Research Foundation For Mental Hygiene Inc

NYS OASAS SOR 3 - NEW YORK PROPOSES TO CONTINUE INVESTING IN REGIONAL NETWORKS TO BUILD CROSS-SYSTEM COLLABORATION AND INCREASE CONNECTIONS TO CARE. NEW YORK FUNDED REGIONAL NETWORKS THROUGH SOR 2 TO PROVIDE SERVICES ACROSS THE CONTINUUM OF CARE TO CREATE A WHOLISTIC APPROACH TO COMMUNITY INTERVENTION AT THE REGIONAL LEVEL. THIS INCLUDED UTILIZING MEASURES TO ENCOURAGE NETWORK AND PROVIDER COLLABORATION TO ATTAIN FURTHER INCREASES IN MAT INITIATION, MAT ADHERENCE, CONTINUATION OF ENGAGEMENT IN TREATMENT, AND CONTINUITY BETWEEN LEVELS OF CARE, AS WELL AS DEMONSTRABLY IMPROVED OUTREACH TO PEOPLE WHO USE OPIOIDS AND/OR STIMULANTS WHO ARE NOT ENGAGED IN CARE. THE NETWORKS INCORPORATED THE FULL CONTINUUM OF OASAS SERVICES INCLUDING PREVENTION AND RECOVERY INTO THE NETWORK AND INCLUDED A REPRESENTATIVE FROM EACH ON THE LEADERSHIP TEAM. EACH NETWORK WAS ENCOURAGED TO INCLUDE A FULL ARRAY OF SUD SERVICES INCLUDING HARM REDUCTION, CRISIS SERVICES, AND EVIDENCE-BASED PREVENTION PRACTICES. EACH OF THE NETWORKS HAS HAD SUCCESS IN BRINGING PROVIDERS TOGETHER, IMPLEMENTING SCOPES OF WORK AS PROPOSED IN THEIR APPLICATION, AND SOLVING PROBLEMS RELATED TO GAPS AND BARRIERS TO CARE IN THEIR COMMUNITIES. AN EXAMPLE OF THIS IS THE RECENT OPPORTUNITY THROUGH ANOTHER FUNDING SOURCE TO IMPLEMENT TRANSPORTATION WITHIN THE REGION FOR NON-MEDICAL SERVICES TO SUPPORT RECOVERY. EACH OF THE NETWORKS APPLIED FOR THE FUNDING WITH UNIQUE SOLUTIONS BASED ON THE NEEDS OF THEIR REGION CAPITALIZING ON THE COLLABORATION OF THE NETWORK AND THE CURRENT SUD ASSETS IN THE REGION. THROUGH A REQUEST FOR APPLICATIONS, EACH REGIONAL NETWORK WILL IDENTIFY THE INNOVATIVE MODELS OF SERVICE PROVISION IN PREVENTION, TREATMENT, AND RECOVERY THAT ADDRESS THE EXISTING NEEDS OF THEIR POPULATION. OASAS WILL PROVIDE A LIST OF SERVICES WHICH THE REGIONAL NETWORK WILL SELECT FROM TO BEST ADDRESS LOCAL NEEDS. AMONG THESE SERVICES, OASAS WILL PLACE AN EMPHASIS ON IN-COMMUNITY SERVICES AS MODELED IN THE CENTER OF TREATMENT INNOVATION (COTI) PROGRAM INITIATED UNDER STR AND CONTINUED THROUGH THE SOR GRANT. THE MODEL INCLUDES TRANSPORTATION AND MOBILE TREATMENT, THE USE OF A PEER OUTREACH WORKFORCE, TELE-PRACTICE AND LINKAGES MENTAL HEALTH AND MEDICAL SERVICES. OTHER MODELS AND TYPES OF SERVICE THE NETWORKS WILL INCLUDE ARE: LINKING EMERGENCY ROOMS TO PEERS, OUTPATIENT TREATMENT PROGRAMS, AND ADDICTION MEDICINE SPECIALISTS TO IMPROVE INTERVENTION AND INITIATION OF MEDICATION FOR OPIOID USE DISORDER; LINKING OUTPATIENT TREATMENT PROVIDERS TO FEDERALLY QUALIFIED HEALTH CENTERS; IMPROVE PROVIDER CAPACITY TO USE QUALITY IMPROVEMENT STRATEGIES TO INCREASE ACCESS TO MAT INITIATION, MAT ADHERENCE AND IMPROVED RATES OF FOLLOW UP AFTER HIGH INTENSITY SERVICES; IMPROVE SUD PROVIDER NETWORK COLLABORATION FOR SHARED AND AGGREGATED DATA ACROSS A NETWORK OF PROVIDERS, IMPLEMENTATION OF COORDINATED PREVENTION, CLINICAL AND PEER INTERVENTIONS ACROSS THE NETWORK; AND INCREASE POSITIVE FAMILY MANAGEMENT; ADULT ORIENTED RECOVERY CENTERS AND YOUTH CLUBHOUSES TO PROMOTE SUBSTANCE FREE POSITIVE SOCIAL ACTIVITIES TO PROMOTE RECOVERY. THE EXISTING REGIONAL NETWORKS PROVIDE AN OPPORTUNITY FOR THE STATE TO MEET THE GOALS OF THE SOR GRANT AT A REGIONAL LEVEL, ACROSS THE STATE TO ENSURE UNIVERSAL ACCESS TO OUD IDENTIFICATION, OUTREACH, HARM REDUCTION SERVICES, MEDICATION ACCESS, PREVENTION, AND RECOVERY SUPPORT.

NYS OASAS SOR 4 - THE NEW YORK STATE (NYS) OFFICE OF ADDICTION SERVICES AND SUPPORTS (OASAS) WILL CONTINUE TO FUND THE REGIONAL NETWORK APPROACH TO PREVENTION, HARM REDUCTION, TREATMENT, AND RECOVERY TO SERVE NYS RESIDENTS WHO HAVE AN OPIOID USE DISORDER (OUD) OR STIMULANT USE DISORDER (STUD), ARE AT RISK FOR DEVELOPING AND OUD OR STUD, OR ARE IN RECOVERY FROM AN OUD OR STUD. THE REGIONAL NETWORK APPROACH, INITIATED UNDER THE 2020 STATE OPIOID RESPONSE GRANT, GAVE PROVIDERS THE OPPORTUNITY TO DEVELOP A REGIONAL NETWORK OF CARE FOR OUD AND STUD THROUGH SHARED KNOWLEDGE, THE IDENTIFICATION OF OPPORTUNITIES FOR PARTNERSHIP AND THE SHARING OF, OR CO CREATION OF, PROGRAMS. NETWORKS WILL CONTINUE TO INVEST IN REGIONAL INITIATIVES AIMED AT IMPROVING DATA QUALITY, PROMOTING STAFF TRAINING/WELLNESS AND DEVELOPING SHARED REFERRAL SYSTEMS USING TECHNOLOGY. NETWORK PROVIDERS FORMALIZED COLLABORATIONS WITH MEMORANDUMS OF UNDERSTANDING, BUILT NEW SERVICES, AND JOINTLY PURSUED PROGRAM FUNDING OPPORTUNITIES. WITHIN EACH OF THE 13 REGIONAL NETWORKS, PROVIDERS WILL CONTINUE DELIVERING SERVICES INCLUDING: EXPANDING ACCESS TO MEDICATION FOR OPIOID USE DISORDER (MOUD); LINKING HOSPITAL EMERGENCY DEPARTMENTS AND URGENT MEDICAL CARE CENTERS TO PEER SUPPORTS, OUTPATIENT TREATMENT PROGRAMS, AND ADDICTION MEDICINE SPECIALISTS TO IMPROVE INTERVENTION AND INITIATION OF MOUD; LINKING FEDERALLY QUALIFIED HEALTH CENTERS TO OUTPATIENT TREATMENT PROGRAMS TO INCREASE PATIENT ACCESS TO MOUD AND LEVERAGE RESOURCES AND EXPERTISE ACROSS PATIENT SETTINGS; INTEGRATING AND SUPPORTING THE PEER WORKFORCE WITHIN TREATMENT AND RECOVERY SETTINGS; DELIVERING RECOVERY SERVICES, INCLUDING PEER SERVICES, HOUSING ASSISTANCE, VOCATIONAL SUPPORT, NON-MEDICAL TRANSPORTATION, AND SERVICES FOR THE CHILDREN AND FAMILIES OF THOSE IN RECOVERY; INNOVATIVE TELEHEALTH STRATEGIES IN RURAL AND UNDERSERVED AREAS TO INCREASE THE CAPACITY OF COMMUNITIES TO SUPPORT OUD/STUD TREATMENT AND RECOVERY; OPERATING ACCESS AND SUPPORT HOTLINES TO SUPPORT REGIONAL NETWORKS; PROVIDING SERVICES AND SUPPORTS SPECIFICALLY DESIGNED TO MEET THE NEEDS OF THE YOUTH AND YOUNG ADULT POPULATIONS; PARTNERING WITH EXISTING RECOVERY COMMUNITY AND OUTREACH CENTERS AND YOUTH CLUBHOUSES; PROVIDING SERVICES AND SUPPORTS THAT TARGET CRIMINAL LEGAL SYSTEM POPULATIONS; AND MAINTAINING A JUSTICE-INVOLVED PEER PROGRAM TO ADDRESS SIGNIFICANT CHALLENGES UPON REENTRY INTO THE COMMUNITY FROM THE CRIMINAL LEGAL SYSTEM. ADDITIONALLY, OASAS WILL CONTINUE TO SUPPORT THE DISTRIBUTION OF HARM REDUCTION SUPPLIES THROUGH OPIOID OVERDOSE PREVENTION COMMUNITY TRAININGS, AN OASAS WEB-BASED HARM REDUCTION SUPPLY ORDERING PORTAL, AND HARM REDUCTION VENDING MACHINES ACROSS THE STATE. PROJECT GOALS ARE TO: ENHANCE COORDINATION AND DELIVERY OF COMPREHENSIVE PREVENTION SERVICES THROUGH REGIONAL NETWORKS; INCREASE THE NUMBER OF PERSONS WITH OUD OR STUD RECEIVING TREATMENT THROUGH PEER OUTREACH AND ENGAGEMENT ENCOUNTERS; INCREASE THE CAPACITY OF THE SUD PROVIDERS TO PROVIDE HARM REDUCTION SERVICES TO PEOPLE WHO USE DRUGS; INCREASE THE NUMBER OF PERSONS WITH OUD OR STUD RECEIVING INITIAL OR RE-ENGAGEMENT IN RECOVERY-RELATED SERVICES BY ESTABLISHING AND STRENGTHENING LINKAGES BETWEEN PROGRAMS; AND INCREASE THE NUMBER OF VULNERABLE PERSONS WITH OUD OR STUD RECEIVING RECOVERY-RELATED SERVICES THROUGH EXPANSION AND ENHANCEMENT OF SERVICES AND ACCESS. THIS PROJECT ANTICIPATES SERVING APPROXIMATELY 5,100 PERSONS PER YEAR THROUGH PREVENTION SERVICES, 22,000 PER YEAR THROUGH TREATMENT SERVICES, AND 16,200 PER YEAR THROUGH RECOVERY SERVICES.

