two CNB doses and placebo of smoked cannabis (paced inhalation using a vaporizer) to 48 regular and 48 occasional cannabis users on 3 separate occasions. Following CNB dosing we will assess cognitive and driving impairment longitudinally for several hours using a combination of fMRI and neuropsychological tests, to clarify relationships between subjective and objective measures of intoxication and of impairment, that include expert assessment of THC and its metabolite levels in blood and saliva.

DESCRIPTION (provided by applicant): The major psychoses (SZ, SAD, BDP), when defined by clinical phenomenology alone, overlap extensively on neurobiological, biomarker, co-morbid, symptomatic, and genetic characteristics. Our field may benefit from transformational re-conceptualizations of disease seen in other areas of medicine when biological variables are considered in disease definitions and identification. This approach in psychiatry will depend on: (i) use of well- defined disease domains, (ii) large samples that capture clinical heterogeneity and support statistical approaches, and (iii) ability to acquire quantifiable laboratory measures t inform re-conceptualization of disease characteristics. The 5-site B-SNIP focus is psychosis, an ideal clinical phenotype for this purpose. B- SNIP1 recruited over 2500 volunteers and performed dense phenotyping across multiple levels of analysis (cognitive, psychophysiological, brain imaging, social and clinical). The overall data described a continuum of phenotypic alterations across the DSM psychosis diagnoses (BDP, SAD, SZ) with little evidence of diagnostic specificity. In an attempt to use these dense phenotypic characteristics to define biologically based subgroups, we re-grouped probands using biomarkers and a multistage multivariate analysis procedure. We identified 3 psychosis Biotypes based on core phenotypic features. Biotypes showed unique differences across external validators that were not used in the initial construction of the categories. B-SNIP2 will replicate and extend B- SNIP1 using enhanced proband number, biomarker panel, and sophistication of multivariate statistical approaches. We will accomplish our goals within the context of two specific aims. SA(1) Construct a 'Psychosis Biomarker Database' (PBD): Recruit 3000 new psychosis probands and 600 healthy volunteers and collect data including clinical, psychosocial, electrophysiological, ocular motor, imaging and blood biomarkers. Core biomarkers (used for Biotype definition) and external validators (used for verifying neurobiological distinctiveness of Biotypes) will be collected as specified. Genetic characteristics of the participants will be obtained in collaboratin with the Broad Institute. SA(2) Contrast and test taxometric approaches to categorizing psychosis: Evaluate the ability of different taxonomic structures to define psychosis subgroups, based on data in the PBD: (i) DSM, (ii) B-SNIP2 biotypes based on clinical variables, (iii) B-SNIP1 Biotypes, (iv) B-SNIP2-generated biotypes based on biomarkers, and (v) B-SNIP2 biotypes based on both clinical variables and biomarkers. Beginning with traditional DSM diagnostic criteria as the taxonomy and testing (i)-(v) we will use linear, quadratic and nonparametric discriminant function analysis applied to external biomarker validators to examine the association between the traditional diagnostic system and the biologically- derived classification (imaging, psychosocial and genetic external validators). We will be able to determine the strongest taxonomic approach based on biological characteristics. We seek a rational classification of psychotic disorders that will be successful in identifying novel disease targets and treatments approaches.

Project 2: Functional Neuroimaging of Alcoholism Vulnerability: Probing Glutamate and Reward, Using the Fyn Kinase Inhibitor Drug, Saracatinib Godfrey Pearlson, M.D. Abstract This project will test the impact of a direct manipulation of a specific, alcoholism risk-relevant mechanism involving intracellular signaling, on functional MRI-measured human reward brain circuit function. It tests the dose-related effects of the Fyn kinase (Fyn) inhibitor drug, saracatinib (AZD0530) in a placebo-controlled, double-blind, randomized, counterbalanced study design. All proposed aims for Project 2 compare family history positive for alcoholism (FHP; i.e., affected parent plus other close relatives, N=40) to matched family history negative (FHN; i.e., no affected first-degree relative, N=40) participants on four fMRI tasks, with the goal of clarifying the interplay of the neurotransmitters dopamine and glutamate via protein kinase A- related signaling pathways in reward circuit dysfunction associated with familial risk for alcoholism.