NYS OASAS SOR 2020

THE NEW YORK STATE OFFICE OF MENTAL HEALTH

NYS OASAS SOR

CRISIS COUNSELING

HIV CENTER FOR CLINICAL AND BEHAVIOR STUDIES

PROMOTING THE READINESS OF MINORS IN SUPPLEMENTAL SECURITY INCOME (PROMISE)

CLINICAL TRIALS NETWORK: LONG ISLAND REGIONAL NODE

CELL AND MOLECULAR PATHOBIOLOGY OF ALZHEIMER'S DISEASE

THE NEW YORK STATE OFFICE OF ALCOHOLISM AND SUBSTANCE ABUSE SERVICES (OASAS) IN PARTNERSHIP WITH THE RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC. (RFMH) WILL UNDERTAKE A MULTI-PRONGED APPROACH TO ADDRESS THE ISSUES OF OPIOID USE DISORDERS IN THE UNSERVED AND UNDERSERVED AREAS OF THE STATE. OASAS HAS IDENTIFIED HIGH NEED AREAS IN THE STATE AND THROUGH ITS EXISTING INFRASTRUCTURE WILL ENHANCE TREATMENT AND RECOVERY SERVICES. OASAS'S PROPOSAL IS TO DEVELOP CENTERS OF TREATMENT INNOVATION IN HIGH NEED AREAS WHICH WILL INCLUDE DEVELOPING TELE-HEALTH CAPACITY; INCREASING THE NUMBER OF PRESCRIBING PRACTITIONERS FOR MEDICATION ASSISTED TREATMENT VIA TRAINING AND MENTORING; HAVING CARE MANAGERS TO BRIDGE THE GAP BETWEEN BEHAVIORAL HEALTH AND PRIMARY CARE; USE OF LOCALLY PLACED PEER RECOVERY SUPPORT STAFF TO IMPROVE TREATMENT ENGAGEMENT AND RETENTION; ENHANCED CLINICAL STAFF; AND PROVIDING REENTRY SUPPORT FOR INDIVIDUALS BEING RELEASED FROM JAILS/CORRECTIONAL FACILITIES. OASAS WILL ALSO UTILIZE A MULTI-LEVEL PREVENTION APPROACHES INCLUDING DELIVERY OF EVIDENCE-BASED PREVENTION SERVICES TO UNDERSERVED, HARD-TO-REACH YOUTH AND OTHER AT RISKS POPULATIONS, FOSTER CARE SETTINGS AND PERMANENT SUPPORTIVE HOUSING; PROVIDE TRAINING AND DISTRIBUTION OF NALOXONE KITS; AND A TARGETED MEDIA CAMPAIGN. TO SUPPORT A GROWING RECOVERY COMMUNITY OASAS WILL DEVELOP A YOUTH AND YOUNG ADULT STATEWIDE RECOVERY NETWORK AND LOCAL COMMUNITY NETWORKS. OASAS LOOKS TO ESTABLISH A SOCIAL MEDIA CAMPAIGN THAT PROMOTES HEALTH, RECOVERY AND WELLNESS, ESTABLISH PEER SUPPORTS AND TO PROVIDE TECHNICAL ASSISTANCE AND SUPPORT TO LOCAL COMMUNITIES AND NETWORKS OF YOUNG PEOPLE ACROSS NEW YORK STATE.

NYS OPIOID STR PROJECT

ANTECEDENTS OF SUICIDAL BEHAVIOR RELATED NEUROBIOLOGY

NEUROBIOLOGY AND DYNAMICS OF ACTIVE SENSING

NOVEL MEDICATION APPROACHES FOR SUBSTANCE ABUSE

BREAKING THE CYCLE OF INTERGENERATIONAL DISADVANTAGE: NEURODEVELOPMENT AMONG PUERTO RICAN CHILDREN.

SHARED PHARMACOTHERAPEUTIC STRATEGIES FOR CANNABINOID & OPIOID USE DISORDERS

NEW YORK SERVICE OPPORTUNITIES TO ACCESS RECOVERY SUCCESSFULLY (NY SOARS)

EVALUATION OF SAFETY AND PHARMACOKINETICS OF NALTREXONE IMPLANT - NEW MEDICATION TREATMENT APPROACHES ARE NEEDED TO HELP ADDRESS THE SEVERE EPIDEMIC OF OPIOID USE DISORDER (OUD) AND OPIOID OVERDOSE DEATHS IN THE US. CURRENTLY AVAILABLE MEDICATIONS, METHADONE, BUPRENORPHINE, AND EXTENDED RELEASE INJECTION NALTREXONE (XR-NTX; TRADE NAME: VIVITROL), ARE HIGHLY EFFICACIOUS, BUT THEIR EFFECTIVENESS IN PRACTICE IS LIMITED BY POOR ADHERENCE, WITH MANY PATIENTS STOPPING TREATMENT PREMATURELY AND RELAPSING. THE GOAL OF THIS PROPOSAL IS TO DEVELOP AN INNOVATIVE LONG ACTING SUBCUTANEOUS IMPLANTED FORMULATION OF NALTREXONE, THE O’NEIL LONG-ACTING NALTREXONE IMPLANT (OLANI), TOWARDS FDA APPROVAL. EXPECTED TO PRODUCE NALTREXONE BLOOD LEVELS SUFFICIENT TO BLOCK THE EFFECTS OF OPIOIDS FOR 6 MONTHS AFTER IMPLANT, OLANI CIRCUMVENTS THE NEED FOR ADHERENCE TO MONTHLY INJECTIONS WITH XR-NTX, AND COULD REPRESENT AN IMPORTANT NEW ADDITION TO THE MEDICAL ARMAMENTARIUM FOR TREATMENT OF OUD. THE OLANI HAS BEEN IN DEVELOPMENT BY AN AUSTRALIAN COMPANY GO MEDICAL FOR 20 YEARS WITH SEVERAL PROTOTYPES EVALUATED IN CONTROLLED CLINICAL TRIALS AND USED CLINICALLY IN AUSTRALIA. THE CURRENT FORMULATION HAS HIGHER DRUG LOADING AND A BETTER RELEASE PROFILE AND IS MANUFACTURED IN A GMP FACILITY. IT HAS BEEN USED CLINICALLY IN OVER 800 PATIENTS, GIVING CONFIDENCE THAT THE PRODUCT CAN BE SUCCESSFULLY DEVELOPED IN THE US. GO MEDICAL AND THE CURRENT TEAM OF INVESTIGATORS MET WITH THE FDA TO CHART A DEVELOPMENT PATH TOWARDS A NEW DRUG APPLICATION (NDA) VIA THE 505 B(2) PATHWAY WITH VIVITROL AS A COMPARATOR PRODUCT. AN APPLICATION FOR AN IND (# 134996) IS UNDER REVIEW BY THE FDA. THIS PROPOSAL SEEKS NIDA’S SUPPORT UNDER THE UG3/UH3 MECHANISM TO CONDUCT THE STUDIES RECOMMENDED BY THE FDA FOR THE 505 B(2) PATHWAY TO APPROVAL. UNDER THE UG3 PHASE, STUDY 1 WILL EVALUATE LOCAL TISSUE TOXICITY OF OLANI IN A MINIPIG MODEL, AND STUDY 2 WILL GENERATE PILOT PHARMACOKINETIC (PK) DATA OF OLANI IN HEALTHY SUBJECTS IN ORDER TO DETERMINE POWER AND FINALIZE SAMPLE SIZE FOR A SUBSEQUENT BIOEQUIVALENCE (BE) STUDY AND TO SUPPORT FEASIBILITY AND TOLERABILITY. IF THERE ARE NO SAFETY CONCERNS AND NALTREXONE BLOOD LEVELS ARE ADEQUATE IN THE UG3 PHASE, THEN IN THE UH3 PHASE (STUDY 3) WILL BE FINALIZED IN CONSULTATION WITH NIDA AND FDA. STUDY 3 WILL COMPARE 6-MONTH PK OF OLANI VERSUS XR-NTX AS THE REFERENCE DRUG TO ESTABLISH BIOEQUIVALENCE (BE) IN TERMS OF NALTREXONE BLOOD LEVELS, SAFETY AND COMPARATIVE EFFECTIVENESS IN PATIENTS WITH OUD. PATIENTS WILL BE RANDOMIZED TO RECEIVE EITHER A SINGLE SUBCUTANEOUS IMPLANTATION OF 3.6G DOSE OF OLANI OR REPEAT DOSES OF VIVITROL 380 MG IM Q4 WEEKS FOR 24 WEEKS. PARTICIPANTS RANDOMIZED TO OLANI WILL BE OFFERED AN ADDITIONAL IMPLANT AT MONTH 6. WE HYPOTHESIZE THAT OLANI WILL HAVE A SYSTEMIC EXPOSURE (CMAX,CMIN,AUC0-180) AND MEC OF NALTREXONE BLOOD LEVELS COMPARABLE TO XR-NTX. IF OLANI IS SHOWN TO PROVIDE A SAFE, FEASIBLE AND EFFECTIVE METHOD OF DELIVERY OF NALTREXONE AT THERAPEUTIC LEVELS FOR AT LEAST 6 MONTHS, IT WOULD REPRESENT A MAJOR ADVANCE IN THE FIELD OF OUD TREATMENT, PROVIDING EFFECTIVE LONG TERM RELAPSE-PREVENTION TREATMENT TO INDIVIDUALS WITH OUD.

MENTAL HEALTH AND RISK IN HIV+ YOUTH AND SEROREVERTERS

NYS SYSTEM OF CARE

PREVENTION FIRST - NY!

NYSBIRT PROJECT

NYS OASAS PIPBHC PROJECT

NOVEL COGNITIVE AND FUNCTIONAL MEASURE FOR ALZHEIMER'S DISEASE PREVENTION TRIALS

STRUCTURE AND FUNCTION OF DOPAMINE RECEPTORS

SEROTONERGIC MODULATION OF BRAIN DEVELOPMENT: GENETIC AND PHARMACOLOGIC INFLUENC

DOPAMINE DYSFUNCTION IN SCHIZOPHRENIA

LEVERAGING SOCIAL NETWORKS TO INCREASE COVID-19 TESTING UPTAKE: A COMPARISON OF CREDIBLE MESSENGER AND CHAIN REFERRAL RECRUITMENT APPROACHES

CHILDREN AT HIGH AND AT LOW RISK FOR DEPRESSION

PHASE 1A/1B CLINICAL TRIALS OF MULTIVALENT OPIOID VACCINE COMPONENTS

OPTIMIZING AND PERSONALIZING INTERVENTIONS FOR SCHIZOPHRENIA ACROSS THE LIFESPAN (OPAL)

NYSBIRT

ADDRESSING THE YOUTH MENTAL HEALTH CRISIS THROUGH COLLABORATIVE CARE EXPANSION IN NEW YORK STATE - THE NEW YORK STATE OFFICE OF MENTAL HEALTH (NYS OMH) HAS LED THE NATION IN ADOPTION AND SCALE OF THE PSYCHIATRIC COLLABORATIVE CARE MODEL (COCM) AND SEEKS TO BUILD ON THAT SUCCESS BY EXPANDING THE NUMBER OF YOUTH-SERVING PRIMARY CARE PRACTICES PARTICIPATING IN THE PROGRAM TO ADDRESS THE YOUTH MENTAL HEALTH CRISIS AND ADVANCE HEALTH EQUITY. THIS INITIATIVE WILL ADDRESS MENTAL AND BEHAVIORAL HEALTH PROBLEMS AMONG CHILDREN AND ADOLESCENTS WITH CO-OCCURRING SERIOUS EMOTIONAL DISTURBANCE (SED) AND PHYSICAL HEALTH CONDITIONS OR CHRONIC DISEASE, SUCH AS DEPRESSION, ANXIETY, ADHD, SUBSTANCE USE DISORDERS, AND SUICIDAL THOUGHTS AND BEHAVIORS, BY PROVIDING INTEGRATED BEHAVIORAL HEALTH SERVICES. AN EXPLICIT GOAL OF THE PROJECT IS TO ENSURE EQUITABLE ACCESS OF SERVICES TO POPULATIONS WHO HAVE HISTORICALLY LACKED ACCESS, INCLUDING BIPOC, LGBTQ+, AND RURAL YOUTH. THIS PROJECT WILL BE IMPLEMENTED STATEWIDE IN NEW YORK, THE FOURTH MOST POPULOUS STATE IN THE COUNTRY. PARTICIPATING PROVIDERS WILL REPRESENT THE DIVERSITY OF NYS, INCLUDING BOTH URBAN AND RURAL PRIMARY CARE SETTINGS, LARGE PUBLIC HOSPITAL CLINICS, AND SMALL PRIVATE PRACTICES SERVING OVER 3500 YOUTH ACROSS 15 SITES. THE HALLMARKS OF THE NYS COCM IMPLEMENTATION APPROACH ARE 1) EXTENSIVE TECHNICAL ASSISTANCE AND SUPPORT FOR PARTICIPATING PRACTICES AND 2) ROBUST PROCESS AND OUTCOMES METRICS TO ENSURE DELIVERY OF CARE THAT MAKES A DIFFERENCE IN THE LIVES OF YOUTH AND THEIR FAMILIES. IN ADDITION TO TECHNICAL ASSISTANCE AND SUPPORT FOR THE ADOPTION OF COCM, PARTICIPATING PRACTICES WILL ALSO RECEIVE TRAINING IN SUICIDE PREVENTION BEST PRACTICES. A SIGNIFICANT PORTION OF AWARD FUNDS WILL BE AIMED AT OVERCOMING WORKFORCE SHORTAGES, AN IDENTIFIED BARRIER, AND SUPPORTING DEVELOPMENT OF A SUSTAINABLE MODEL BY THE END OF THE FIVE-YEAR PROJECT.

PHASE 1A/1B CLINICAL TRIALS OF MULTIVALENT OPIOID VACCINE COMPONENTS - PROJECT SUMMARY CURRENTLY, ABUSE OF PRESCRIPTION OPIOID ANALGESICS AND HEROIN IS A PERVASIVE PROBLEM IN THE U.S. ALTHOUGH SEVERAL MEDICATIONS, INCLUDING METHADONE, BUPRENORPHINE, AND NALTREXONE, ARE AVAILABLE AND EFFECTIVE IN TREATING OPIOID USE DISORDER (OUD), LONG-TERM RELAPSE RATES REMAIN HIGH. THE CURRENT STUDIES ARE DESIGNED TO EXAMINE A NOVEL APPROACH TO TREATING OUD, NAMELY USE OF A VACCINE (OXY-KLH) TARGETED AGAINST OXYCODONE, ONE OF THE MOST COMMONLY ABUSED PRESCRIPTION OPIOIDS, AND A VACCINE (M-KLH) TARGETED AGAINST HEROIN/MORPHINE. ULTIMATELY, A BIVALENT VACCINE (OXY-KLH AND M-KLH) WILL BE DEVELOPED THAT WILL TARGET OXYCODONE AND HEROIN. THE LONG-TERM GOAL OF THIS RESEARCH IS TO DEVELOP A MULTIVALENT VACCINE DIRECTED AGAINST OXYCODONE, HEROIN, AND OTHER RELEVANT OPIOIDS. HOWEVER, DURING OUR PRE-IND MEETING, THE FDA/CBER ASKED THAT WE STUDY EACH VACCINE SEPARATELY BEFORE MOVING FORWARD WITH DEVELOPMENT OF THE BIVALENT VACCINE. THE CURRENT APPLICATION PROPOSES A PHASE 1A/1B STUDY DESIGNED TO EVALUATE THE SAFETY (AIM 1), IMMUNOGENICITY (AIM 2), AND PRELIMINARY EFFICACY (AIM 3) OF OXY-KLH DURING THE UG3 PHASE OF THE GRANT PERIOD (STUDY 1) AND A SIMILAR PHASE 1A/1B STUDY OF M-KLH DURING THE UH3 PHASE OF THE GRANT PERIOD (STUDY 2). TRANSITION TO THE UH3 PHASE WILL BE DETERMINED AFTER SAFETY, IMMUNOGENICITY, AND PRELIMINARY EFFICACY ANALYSES HAVE BEEN PERFORMED FOR THE OXY-KLH VACCINE. OVERALL, THE PROPOSED STUDIES WILL PROVIDE A GREAT DEAL OF INFORMATION ABOUT THE SAFETY AND POTENTIAL EFFICACY OF THE VACCINES IN REDUCING THE ABUSE LIABILITY OF OPIOIDS, WHICH WILL BE ADMINISTERED IN A CONTROLLED LABORATORY SETTING. IF THE OUTCOMES OF THE PROPOSED STUDIES WITH OXY-KLH AND M- KLH ARE FAVORABLE, WE WILL PROCEED WITH DEVELOPMENT OF THE BIVALENT VACCINE (OXY-KLH PLUS M-KLH).

EARLY CORTICAL PROCESSING IN SCHIZOPHRENIA

HUMAN TRIAL OF ALLOSTERIC MODULATOR ALPHA7 NICOTINIC RECEPTORS IN SCHIZOPHRENIA

ADAPTING COORDINATED SPECIALTY CARE IN THE POST COVID-19 ERA

NEW YORK SPF-PFS PROJECT

EVALUATION OF SAFETY AND PHARMACOKINETICS OF NALTREXONE IMPLANT

NYS YOUTH AND FAMILIES ACHIEVE

NYS YOUTH AND FAMILIES ACHIEVE

NYS OASAS MAT-PDOA

PRIDE SSA - PARTNERSHIPS IN RESEARCH TO IMPLEMENT AND DISSEMINATE SUSTAINABLE AND SCALABLE EVIDENCE BASED PRACTICES IN SUB-SAHARAN AFRICA

EFFECT OF MAJOR DEPRESSION AND ANTIDEPRESSANTS ON HUMAN NEUROGENESIS

SEROTONIN AND THE MODULATION OF BRAIN DEVELOPMENT

CORTICAL AND THALAMIC MECHANISMS OF SELECTIVE AUDITORY ATTENTION

MARIJUANA RELAPSE: INFLUENCE OF TOBACCO CESSATION AND VARENICLINE

DEFINING NEURONAL CIRCUITS AND CELLULAR PROCESSES UNDERLYING RESTING FMRI SIGNALS

MEDIUM SPINY NEURON EXCITABILITY AND MOTIVATION

NYS PARTNERSHIP FOR SUCCESS 2022 - THE NYS SPF-PFS 2022'S GOAL IS TO REDUCE BEHAVIORAL HEALTH DISPARITIES AMONG OUR MOST VULNERABLE POPULATIONS BY STRENGTHENING THE STATE AND LOCAL COMMUNITY'S CAPACITY TO BUILD AND SUSTAIN CULTURALLY APPROPRIATE PREVENTION SERVICES IN HIGH-RISK UNDERSERVED I.E. BLACK, INDIGENOUS, AND PEOPLE OF COLOR (BIPOC); LESBIAN, GAY, BISEXUAL, TRANSGENDER PLUS (LGBT+); AND RURAL COMMUNITIES. WE INTEND TO INCREASE ACCESS TO QUALITY PREVENTION SERVICES WITHIN OUR MOST HIGH-RISK COMMUNITIES USING THE DATA-DRIVEN STRATEGIC PREVENTION FRAMEWORK (SPF) TO DEVELOP AND TO WIDELY DISSEMINATE CULTURALLY RESPONSIVE PREVENTION STRATEGIES ADDRESSING UNDERAGE AND PROBLEM ALCOHOL AND CANNABIS USE. USING STATE AND LOCAL DATA TO IDENTIFY AREAS OF HIGHEST PREVENTION NEED, OASAS WILL FUND SIX HIGH-CAPACITY COMMUNITY COALITIONS BASED ON THEIR ABILITY TO REACH VULNERABLE, HIGH-RISK, OR UNDERSERVED COMMUNITIES SUCH AS BIPOC, LGBT+, AND RURAL COMMUNITIES. THE SELECTED COALITIONS WILL RECEIVE TARGETED TRAINING AND TECHNICAL ASSISTANCE TO IMPLEMENT THE SPF PROCESS AND TO ADAPT ENVIRONMENTAL CHANGE STRATEGIES, INCLUDING MEDIA, POLICY, AND COMPLIANCE COMPONENTS, TO REDUCE OR DELAY UNDERAGE ALCOHOL/CANNABIS USE AND REDUCE ADULT PROBLEM ALCOHOL/CANNABIS USE. EACH COALITION WILL BUILD LOCAL RESOURCES TO DEVELOP AND EVALUATE CULTURALLY RESPONSIVE MESSAGING TO PREVENT THE ONSET AND REDUCE THE PROGRESSION OF SUBSTANCE MISUSE AND ITS RELATED HEALTH PROBLEMS WHILE STRENGTHENING COMMUNITY AND STATE LEVEL PREVENTION CAPACITY TO ENGAGE HEALTH DISPARATE POPULATIONS. USING A MIX OF EVIDENCED-BASED PROGRAMS, POLICIES AND PRACTICES, EACH COALITION WILL FOCUS ON CREATING POPULATION CHANGE AND SUSTAINABLE PREVENTION. OUR MEASURABLE OBJECTIVES OUTLINED BELOW ARE DERIVED FROM OUTCOMES ASSOCIATED WITH NYS OASAS'S PREVIOUS IMPLEMENTATION OF SAMHSA'S STATE INCENTIVE GRANT 1999-2003, THE NYS SPF-SIG 2009, AND NYS PFS 2014 WHICH FUNDED ENVIRONMENTAL STRATEGY COALITION WORK: 1. INCREASE AWARENESS WITHIN HIGH-RISK UNDERSERVED COMMUNITIES (E.G. BIPOC, LGBT+, AND RURAL) OF THE DANGERS OF UNDERAGE PROBLEM ALCOHOL AND CANNABIS USE THROUGH CULTURALLY RESPONSIVE PREVENTION MESSAGING. 2. PREVENT THE ONSET AND REDUCE THE PROGRESSION OF PROBLEM ALCOHOL/CANNABIS USE IN HIGH-RISK UNDERSERVED COMMUNITIES (E.G. BIPOC, LGBT+ AND RURAL) BY IMPLEMENTING ENVIRONMENTAL CHANGE STRATEGIES (ECS). 3. INCREASE CAPACITY AND INFRASTRUCTURE FOR COLLABORATIONS TO IMPLEMENT CULTURALLY RESPONSIVE, DATA-DRIVEN PREVENTION FOR HIGH-RISK UNDERSERVED COMMUNITIES. THIS INITIATIVE'S NEEDS, RESOURCE, AND CAPACITY ASSESSMENTS WILL SERVE AS A FOUNDATION FOR OASAS'S STATEWIDE COMMUNITY HEALTH ASSESSMENT (CHA) AND A STATEWIDE COMMUNITY HEALTH IMPROVEMENT PLAN (CHIP) FOR SUBSTANCE USE PREVENTION TO ADVANCE BEHAVIORAL HEALTH EQUITY ACROSS NYS'S DIVERSE COMMUNITIES. THE CHA WILL IDENTIFY KEY SUBSTANCE USE AND MISUSE PREVENTION PRIORITIES, GAPS IN SERVICES, AND BEHAVIORAL HEALTH DISPARITIES THROUGH A SYSTEMATIC, COMPREHENSIVE DATA COLLECTION PROCESS, ANALYSIS, AND DISSEMINATION. THE CHIP WILL ACT AS A STATE AND LOCAL FRAMEWORK FOR LONG-TERM SUBSTANCE USE/MISUSE PREVENTION. THE PLAN WILL IDENTIFY PRIORITY COMMUNITIES AND OFFER BEST PRACTICE GUIDELINES TO BUILD CAPACITY FOR EFFECTIVE RESPONSIVE PREVENTION STRATEGIES GLEANED FROM NYS PFS 2022. BOTH THE CHA AND CHIP WILL BE A DATA-DRIVEN APPROACH TO ADDRESS THE LASTING HEALTH CONSEQUENCES ASSOCIATED WITH SUBSTANCE USE AND MISUSE SPECIFICALLY IN HEALTH DISPARATE POPULATIONS.