Project Summary Treatment advances in psychosis are limited by the use of phenomenology-defined diagnoses based on symptomatic outcomes, rather than by neurobiological constructs monitored by quantitative characteristics. The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) uses biomarkers to define psychosis subgroups with the goal of testing the advantages of B-SNIP biomarkers for diagnostic and therapeutic decisions, consistent with principles in the NIMH Strategic Plan (NSP). With >3000 phenotyped psychosis probands, relatives and healthy controls (HC), B-SNIP has a multilevel biomarker library for psychosis and used that library to re-conceptualize psychosis subgroups as biomarker-defined Biotypes (B1, B2, B3), where B1 and B2 are the low cognition/high symptom groups and B3 shows lower symptoms and relatively normal cognition. We replicated Biotypes in a new sample, ?forging a future where measures of an individual?s ? neural and physiological state will form the basis of an increasingly specific and informative diagnosis? (NSP). In this grant we propose that B1, with its low cognition and low cortical activity, will respond uniquely to clozapine, a drug which will generate active cortical attractor networks in B1 to support symptomatic improvement. Clozapine is the most effective antipsychotic drug (APD) with unique clinical efficacy. It is the least used APD because its side effects are serious (neutropenia, myocarditis, seizures) and its administration complex. A predictive biomarker would allow targeting of cases most likely to respond and improve prognosis in psychosis. B-SNIP has shown that clozapine is associated with increases in EEG measures of alpha/theta power, and we identify this increase in time periods without stimulus processing requirements as intrinsic EEG activity (IEA), across all Biotypes. Because B1 cases express low IEA, clozapine?s action to increase EEG power will be normalizing for this psychosis subgroup, with increased cortical attractor states. Because B2 express accentuated IEA, clozapine is associated with more deviant IEA in B2. We propose to test B1 psychosis cases with clozapine vs. risperidone (n=40/group clinical trial completers), over a 6 week cross-titration (to therapeutic plasma levels) and a 9 week stable dose extension, predicting that the B1/clozapine group will respond significantly better, as measured with total PANSS, than the B1/risperidone group and also better than either B2 group. It is our hypothesis that the cortical attractor networks will be normalized and their function increased by the increase in intrinsic EEG activity.

P2: Pearlson, Stevens. Functional neuroimaging of alcoholism vulnerability: probing glutamate and reward using the mGluR5 inhibitor mavoglurant. Alcohol use disorder (AUD) is prevalent and a major cause of morbidity and mortality; a portion of the risk for the condition is familial. A significant portion of inherited risk for AUD likely involves dominance of glutamate over dopamine in brain circuits governing certain types of reward responsiveness, impulsivity and learning. Project 2 will use the mGluR5 negative allosteric modulator drug mavoglurant as a probe in conjunction with 4 functional MRI paradigms to understand how the drug targets the brain systems implicated in familial alcoholism risk. These fMRI paradigms are 1. Response to rewards and punishments (monetary incentive delay task, MID), 2. Inhibiting response to prepotent cues (go/no-go task, GNG), 3. Responsiveness to alcohol-related as opposed to soft-drink or neutral cues (alcohol cue reactivity task, ACR) and 4. the ability to benefit from ?model-based,? goal-directed learning strategies versus ?model-free? learning, that is a less advantageous strategy involving dominance of immediate rewards or habit over behavior (multi-stage decision-making, MSDM task). This project will compare equal numbers of individuals who have strong positive family history of alcoholism and are thus at increased risk for the disorder (family history positive or FHP) to those who have no affected relatives (family history negative or FHN). We will compare fMRI-assessed brain responses during task performance following single doses of mavoglurant and placebo, administered under double-blind, randomly assigned, cross- over conditions, at 2 separate visits. We predict that on placebo FHP will: 1. Be overly- responsive to rewards on the MID, 2. Show different brain signaling during performance of the GNG and ACR, and 3. Manifest an instrumental learning bias on the MSDN accompanied by altered relationships between nucleus accumbens and medial frontal cortex. Unifying these predictions, we also hypothesize 4. That in the case of MID, ACR and MSDM, but not the GNG, these altered brain circuit relationships in FHP will be restored by the study drug mavoglurant such that they more closely resemble patterns seen in FHN in the placebo condition. The use of variants of the MSDM task provides a useful conceptual link that binds the three major CTNA projects together, offering the opportunity to link understanding of neural circuits related to AUD, alcoholism risk and alcohol-related learning bias in a specific, focused, neurotransmitter receptor hypothesis-driven context.