HEALTH AND JUSTICE: A CONTINUUM OF CARE FOR HIV AND SU FOR JUSTICE-INVOLVED YOUTH

THE ROLE OF CA2 IN EPILEPSY AND SOCIAL COMORBIDITY

PROMOTING HOPE AND OPPORTUNITIES FOR YOUTH WITH EARLY PSYCHOSIS

SBIRT COMMUNITY BASED OUTREACH - THE NEW YORK SBIRT COMMUNITY OUTREACH PROJECT WILL IMPLEMENT AND EVALUATE AN INNOVATIVE, CULTURALLY RESPONSIVE MODEL TO DELIVER SBIRT SERVICES TO UNDERSERVED ADOLESCENT AND ADULT POPULATIONS HISTORICALLY UNLIKELY TO ACCESS TREATMENT SERVICES (SEXUAL MINORITY [LGBT+]; ECONOMICALLY DISADVANTAGED; LATINX IMMIGRANT; NATIVE AMERICAN; AND RURAL) IN 4 AREAS OF THE STATE: NEW YORK CITY (NYC); FIVE TOWNS, LONG ISLAND; FINGER LAKES; AND ST. REGIS MOHAWK RESERVATION. SBIRT WILL BE DELIVERED WITHIN COMMUNITY-BASED SETTINGS BY TRAINED OUTREACH WORKERS FROM THE TARGETED POPULATION. THE RECOMMENDED SCREENING TOOLS TO IDENTIFY SUBSTANCE USE (CRAFFT+N 2.1 FOR ADOLESCENTS; AUDIT AND DAST-10 FOR ADULTS) AND SUICIDE (C-SSRS FOR ADOLESCENTS AND ADULTS) RISK. IF SCREENED POSITIVE FOR SUBSTANCE USE RISK, THE INDIVIDUAL WILL RECEIVE BRIEF INTERVENTION (BI) WITH A BRIEF NEGOTIATED INTERVIEW (BNI) USING MOTIVATIONAL INTERVIEWING (MI) TECHNIQUES. IF SCREENED POSITIVE FOR SUICIDE RISK, THE SAFETY PLANNING INTERVENTION (SPI) WITH FOLLOW-UP WILL BE USED. IF BRIEF TREATMENT (I.E., COGNITIVE BEHAVIORAL THERAPY) OR SPECIALTY TREATMENT (I.E., MEDICATION ASSISTED TREATMENT [MAT] IS WARRANTED, THE ACTIVE REFERRAL TO TREATMENT (ART) MODEL WILL BE FOLLOWED TO ENSURE HOT HANDOFFS TO SUBSTANCE USE DISORDER (SUD), MAT, AND/OR MENTAL HEALTH MH PROVIDERS. PRE-ESTABLISHED AND CONTINUED COLLABORATIONS WILL ASSIST IN CARE TRANSITIONS. PROJECT GOALS ARE TO: (1) DEVELOP, REFINE, AND PILOT AND INNOVATIVE SBIRT COMMUNITY OUTREACH MODEL TO REDUCES ACCESS BARRIERS AND INCREASE SERVICE USE AMONG HIGH-RISK POPULATIONS HESITANT TO SEEK SERVICES. OASAS WILL USE FOCUS GROUPS AND KEY INFORMANT INTERVIEW DATA TO DESIGN A CULTURALLY APPROPRIATE MODEL, TRAIN SITES TO DELIVER IT, PILOT IT, AND THEN REFINE IT BASED ON FEEDBACK. (2) DELIVER THE REFINED MODEL IN AT LEAST 12 SEPARATE COMMUNITY SETTINGS DOCUMENTING CULTURAL MODIFICATIONS TO INCREASE SERVICE ACCESS, DECREASE HEALTH DISPARITIES, SUBSTANCE USE, RISK BEHAVIORS, AND SUICIDE RISK IN NYC, FIVE TOWNS, THE FINGER LAKES, AND ST. REGIS MOHAWK RESERVATION. 5,000 SCREENINGS, 1,000 BIS, AND 350 RTS WILL BE DELIVERED PER YEAR. (3) DISSEMINATE OUR MODEL TO OTHER HIGH-RISK COMMUNITIES AND SUSTAIN IT. IN YEARS 3-5, AT LEAST 3 MORE PROVIDERS WILL IMPLEMENT THE SBIRT MODEL AND BECOME CERTIFIED CHILDREN AND FAMILY TREATMENT SERVICE PROVIDERS. IN YEARS 2-5, NEW PROVIDERS WILL BE TRAINED, TRAINING MATERIALS WILL BE UPDATED AND STATE TRAINING CAPACITY INCREASED. IN YEARS 4-5, TRAINING OF THE TRAINER (TOT) WILL BUILD CAPACITY TO SUSTAIN OUR SBIRT MODEL FOLLOWING THE GRANT. (4) EVALUATE PROCESSES AND OUTCOMES OF THE SBIRT OUTREACH MODEL AND IMPACT ON SERVICE UTILIZATION, SUBSTANCE USE, AND SUICIDE RISK. PROJECT SITES WILL COLLECT DATA BY MONTH 4 AND TRACK THE NUMBER OF SCREENS, BIS, RTS, AND SUICIDE SPECIFIC SCREENINGS AND INTERVENTIONS. BETWEEN BASELINE AND 6-MONTH FOLLOW-UP, OASAS WILL ASSESS CHANGES IN SUBSTANCE USE RESULTING FROM BI, AND STARTING IN YEAR 2, OASAS WILL ASSESS INCREASED IDENTIFICATION OF SUBSTANCE MISUSE RISK AND CONNECTION TO SUD TREATMENT AMONG THE TARGET POPULATIONS AS COMPARED TO A SIMILAR GROUP OF INDIVIDUALS RECEIVING ONLY SCREENING AND REFERRAL.

USE OF ARV DRUG LEVELS IN DBS TO ASSESS AND MANAGE ART ADHERENCE IN SOUTH AFRICA

NEW TECHNOLOGIES TO IDENTIFY MOLECULAR REGULATORS OF THE HUMAN HIPPOCAMPUS NEUROGENIC NICHE IN HEALTHY AGING AND ALZHEIMER'S DISEASE - THE HIPPOCAMPUS NEUROGENIC NICHE (HNN) GENERATES NEW NEURONS IN MAMMALS, BUT IT IS UNCLEAR IF THIS IS HAPPENING IN HUMANS. ADULT HIPPOCAMPAL NEUROGENESIS IS NECESSARY TO MAINTAIN INTACT COGNITIVE AND EMOTIONAL FUNCTIONS REGULATED BY THE HIPPOCAMPUS. MARKERS OF IMMATURITY HAVE BEEN DETECTED IN NEURONAL CELLS OF THE HNN BUT IT IS STILL UNCLEAR IF THEY REPRESENT ADULT-BORN NEURONS, OR NEURONAL CELLS THAT HAVE MAINTAINED THEIR IMMATURITY SINCE BIRTH. WE FOUND THAT THE NUMBER OF NEURAL PROGENITOR CELLS (NPCS) AND IMMATURE NEURONS WAS STABLE THROUGHOUT THE EIGHTH DECADE OF LIFE IN NORMAL AGING (NA) SUBJECTS, BUT ANGIOGENESIS AND NEUROPLASTICITY WERE DECREASED IN OLDER PEOPLE. OTHER GROUPS HAVE SUPPORTED OUR FINDINGS, WHILE SOME COULD NOT DETECT IMMATURE NEURONAL CELLS IN HUMAN HIPPOCAMPUS. MOREOVER, IN AGING MICE, MORE NPCS DIFFERENTIATE INTO GLIA RATHER THAN NEURONS, COMPARED TO YOUNGER ANIMALS, BUT WE DO NOT KNOW IF THIS HAPPENS IN HUMANS. ADULT NEUROGENESIS IS LOWER IN ALZHEIMER’S DISEASE (AD) AND IT IS UNKNOWN IF THIS IS BECAUSE MORE NPCS DIFFERENTIATE INTO GLIA OR THROUGH OTHER MECHANISMS. THESE GAPS IN KNOWLEDGE WARRANT THE USE OF NEW TECHNOLOGIES TO INVESTIGATE CELLULAR LINEAGES IN THE HUMAN HNN, AND MOLECULAR REGULATORS OF NPCS PROLIFERATION, CELL FATE, DIFFERENTIATION, MATURATION AND SURVIVAL. THIS PROJECT AIMS TO IDENTIFY DIFFERENTIALLY EXPRESSED PROTEINS (DEPS) AND GENES (DEGS) IN THE HUMAN HNN, AT THE REGIONAL AND SINGLE CELL LEVEL, COMPARING NA AND AD. WE WILL APPLY OUR PIPELINE USING HIGH RESOLUTION MASS SPECTROMETRY FOR PROTEOMICS ANALYSIS, AND SINGLE NUCLEI (SN) RNA AND ATAC (ASSAY FOR TRANSPOSASE- ACCESSIBLE CHROMATIN) SEQUENCING (SEQ), TO IDENTIFY GENE EXPRESSION AND EPIGENETIC CHANGES. IN SLIDE-MOUNTED HIPPOCAMPUS TISSUE, WE WILL APPLY VISIUM (10X GENOMICS) AND OUR CUSTOM-MADE SPATIAL TRANSCRIPTOMIC TECHNOLOGY FOR ANATOMICAL CO-MAPPING OF CELL-TYPE SPECIFIC MRNAS AND PROTEINS (DBIT-SEQ). NOVEL COMPUTATIONAL APPROACHES WILL IDENTIFY NEUROGENESIS REGULATORS IN THE HUMAN HNN THAT CAN BE TESTED IN CELLULAR OR ANIMAL MODELS. FINDINGS OBTAINED WITH THESE “OMICS” APPROACHES WILL BE VALIDATED USING HIGHPLEX RNASCOPE® (ADCBIO) AND IMMUNOFLUORESCENCE, AND QPCR, WESTERN BLOTS, AND ELISA ASSAYS, TO VISUALIZE AND QUANTIFY DEP AND DEG EXPRESSION AT THE SINGLE CELL AND REGIONAL LEVEL. OUR RIGOROUS BRAIN COLLECTION METHODS ASSURE TISSUE QUALITY, UNIFORM PROCESSING, USE OF TOXICOLOGY AND NEUROPATHOLOGY, AND STRICT CLINICAL INCLUSION/EXCLUSION CRITERIA. GROUPS INCLUDE: NA SUBJECTS (N=100), BRAAK STAGE 0-1, AGE 14-99 YRS., 40 OF WHICH (60 YEARS OF AGE AND OLDER) ARE MATCHED (BY AGE, SEX AND POSTMORTEM INTERVAL BETWEEN DEATH AND BRAIN COLLECTION) WITH 40 AD CASES (FROM THE COLUMBIA TAUB INSTITUTE COLLECTION), BRAAK STAGE 1 THROUGH 4. AIMS: 1. IDENTIFY HNN DEPS ASSOCIATED WITH NA AND AD. 2. IDENTIFY DEGS IN IMMATURE AND MATURE NEURONAL AND GLIAL CELL POPULATIONS OF THE DG IN NA AND AD SUBJECTS, USING SN-RNA AND SN-ATAC-SEQ (10X GENOMICS). 3. DETERMINE THE ANATOMICAL LOCALIZATION OF CELL EXPRESSING DEGS AND DEPS ASSOCIATED WITH NA AND AD, USING VISIUM AND DBIT-SEQ. 4. TEST CORRELATIONS BETWEEN DEPS AND DEGS, AND NUMBERS OF NPCS AND IMMATURE NEURONS AND GLIA IN NA AND AD.

COGNITIVE CONTROL IN CHILDREN OF SUD PARENTS: A LONGITUDINAL MULTIMODAL MRI STUDY

CELLULAR MECHANISMS OF ANTIDEPRESSANT ACTION

PRENATAL FACTORS AND RISK OF SCHIZOPHRENIA IN A FINNISH NATIONAL BIRTH COHORT

OLANZAPINE VERSUS PLACEBO IN OUTPATIENTS WITH ANOREXIA NERVOSA

COGNITIVE AND NEURAL MECHANISMS OF THE ACCELERATED AGING PHENOTYPE IN PTSD

THE NEUROBIOLOGY OF SUICIDAL BEHAVIOR

BREAKING THE CYCLE OF INTERGENERATIONAL DISADVANTAGE: NEURODEVELOPMENT AMONG PUERTO RICAN CHILDREN.

PATH

IDENTIFYING REPRODUCIBLE BRAIN SIGNATURES OF OBSESSIVE-COMPULSIVE PROFILES

IMPACT OF MEDICAL AND RECREATIONAL MARIJUANA LAWS ON CANNABIS, OPIOIDS AND PSYCHIATRIC MEDICATIONS: NATIONAL STUDY OF VA PATIENTS, 2000 -2024

1/7 CLOZAPINE FOR THE PREVENTION OF VIOLENCE IN SCHIZOPHRENIA: A RANDOMIZED CLINICAL TRIAL - WHILE MOST PEOPLE WITH PSYCHOSIS ARE NOT DANGEROUS AND MOST VIOLENCE IS COMMITTED BY NON-PSYCHOTIC PEOPLE, PEOPLE WITH PSYCHOTIC DISORDERS ARE AT INCREASED RISK FOR VIOLENCE, AND VIOLENCE IS ASSOCIATED WITH WORSE OUTCOMES AND INCREASED STIGMA. THEREFORE, DECREASING VIOLENCE RISK IN PSYCHOSIS IS CLINICALLY RELEVANT AND HAS IMPORTANT PUBLIC HEALTH IMPLICATIONS. SEVERAL CLINICAL STUDIES SUGGEST THAT CLOZAPINE IS SUPERIOR TO OTHER ANTIPSYCHOTIC MEDICATIONS IN REDUCING VIOLENCE OR AGGRESSION. HOWEVER, THERE WERE NUMEROUS LIMITATIONS OF THESE STUDIES INCLUDING THAT MOST OF THEM WERE OBSERVATIONAL AND NON-RANDOMIZED, INCLUDED SMALL SAMPLE SIZES, OR FOCUSED ON HOSTILITY, NON-PHYSICAL AGGRESSION, OR SELF-HARM, RATHER THAN VIOLENT ACTS. FURTHER, THE MAJORITY OF THESE TRIALS WERE NOT GENERALIZABLE TO OUTPATIENT, COMMUNITY SETTINGS. NO LARGE EFFECTIVENESS STUDY HAS EXAMINED THE EFFECTS OF CLOZAPINE ON VIOLENT BEHAVIOR IN COMMUNITY SETTINGS. WE PROPOSE A RANDOMIZED, PARALLEL-GROUP, 24-WEEK, OPEN-LABEL, SINGLE (RATER)-BLIND, 7-SITE CLINICAL TRIAL TO EXAMINE THE EFFECTS OF TREATMENT WITH CLOZAPINE VS. TREATMENT AS USUAL (TAU) ON THE RISK OF VIOLENT ACTS IN 280 INDIVIDUALS WITH SCHIZOPHRENIA AT HIGH RISK FOR VIOLENCE. THIS TRIAL WILL BE A COLLABORATION OF 7 SITES, COORDINATED BY THE NEW YORK STATE PSYCHIATRIC INSTITUTE. THE 6 ADDITIONAL COLLABORATING SITES CONTRIBUTE UNIQUE EXPERTISE AND WILL ENSURE AN ADEQUATE SAMPLE SIZE FOR THIS TRIAL. OUR PRIMARY EFFECTIVENESS OUTCOME IS TIME TO VIOLENT ACTS AS MEASURED BY THE MACARTHUR COMMUNITY VIOLENCE INTERVIEW (MCVI). WE WILL ALSO EXPLORE THE EFFECTS OF CLOZAPINE ON THE POINT SUBTRACTION AGGRESSION PARADIGM. WHILE MANY FACTORS MAY CONTRIBUTE TO VIOLENT BEHAVIOR IN INDIVIDUALS WITH SCHIZOPHRENIA, INCLUDING POSITIVE SYMPTOMS, PSYCHOPATHY, IMPULSIVITY, AND SUBSTANCE USE, EVIDENCE SUGGESTS THAT THE FINAL COMMON PATHWAY FOR MANY OF THESE DISPARATE CAUSAL INFLUENCES LIKELY RUNS THROUGH BEHAVIORS CAPTURED BY THE EXCITEMENT FACTOR OF THE POSITIVE AND NEGATIVE SYNDROME SCALE (I.E., A COMPOSITE OF THE SCORES OF EXCITEMENT, UNCOOPERATIVENESS, POOR IMPULSE CONTROL, AND HOSTILITY). IMPORTANTLY, OUR TARGET (THE EXCITEMENT FACTOR OF THE PANSS) HAS BEEN VALIDATED TO MEASURE EXCITEMENT-LIKE SYMPTOMS IN CLINICAL TRIALS IN SCHIZOPHRENIA, IS SENSITIVE TO TREATMENT, HAS BEEN LINKED TO THE NEUROBIOLOGY OF VIOLENCE IN SPECTROSCOPY AND PET STUDIES, AND DIFFERENTIATES CLOZAPINE FROM OTHER ANTIPSYCHOTIC DRUGS. WE WILL ALSO EXPLORE THE EFFECTS OF CLOZAPINE VS. TAU ON POSITIVE SYMPTOMS (E.G., PERSECUTORY DELUSIONS) AND ALCOHOL AND SUBSTANCE USE, AND HOW THESE EFFECTS INFLUENCE THE RISK FOR VIOLENT ACTS. TO ENHANCE THE SAFE IMPLEMENTATION OF THIS STUDY IN THIS VULNERABLE POPULATION AT RISK OF VIOLENT BEHAVIORS, WE WILL IMPLEMENT CLINICAL SAFETY AND TREATMENT ENGAGEMENT PROTOCOLS THAT RELY UPON STANDARD PERSONNEL AND THAT WILL BE READILY GENERALIZABLE. THIS TRIAL WILL PROVIDE GUIDANCE ON THE USE OF CLOZAPINE FOR VIOLENCE IN COMMUNITY SETTINGS AND WILL DEFINITIVELY TEST HYPOTHESES REGARDING MECHANISMS OF ITS ANTI-VIOLENCE EFFECTS. THE RESULTS WILL BE IMMEDIATELY RELEVANT TO PRACTICE AND WILL IMPACT PUBLIC HEALTH BECAUSE THERE IS CURRENTLY NO STANDARD APPROACH FOR THE TREATMENT OF VIOLENCE IN SCHIZOPHRENIA.

POSTMORTEM NEUROCHEMICAL STUDIES IN SUICIDE

REGION 2 ATTC: NJ, NY, PR & THE U.S. VI

IMPROVING LIFE TRAJECTORIES FOR YOUTH WITH EARLY PSYCHOSIS

THE IMPACT OF 9/11 ON YOUTH: MENTAL HEALTH, SUBSTANCE USE & OTHER RISK BEHAVIORS

CAPITAL CONNECT - EACH YEAR, APPROXIMATELY 1,700 NEW YORKERS DIE BY SUICIDE, RANKING NEW YORK STATE (NYS) 6TH IN THE NATION FOR OVERALL SUICIDE BURDEN. BETWEEN 2000 AND 2020, THE SUICIDE RATE IN NYS INCREASED 35.6%, FROM 5.9 TO 8.0 PER 100,000 POPULATION, SURPASSING ANNUAL DEATH RATES BY HOMICIDE AND MOTOR VEHICLE ACCIDENTS. IN 2019 THERE WERE AN ESTIMATED 42,600 SUICIDE ATTEMPTS AMONG NEW YORKERS LEADING TO 22,430 HOSPITALIZATIONS AND EMERGENCY DEPARTMENT VISITS. FROM 2015-2019, IT IS ESTIMATED THAT 565,000 NEW YORKERS HAD SUICIDAL THOUGHTS ANNUALLY. THE SCALE OF THE PROBLEM IS GREATLY EXPANDED BY THE GRIEF OF FRIENDS AND FAMILY MEMBERS OF THOSE WHO ATTEMPTED OR DIED BY SUICIDE. COVID-19’S ONGOING IMPACT IN NYS ADDS TO THE PROBLEM. AS OF MAY 21, 2022, THERE HAVE BEEN 5,346,809 INFECTIONS AND 55,917 DEATHS RESULTING FROM COVID-19. RESEARCH CONDUCTED DURING THE PANDEMIC REVEALS SIGNS OF BROAD INCREASES IN MENTAL DISTRESS ACROSS THE POPULACE, BUT PARTICULARLY AMONG YOUTH. HOWEVER, COVID-19’S FULL IMPACT ON MENTAL HEALTH AND SUICIDE RISK IS NOT WELL UNDERSTOOD. CONTINUED MONITORING ON SUICIDE RISK IS IMPERATIVE. THE NYS OFFICE OF MENTAL HEALTH (OMH) REQUESTS FUNDING TO IMPLEMENT A COMPREHENSIVE, MULTI-TIERED APPROACH TO SUICIDE PREVENTION IN ALBANY, RENSSELAER, SARATOGA, AND SCHENECTADY COUNTIES, A FOUR-COUNTY REGION IN THE HEART OF THE NEW YORK’S CAPITAL DISTRICT WHERE SUICIDE MORBIDITY AND MORTALITY EXCEED STATE AVERAGES. THE PROPOSED INITIATIVE IS CALLED CAPITAL CONNECT, AS IT AIMS TO PROVIDE CRITICAL SUPPORT AND FOSTER CONNECTION AMONG THE MOST AT-RISK. OMH PROPOSES TARGETING TWO POPULATIONS FOUND TO BE AT PARTICULARLY HIGH-RISK BASED ON NYS SURVEILLANCE DATA: ADOLESCENT GIRLS (AGED 10-19) AND WORKING-AGED MEN (AGED 25-64). OMH WILL UTILIZE A DATA-DRIVEN APPROACH FOR SUICIDE PREVENTION WITH THE PRIMARY GOAL OF REDUCING SUICIDE MORBIDITY AND MORTALITY IN THESE DISPROPORTIONALLY AFFECTED POPULATIONS BY 10% OVER THE FIVE-YEAR GRANT PERIOD. SECONDARY GOALS INCLUDE INCREASING ACCESS TO EVIDENCE-BASED SUICIDE PREVENTION INTERVENTIONS WITH AN ASSOCIATED REDUCTION IN DISPARITIES WITHIN THE CATCHMENT AREA. THE PROPOSED APPROACH WILL BE RIGOROUSLY EVALUATED WITH A FOCUS ON CONTINUOUS QUALITY IMPROVEMENT AND SUSTAINED IMPACT. IN PURSUING IMPLEMENTATION OF THE PROPOSED PROJECT IN THE FOUR-COUNTY JURISDICTION, AN EXPLICIT AIM IS TO TEST THE FEASIBILITY OF A MODEL WITH STATEWIDE SCALING POTENTIAL. LED BY THE OMH SUICIDE PREVENTION CENTER OF NEW YORK IN CLOSE PARTNERSHIP WITH THE NYS DEPARTMENT OF HEALTH, THE PROJECT WILL LEVERAGE AND STRENGTHEN A MULTI-SECTORAL PARTNERSHIP PLAN THAT INCLUDES PARTNERS IN STATE AND LOCAL GOVERNMENT, ACADEMIA, JUVENILE JUSTICE, SCHOOLS, LOCAL HOSPITALS AND PRIMARY CARE CLINICS, CRISIS SERVICES, ADVOCATES, THE LIVED EXPERIENCE COMMUNITY, AND A SUICIDE PREVENTION DIGITAL TECHNOLOGY START-UP FIRM. REGULARLY REVIEWING THE LATEST SURVEILLANCE DATA TO GUIDE EFFORTS, PARTNERS WILL IMPLEMENT NINE SEPARATE EMPIRICALLY SUPPORTED APPROACHES TO CARRY OUT A COMPREHENSIVE APPROACH TO SUICIDE PREVENTION.

PHENOTYPES FOR DRUG ABUSE:EPIDEMIOLOGIC-GENETIC APPROACH

LONGITUDINAL ASSESSMENT OF NEURAL CIRCUITS IN ADOLESCENTS WITH ANOREXIA NERVOSA

SINGLE-CELL AND TARGET-SPECIFIC RESOLUTION OF MULTIPLE MEMORIES ACROSS THE BRAIN

CRISIS COUNSELING

PATERNAL CRIMINAL JUSTICE INVOLVEMENT AND SUBSTANCE USE IN CHILDREN & ADOLESCENTS

TEMPORAL DYNAMICS OF NEUROPHYSIOLOGICAL PATTERNS AS TREATMENT TARGETS IN SZ

SOCIAL CONVOYS, COGNITIVE RESERVE AND RESILIENCE, AND RISK FOR ALZHEIMER'S DISEASE AND RELATED DEMENTIAS

MRI: DEVELOPMENT OF A NEXT GEN 9.4T MAGNETIC RESONANCE SYSTEM FOR TRANSLATIONAL NEUROSCIENCE

CELLULAR MECHANISMS OF ANTIDEPRESSANT ACTION

SOCIAL PROCESSING DEFICITS IN REMITTED ADOLESCENT DEPRESSION

THE NKI ROCKLAND SAMPLE II: AN OPEN RESOURCE OF MULTIMODAL BRAIN, PHYSIOLOGY & BEHAVIOR DATA FROM A COMMUNITY LIFESPAN SAMPLE - ABSTRACT. THE PRESENT COMPETING RENEWAL APPLICATION PROPOSES TO CREATE THE NEXT GENERATION NKI-ROCKLAND SAMPLE (NKI-RS) INITIATIVE. THE NKI-ROCKLAND SAMPLE (NKI-RS) HAS SERVED AS A BEACON FOR LIFESPAN CONNECTOMICS RESEARCH, PROVIDING A MODEL FOR ACCELERATING THE PACE OF PSYCHIATRIC DISCOVERY SCIENCE. MORE THAN 200 PUBLICATIONS HAVE USED NKI-RS, GENERATED LARGELY BY INDEPENDENT INVESTIGATORS AND IN MAJOR JOURNALS. SINCE 2011, IT HAS GENERATED AND PUBLICLY SHARED (ON A QUARTERLY BASIS) A LARGE-SCALE (N > 1400), DEEPLY PHENOTYPED, COMMUNITY-ASCERTAINED, CROSS-SECTIONAL, LIFESPAN SAMPLE (AGES 6–85 YEARS OLD) WITH ADVANCED CONNECTOMICS- FOCUSED NEUROIMAGING (I.E., DIFFUSION MRI, RESTING STATE FMRI [R-FMRI]) AND GENETIC SAMPLES. RECENTLY LAUNCHED LARGE- SCALE EFFORTS, SUCH AS THE HCP LIFESPAN STUDIES AND THE NIH ABCD STUDY ARE WORKING TO BRING TO SCALE HUMAN CONNECTOME MAPPING AND BRAIN FUNCTION ACROSS THE LIFESPAN, USING ‘BATTLE-TESTED’ IMAGING TECHNOLOGIES AND STRATEGIES. THESE ONGOING STUDIES ARE LESS FOCUSED ON MENTAL HEALTH. MOREOVER, TECHNOLOGIES AND IDEAS CONTINUE TO EVOLVE - OFTEN TOO RAPIDLY TO PERMIT TIMELY TESTING AND INCLUSION IN ONGOING RESEARCH. THE OVERARCHING GOAL OF THE PRESENT PROPOSAL IS TO CREATE THE NEXT GENERATION NKI-RS INITIATIVE THAT WILL ONCE AGAIN EXTEND THE VANGUARD IN THE STUDY OF LIFESPAN CONNECTOMICS BY ENRICHING AND EXPANDING THE LANDSCAPE FOR NEUROSCIENTIFIC ADVANCEMENT AND BIOMARKER DISCOVERY. THREE MAJOR THEMES HAVE GUIDED THE DESIGN OF THE PROPOSED NKI-RS-II LIFESPAN RESOURCE: 1) MULTIMODAL MEASUREMENT INTEGRATION ACROSS FUNCTIONAL DOMAINS (E.G., FMRI, EEG, MOBILE BRAIN/BODY IMAGING [MOBI] FRAMEWORK), 2) ECOLOGICAL SAMPLING (E.G., WEARABLES, SENSORS, SMARTPHONES APPS), AND 3) ENHANCED PHYSIOLOGICAL PHENOTYPING FOR CARDIOVASCULAR FITNESS AND OBESITY. SPECIFICALLY, IN A COMMUNITY- ASCERTAINED LIFESPAN SAMPLE (N=600; AGES 9-75; M: F = 1:1; AGE RANGE SELECTED TO MAXIMIZE DATA YIELD AND TOLERABILITY), THE PROPOSED WORK AIMS TO: 1) GENERATE AND SHARE LARGE-SCALE MULTIMODAL MRI/EEG IMAGING DATA COMPLEMENTED BY COMPREHENSIVE PHENOTYPING OF COGNITION, BEHAVIOR, AND PSYCHIATRIC STATUS, FROM HUMAN AND SENSOR-BASED INFORMANTS; 2) OPTIMIZE BRAIN-AGE PREDICTION ACROSS THE LIFESPAN USING MULTIMODAL DATA (R-FMRI, NATURALISTIC VIEWING FMRI [NV-FMRI], DMRI, T2/T1, R-EEG, NV-EEG) AND RELATE DEVIATIONS FROM CHRONOLOGICAL AGE TO DIMENSIONS OF PSYCHOPATHOLOGY AND COGNITIVE PERFORMANCE; AND 3) IDENTIFY THE RELATIONSHIP OF MODIFIABLE HEALTH RISK FACTORS (E.G., FITNESS, OBESITY, PHYSICAL ACTIVITY, SUBSTANCE USE) TO DEVIATIONS BETWEEN PREDICTED BRAIN AGE AND CHRONOLOGICAL AGE ACROSS THE LIFESPAN. CONSISTENT WITH THE MODEL ESTABLISHED BY THE PREVIOUSLY FUNDED NKI-RS INITIATIVES, ALL DATA WILL BE SHARED PROSPECTIVELY, ON A QUARTERLY BASIS, VIA THE INTERNATIONAL NEUROIMAGING DATA-SHARING INITIATIVE (INDI) AND THE NIMH DATA ARCHIVE (NDA).

MATERNAL INCARCERATION AND COURSE OF CHILD PSYCHOPATHOLOGY IN THE SOUTH BRONX

LONGITUDINAL DISCOVERY OF BRAIN DEVELOPMENTAL TRAJECTORIES

NYS OASAS PREVENTION OF OVERDOSE THROUGH OUTREACH TO FAMILIES - THE NEW YORK STATE OFFICE OF ADDICTION SERVICES AND SUPPORTS (NYS OASAS) PREVENT PRESCRIPTION DRUG/OPIOID OVERDOSE-RELATED DEATHS PROJECT, TITLED PREVENTION OF OVERDOSE THROUGH OUTREACH TO FAMILIES (POOF) WILL EXPAND AND ENHANCE OVERDOSE PREVENTION SERVICES IN NEW YORK. TO THAT END, OASAS WILL COLLABORATE WITH THE PARTNERSHIP TO END ADDICTION TO CREATE A COMPREHENSIVE OVERDOSE PREVENTION TRAINING. OVER THE COURSE OF FIVE YEARS, OASAS WILL PARTNER WITH THE NEW YORK STATE DEPARTMENT OF HEALTH (DOH) AND THE NEW YORK STATE OFFICE OF CHILDREN AND FAMILY SERVICES (OCFS) IN ORDER TO PROVIDE THIS TRAINING AND NALOXONE TO THEIR FRONTLINE STAFF IN PROGRAMS SUCH AS OCFS MANAGED DOMESTIC VIOLENCE SHELTERS, HEALTHY FAMILIES NEW YORK HOME VISITING PROGRAM, AND THE MATERNAL AND INFANT COMMUNITY HEALTH COLLABORATIVES. FURTHERMORE, THE SAMHSA TOOLKIT FOR OPIOID OVERDOSE PREVENTION WILL BE UTILIZED TO GUIDE THIS PROCESS. THROUGH THIS WORK, WE HOPE TO REACH UNDERSERVED POPULATIONS BY FOCUSING ON NONTRADITIONAL TREATMENT SETTINGS, INCLUDING BUT NOT LIMITED TO PREGNANT AND PARENTING WOMEN, LGBTQ+ IDENTIFIED PERSONS, TRIBAL COMMUNITIES, AND PERSONS EXPERIENCING INTIMATE PARTNER VIOLENCE. IT IS EXPECTED IN THE FIRST YEAR OF THE GRANT TO TRAIN A TOTAL OF 750 INDIVIDUALS IN OVERDOSE PREVENTION. IN YEAR TWO, THIS NUMBER WILL INCREASE TO 3,000, AND THEREAFTER 4,000 PEOPLE WILL BE TRAINED PER YEAR FOR A TOTAL OF 15,750 UNDUPLICATED PERSONS TRAINED BY THE END OF YEAR 5. OASAS WILL DEVELOP SYSTEMS AND PROCEDURES DEEMED NECESSARY TO SUSTAIN THESES PROPOSED SERVICES BEYOND THE FIVE-YEAR GRANT PERIOD TO CONTINUE EXPANDING PREVENTION SERVICES. SPECIFIC GOALS OF THE PREVENTION OF OVERDOSE THROUGH OUTREACH TO FAMILIES INCLUDE: (1) IDENTIFY AREAS OF GREATEST NEED IN RELATION TO PRESCRIPTION DRUG/OPIOID OVERDOSE IN NEW YORK, (2) INCREASE ACCESS TO OPIOID AND PRESCRIPTION DRUG OVERDOSE AND KNOWLEDGE OF OVERDOSE TRAINING IN NEW YORK, (3) INCREASE THE NUMBER OF OPIOID OVERDOSE PREVENTION MASTER TRAINERS IN NONTRADITIONAL SETTINGS, (4) INCREASE ACCESS TO OVERDOSE PREVENTION TRAININGS AND RESOURCES IN NONTRADITIONAL, NON-OASAS SETTINGS, AND (5) INCREASE ACCESS TO AND AWARENESS OF TREATMENT SERVICES.

LONG-LASTING CONSEQUENCES OF EARLY ETHANOL ON NETWORK ACTIVITY DURING SLEEP

INVESTIGATING THE ROLE OF HIPPOCAMPUS - ORBITOFRONTAL CIRCUITS FOR COGNITIVE FLEXIBILITY - PROJECT SUMMARY COGNITIVE FLEXIBILITY ALLOWS AN INDIVIDUAL TO ADAPT ESTABLISHED THINKING PATTERNS AND BEHAVIORAL RESPONSES TO NOVEL SITUATIONS THAT MAY REQUIRE NEW APPROACHES THAN THOSE THAT WERE PREVIOUSLY LEARNED IN ORDER TO BE SOLVED CORRECTLY. COGNITIVE FLEXIBILITY IS THEREFORE NECESSARY TO FLEXIBLY ADJUST ONES THINKING AND BEHAVIOR INSTEAD OF RUMINATING OVER THOUGHTS AND WORRIES, OR INSTEAD OF SHOWING HABITUAL BEHAVIOR THAT MAY NOT BE PRODUCTIVE TO EFFECTIVELY ENGAGE WITH A NEW SITUATION OR TO SOLVE A NEW PROBLEM. IMPAIRMENTS IN COGNITIVE FLEXIBILITY CAN OCCUR AS A RESULT OF CHRONIC STRESS, WHICH IS A MAJOR CONTRIBUTOR TO THE PATHOGENESIS OF MANY PSYCHIATRIC DISORDERS. ACCORDINGLY, COGNITIVE FLEXIBILITY DEFICITS ARE COMMON ACROSS A WIDE RANGE OF MENTAL ILLNESSES AND OFTEN UNRESPONSIVE TO OTHERWISE EFFECTIVE MEDICATION. MOREOVER, INDIVIDUALS WITH HIGH LEVELS OF COGNITIVE FLEXIBILITY HAVE BEEN SHOWN TO COPE BETTER WITH DAY-TO-DAY STRESSORS, AND TO BE LESS VULNERABLE TO DEVELOPING PSYCHIATRIC DISORDERS. IF WE CAN UNDERSTAND THE NEURAL CIRCUITS UNDERLYING COGNITIVE FLEXIBILITY, WE MAY BE ABLE TO IDENTIFY NEW TARGETS FOR ADVANCED THERAPEUTICS TO TREAT THE DEBILITATING COGNITIVE IMPAIRMENTS OF MANY PSYCHIATRIC DISORDERS. IN THIS PROPOSAL, WE WILL STUDY A NOVEL NEURAL CIRCUIT COMPONENT UNDERLYING ONE IMPORTANT FORM OF COGNITIVE FLEXIBILITY: REVERSAL LEARNING. WE WILL SPECIFICALLY INVESTIGATE HOW NEURAL PROJECTIONS FROM THE VENTRAL HIPPOCAMPUS TO THE ORBITOFRONTAL CORTEX (OFC) REGULATE REVERSAL LEARNING AND STRESS RESILIENCE. IN AIM 1, WE WILL INHIBIT DIRECT INPUT PROJECTIONS FROM THE VENTRAL HIPPOCAMPUS TO THE MEDIAL OFC, AND OUTPUT PROJECTIONS FROM THE MEDIAL OFC TO THE LATERAL OFC, TO TEST IF THIS CIRCUIT IS FUNCTIONALLY IMPORTANT FOR REVERSAL LEARNING. IN AIM 2, WE WILL USE IN VIVO CA2+ IMAGING OF NEURAL ACTIVITY IN VENTRAL HIPPOCAMPUS, MEDIAL OFC, AND LATERAL OFC, TO EXAMINE FOR THE FIRST TIME HOW NEURONS IN THESE BRAIN REGIONS STORE, PROCESS, AND UPDATE INFORMATION ABOUT ACTION-OUTCOME VALUE ASSOCIATIONS THAT ARE IMPORTANT FOR REVERSAL LEARNING. IN AIM 3, WE WILL THEN INVESTIGATE HOW THESE SAME BRAIN REGIONS BECOME DYSFUNCTIONAL UNDER CONDITIONS OF CHRONIC STRESS, AND IF STIMULATING THIS CIRCUITRY CAN CONFER STRESS RESILIENCE AND COUNTERACT STRESS-INDUCED DEFICITS IN REVERSAL LEARNING. TOGETHER, THESE EXPERIMENTS WILL PROVIDE FIRST INSIGHT INTO A NEW ELEMENT OF THE NEURAL CIRCUITRY UNDERLYING COGNITIVE FLEXIBILITY AND STRESS RESILIENCE, WHICH HAS GREAT POTENTIAL TO REVEAL NEW NEURAL CIRCUIT-BASED TARGETS FOR NOVEL DRUGS OR FOR ADVANCED COGNITIVE-BEHAVIORAL THERAPIES AIMED AT IMPROVING COGNITIVE FLEXIBILITY IN PATIENTS SUFFERING FROM PSYCHIATRIC DISORDERS.

DEFICIENT BELIEF UPDATING AS A CONVERGENT COMPUTATIONAL MECHANISM OF PSYCHOSIS

NEW YORKERS ADVANCING SUICIDE SAFER CARE FOR YOUTH (NYASSC FOR YOUTH)

SUICIDAL BEHAVIOR IN MOOD DISORDERS:GENES AND INTERMEDIATE PHENOTYPES

UNIVERSAL FOR ALL, FREQUENT FOR SOME: HIV TESTING IN SCHOOL-BASED HEALTH CENTERS

CORTICAL-SUBCORTICAL INTERACTION IN PD AND NORMAL SPEECH

HEALTHCALL: ENHANCING BRIEF INTERVENTION FOR HIV PRIMARY CARE ALCOHOL DEPENDENCE

LONG-TERM IMPACT OF WTC ATTACKS IN PRIMARY CARE

THE NEW YORK STATE OFFICE OF MENTAL HEALTH'S ZERO SUICIDE PROJECT

A SEQUENCED BEHAVIORAL AND MEDICATION INTERVENTION FOR COCAINE DEPENDENCE

PERINATAL ASSESSMENT OF AT-RISK POPULATIONS

PIOGLITAZONE FOR THE TREATMENT OF OPIOID AND OF NICOTINE DEPENDENCE

TRANSDUCTION OF PSYCHOLOGICAL STRESS INTO SYSTEMATIC INFLAMMATION BY MITOCHONDRIAL DNA SIGNALING

ADVERSE CHILDHOOD EXPERIENCES, PERSONALITY PSYCHOPATHOLOGY, AND ALCOHOL DISORDERS

PRECRIPTION OPIOID EFFECTS IN DRUG AND NON-DRUG ABUSERS

PARENT-CHILD TRANSMISSION OF TRAUMA IN A LONGITUDINAL COHORT: IMPACT ON AGING-RELATED MENTAL AND PHYSICAL HEALTH WELL-BEING - WE PROPOSE TO CONDUCT A 4TH WAVE OF DATA COLLECTION ON OUR LONGITUDINAL COHORT OF CHILDREN OF 9/11 DIRECTLY-EXPOSED PARENTS (WTC EVACUEES, GROUND ZERO AREA RESIDENTS AND FIRST RESPONDERS). WHILE THE ATTACK ON 9/11 WAS A TRAGEDY ALMOST BEYOND OUR CAPACITY TO ABSORB, THE LONG-TERM, ONGOING MENTAL AND PHYSICAL EFFECTS ON THOSE PRESENT -- AND THEIR FAMILIES – REMAIN, AT LEAST FOR MANY, UNABATED. SOON AFTER 9/11, OUR TEAM RECRUITED WHAT BECAME A LONGITUDINAL COHORT STUDY OF CHILDREN (CURRENTLY AGES 23-42) AND THEIR PARENTS (CURRENTLY AGES 42-88) WHO HAD EXPERIENCED DIRECT EXPOSURE TO THE WORLD TRADE CENTER (WTC) ATTACK, ALONG WITH COMMUNITY CONTROLS. INDIRECTLY EXPOSED CHILDREN CAME TO BE KNOWN AS THOSE EXPERIENCING “TAKE-HOME” EXPOSURE, BEING NOT DIRECTLY EXPOSED THEMSELVES. HAVING LEARNED THROUGH FOLLOW-UP ASSESSMENTS OF THE CRITICAL ROLE DISASTER-EXPERIENCED FAMILY MEMBERS HAVE ON THEIR CHILDREN’S WELL-BEING, AND THE CHILD’S RECIPROCAL ROLE ON THE EXPOSED ADULTS’ WELL-BEING, WE WILL FOCUS THIS FOURTH WAVE ON UNDERSTANDING THE ROLE OF AGING ON THE INTERGENERATIONAL IMPACT OF DISASTER AND ADVERSE EXPERIENCES AND THE ASSOCIATED OUTCOMES OF INTEREST, INCLUDING PSYCHOPATHOLOGY, PHYSICAL AND COGNITIVE WELL-BEING, COMORBIDITIES, AND MITOCHONDRIAL COPY NUMBER AS AN ADVERSITY-RELATED BIOMARKER OF OXIDATIVE STRESS. AS THE OFFSPRING COHORT REACHES MID-LIFE AND THE PARENTS, OLDER ADULTHOOD, THIS STUDY, UTILIZING FOUR WAVES OF DATA, IS EXPECTED TO YIELD IMPORTANT INSIGHTS INTO THE LONG-TERM IMPACT OF ADVERSE EXPERIENCES, THEIR INTERGENERATIONAL IMPACT, AND INFLUENCE ON AGING PROCESSES. THE 9/11-EXPOSED PARENTS AND THEIR INDIRECTLY EXPOSED CHILDREN HAVE BEEN COMPREHENSIVELY ASSESSED THROUGH IN-HOME INTERVIEWS OVER THREE WAVES OF DATA COLLECTION AND THE STUDY HAS AMASSED A WEALTH OF DATA ON LONG-TERM PSYCHIATRIC-PHYSICAL SEQUALAE TO MASS DISASTER EXPOSURE. THESE DATA HAVE PROVEN SIGNIFICANT, NOT ONLY IN UNDERSTANDING THE INDIRECTLY EXPOSED CHILD, BUT ALSO THE CONSEQUENCES TO THE EXPOSED PARENT. DATA FROM THIS LONGITUDINAL COHORT STRONGLY INDICATE THE NEED TO ASSESS BOTH INDIVIDUALS (PARENT AND CHILD) FROM A FAMILY PERSPECTIVE. WE APPRECIATE THAT THIS IS A TIMELY ISSUE, AS PARENTS AGE AND DISPROPORTIONATELY BECOME ILL AND MAY EXPERIENCE PREMATURE MORTALITY. WE PROPOSE, THEREFORE, TO FOCUS ON THE FAMILY UNIT FOR THE PURPOSE OF UNDERSTANDING THE COMPLEX, LONG-TERM IMPACT THAT PARENTAL DIRECT EXPOSURE HAS ON THE HEALTH AND WELL-BEING OF THEIR CHILDREN AND ON THE DIRECTLY EXPOSED PARENTS THEMSELVES. THIS FAMILY AGING STUDY WILL ALLOW THE FOURTH WAVE OF DATA COLLECTION TO EXAMINE TRAJECTORIES OF AGING-RELATED MEDICAL AND MENTAL WELL-BEING INCLUDING COGNITION, COMORBIDITIES, AND MITOCHONDRIAL COPY NUMBER, AS WELL AS EXAMINATION OF INTERGENERATIONAL EFFECTS. THIS COMPREHENSIVE APPROACH WILL IMPROVE UNDERSTANDING OF THE COMPLEX INTERACTIONS OF EMOTIONAL AND TOXIC 9/11 EXPOSURE THAT HAS IMPACTED BOTH THE MENTAL AND PHYSICAL REALMS AND CONTRIBUTED TO COMPLEX COMORBIDITIES AS EACH GROUP AGES. IT IS ANTICIPATED THAT THIS FAMILY AGING STUDY WILL CONTINUE AS A LONGITUDINAL INVESTIGATION OF ADVERSE EXPERIENCES, AND THEIR INTERGENERATIONAL IMPACT ON AGING PROCESSES.

CENTER TO STUDY RECOVERY IN SOCIAL CONTEXTS

DYNAMIC CIRCUIT MOTIFS UNDERLYING MULTIMODAL INTERACTIONS IN PRIMATE AUDITORY CORTEX - ABSTRACT THERE IS A STRONG MOVEMENT WITHIN THE NEUROSCIENCE COMMUNITY TOWARDS STUDYING THE BRAIN UNDER NATURALISTIC CONDITIONS, IN RICH MULTISENSORY PARADIGMS AND IN THE CONTEXT OF BEHAVIORS OBSERVED IN NATURAL ENVIRONMENTS, SUCH AS FREE VIEWING. THIS REQUIRES TRANSFORMING OUR TRADITIONAL DATA COLLECTION AND ANALYSIS PIPELINES, AND THEIR UNDERLYING THEORETICAL FRAMEWORKS. INSTEAD OF FOCUSING ON ONE SPECIFIC SYSTEM SUPPORTING A PARTICULAR BRAIN FUNCTION, WE MUST CONDUCT MULTISITE RECORDINGS TARGETING MULTIPLE, RECIPROCALLY CONNECTED CIRCUITS, WHICH IS THE MAIN MOTIVATION FOR OUR PROJECT. FORTUNATELY, THIS IS NOW TECHNICALLY FEASIBLE IN BOTH HUMAN AND NONHUMAN PRIMATES. THE OVERARCHING GOAL OF OUR PROJECT IS TO DEFINE INFORMATION TRANSMITTING (“DRIVING”) VS. “MODULATORY” CIRCUITS OF THE AUDITORY SYSTEM. THE RATIONALE FOR THIS GOAL IS THAT IF ONLY DRIVING CIRCUITS EXISTED IN THE BRAIN, WE WOULD NOT HAVE THE ABILITY TO FOCUS ON BEHAVIORALLY RELEVANT ASPECTS OF OUR ENVIRONMENT. FROM THIS PERSPECTIVE, MODULATORY CIRCUITS PLAY AS AN IMPORTANT ROLE IN BRAIN OPERATIONS AS INFORMATION TRANSMITTING ONES. SPECIFICALLY, OUR PROJECT WILL EXPLORE THE INTERACTION OF FOUR DOMAINS OF BRAIN FUNCTION AND THE DISTINCTIVE, DYNAMIC CIRCUIT MOTIFS (CIRCUITS AND THEIR SPECTROTEMPORAL NEURONAL ACTIVITY PATTERNS) THAT UNDERLIE THEM. THESE BRAIN FUNCTIONS ARE AUDITORY PERCEPTION, MULTISENSORY INTERACTIONS WITHIN THE AUDITORY SYSTEM, MOTOR SAMPLING OF THE ENVIRONMENT (EYE MOVEMENTS), AND MEMORY RECALL. WE WILL UTILIZE ELECTROPHYSIOLOGICAL RECORDINGS DURING BEHAVIORAL EXPERIMENTS IN NON-HUMAN AND HUMAN PRIMATES, WITH COMPUTATIONAL MODELING TO BRIDGE THE GAP BETWEEN DIFFERENT RECORDING SCALES (SINGLE UNIT TO EEG), AND SPECIES (NON-HUMAN PRIMATE VS. HUMAN). COMPUTATIONAL MODELS WILL ALSO BE USED TO SUGGEST SPECIFIC TARGET NODES AND PATTERNS OF THE DISTINCT CIRCUITS FOR NEUROMODULATION. USING THE SPECTROTEMPORAL NEURONAL ACTIVITY (A KEY FEATURE OF A DYNAMIC CIRCUIT MOTIF) AND MODEL PREDICTION BASED INTRACRANIAL ELECTRICAL BRAIN STIMULATION, WE WILL VERIFY EACH IDENTIFIED CIRCUIT’S CAUSAL ROLE IN PRODUCING ITS UNIQUE CIRCUIT MOTIFS AND IN SUPPORTING DIFFERENT ASPECTS OF BEHAVIOR.

PHASE 1 AND 2 STUDIES OF SUBLINGUAL DEXMEDETOMIDINE, AN ALPHA 2 ADRENERGIC AGONIST, FOR TREATING OPIOID WITHDRAWAL - PROJECT SUMMARY THE CURRENT EPIDEMIC OF OPIOID USE DISORDER (OUD) IS A SEVERE PUBLIC HEALTH CRISIS IN THE US, AND IN RESPONSE, THE NATIONAL INSTITUTES OF HEALTH (NIH) IS SUPPORTING DEVELOPMENT OF INNOVATIVE MEDICATIONS FOR TREATING OUD. THE WITHDRAWAL SYMPTOMS ASSOCIATED WITH CESSATION OF OPIOID USE ARE SERIOUS OBSTACLES TO INITIATING OPIOID BLOCKERS (NALTREXONE) AND MAY POSE DIFFICULTIES IN TRANSITIONING PATIENTS TO OTHER MEDICATIONS FOR TREATING OPIOID USE DISORDER (MOUD), SUCH AS BUPRENORPHINE. THE FDA APPROVAL OF THE ALPHA-2-ADRENERGIC AGONIST LOFEXIDINE HAS MADE A SIGNIFICANT CONTRIBUTION TO AMELIORATING OUD WITHDRAWAL, BUT ONLY 40% OF SUBJECTS BECAME OPIOID FREE IN A PIVOTAL STUDY. THIS STUDY WAS CONDUCTED PRIOR TO THE WIDESPREAD AVAILABILITY OF THE POTENT SYNTHETIC OPIOID FENTANYL, SO THE EFFECTIVENESS OF LOFEXIDINE IN TREATING OPIOID WITHDRAWAL IN FENTANYL-DEPENDENT PATIENTS IS UNCLEAR. BIOXCEL HAS DEVELOPED ANOTHER ALPHA-2-ADRENERGIC AGONIST DEXMEDETOMIDINE AS A SUBLINGUAL (SL) FILM (BXCL501). BXCL501 IS POTENTIALLY SUPERIOR TO ALTERNATIVES SUCH AS OPIOID TAPERING BECAUSE IT IS A NON-OPIOID WITH MINIMAL ABUSE POTENTIAL, AND AT DOSES THAT REDUCE OPIOID WITHDRAWAL SYMPTOMS, IT HAS MINIMAL ADVERSE EFFECTS ON RESPIRATION, HYPOTENSION, HYPERTENSION, BRADYCARDIA, AND SEDATION. FURTHERMORE, IT AVOIDS POTENTIAL LIVER COMPLICATIONS DUE TO BYPASSING FIRST-PASS METABOLISM. DATA COLLECTED DURING A RECENTLY COMPLETED MULTIPLE ASCENDING DOSE SAFETY AND PRELIMINARY EFFICACY STUDY SHOWED THAT THE HIGHEST DOSE OF BXCL501 TESTED REDUCED ANXIETY AND IMPROVED SLEEP DISTURBANCES, WHICH ARE SYMPTOMS THAT ARE TYPICALLY NOT WELL TREATED WITH LOFEXIDINE. IN THE PROPOSED STUDIES, BXCL501 WILL BE TESTED FOR ITS ABILITY TO DECREASE THE SIGNS AND SYMPTOMS OF OPIOID WITHDRAWAL ACROSS MULTIPLE SITES THROUGH TWO SPECIFIC AIMS: 1 (UG3). A PHASE 1B RANDOMIZED, DOUBLE- BLIND, PLACEBO-CONTROLLED SAFETY, OPTIMAL DOSE FINDING, AND PRELIMINARY EFFICACY INPATIENT STUDY (N=160), AND 2 (UH3). A PHASE 2B RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED OUTPATIENT STUDY COMPARING THE SAFETY AND EFFICACY OF BXCL501 TO PLACEBO AND LOFEXIDINE (N=300). TWO GO/NO-GO CRITERIA FOR MOVING FROM THE UG3 TO THE UH3 PHASES ARE: 1) BXCL501 IS SHOWN TO REDUCE WITHDRAWAL SYMPTOMS (TOTAL SOWS SCORE) MORE THAN 30% COMPARED TO THE SOWS SCORE OF SUBJECTS RECEIVING PLACEBO. 2) NO MORE THAN ONE SERIOUS ADVERSE EVENT ATTRIBUTED TO BXCL501 AMONG THE SUBJECTS RECEIVING ACTIVE BXCL AT THE MINIMUM DOSE IDENTIFIED TO EXHIBIT AT LEAST A 30% REDUCTION IN WITHDRAWAL SYMPTOMS. OUR POSITIVE CLINICAL FINDINGS WITH BXCL501 AND STRONG INVESTIGATIVE TEAM PROMISE HIGH SUCCESS FOR BRINGING THIS NEW TREATMENT TO MARKET.

METABOLIC REGULATION OF HUMAN DNA METHYLATION CLOCKS

ENDOCANNABINOID SIGNALING IN POSTNATAL ETHANOL EFFECTS

SUBSTANCE USE/ABUSE & HIV/STI RISK BEHAVIORS IN PUERTO RICAN YOUTH GROWING UP

THE NEUROBIOLOGY OF VIOLENCE IN A PSYCHOSIS-RISK COHORT

THE CB1 SIGNALING-SPECIFIC INHIBITOR, AEF0117, FOR CANNABIS USE DISORDER: A MULTI-SITE TREATMENT TRIAL - ENTER THE TEXT HERE THAT IS THE NEW ABSTRACT INFORMATION FOR YOUR APPLICATION. THIS SECTION MUST BE NO LONGER THAN 30 LINES OF TEXT. PROJECT SUMMARY: CANNABIS USE DISORDER (CUD) IS A SIGNIFICANT AND ESCALATING PROBLEM IN THE UNITED STATES, AND THE DEVELOPMENT OF AN EFFICACIOUS MEDICATION IS A PUBLIC HEALTH PRIORITY. THE GOAL OF THIS PROPOSAL IS TO CONDUCT THE COMPLEMENTARY DEVELOPMENT AND PHARMACOKINETIC STUDIES NECESSARY TO SUPPORT PHASE 3 TRIALS OF AEF0117, A NOVEL MEDICATION DEVELOPED BY AELIS FARMA SPECIFICALLY FOR THE TREATMENT OF CUD. IN ADDITION TO HIGHLY POSITIVE PRECLINICAL AND PHASE 1 SAFETY DATA, A RECENT HUMAN LABORATORY STUDY SHOWED THAT AEF0117 DECREASED CANNABIS SELF-ADMINISTRATION AND ITS ABUSE-RELATED EFFECTS (‘GOOD DRUG EFFECT’) IN DAILY CANNABIS SMOKERS WITHOUT PRODUCING PHYSICAL DISCOMFORT OR DISRUPTING MOOD OR SLEEP. AEF0117’S FAVORABLE PHARMACOKINETIC AND SAFETY PROFILE COMBINED WITH THE PRECLINICAL AND HUMAN LABORATORY DATA MAKE THIS COMPOUND A HIGHLY PROMISING APPROACH FOR THE TREATMENT OF CUD. PRIOR TO LARGE-SCALE CLINICAL TRIALS TO TEST AEF0117 IN PATIENTS WITH CUD, IT IS NECESSARY TO CONDUCT NON-CLINICAL TOXICOLOGY STUDIES IN PARALLEL WITH SAFETY AND PHARMACOKINETIC STUDIES IN HUMAN VOLUNTEERS: (1) NON-CLINICAL AEF0117 DEVELOPMENT (FOLLOWING FDA AND ICH GUIDELINES): TOXICITY. WE WILL CONDUCT A 6-MONTH RODENT (RATS) AND 9-MONTH NON-RODENT (DOGS) ORAL TOXICITY STUDIES INCLUDING IMMUNOTOXICITY EVALUATION. THE DRUG WILL BE ADMINISTERED TO ANIMALS AT THREE DOSES THAT ARE MULTIPLES IN EXCESS OF THE ANTICIPATED HUMAN DOSE. PHOTOTOXICITY. RATS WILL RECEIVE THREE DAILY ADMINISTRATIONS OF AEF0117 AT THREE DOSES. THE HIGHEST DOSE WILL ALSO BE ADMINISTERED WITHOUT UVR EXPOSURE. REPRODUCTIVE TOXICITY. THE TOXICITY OF AEF0117 WILL BE TESTED AT THREE DOSES IN NON-PREGNANT FEMALE RABBITS DURING A 7-DAY MAXIMUM-TOLERATED DOSE STUDY. A SUBSEQUENT DOSE RANGE-FINDING STUDY WILL TEST THREE DOSES OF AEF0117 IN PREGNANT RATS AND RABBITS, AND EMBRYO-FETAL DEVELOPMENT WILL BE TESTED IN AN ADDITIONAL SET OF PREGNANT FEMALES RATS AND RABBITS. CLINICAL STUDIES: A SINGLE DOSE PARALLEL GROUP PHARMACOKINETIC STUDY IN TWO PARTS WILL BE CONDUCTED TO INVESTIGATE A) THE EFFECT OF FOOD ON ORAL BIOAVAILABILITY OF AEF0117 AND 2) A POTENTIAL PHARMACOKINETIC INTERACTION BETWEEN SMOKED CANNABIS AND ORAL ADMINISTRATION OF AEF0117. SPECIFICALLY, THE PHARMACOKINETICS OF AEF0117 (1 MG PO) WILL BE ASSESSED OVER 14 DAYS UNDER 10-HOUR FASTING (N=24) AND NON-FASTING CONDITIONS (N= 24). IN ADDITION, THE PHARMACOKINETICS OF AEF0117 AND/OR CANNABIS WILL BE COMPARED OVER 14 DAYS ACROSS 3 GROUPS OF CANNABIS SMOKERS (N=15/GROUP) WHO WILL RECEIVE EITHER (A) AEF0117 (1 MG) ALONE, (B) AEF0117 (1 MG) AND CANNABIS (7.0%), (C) CANNABIS (7.0%) ALONE. TO CONCLUDE, A SUBSTANTIAL STRENGTH OF THIS PROPOSAL IS IN PAIRING AELIS FARMA, A COMPANY DEDICATED TO THE DEVELOPMENT OF A TREATMENT FOR CUD, WITH LEADING ACADEMIC INVESTIGATORS IN THE FIELD OF CUD TREATMENT. WITH THIS PARTNERSHIP, WE WILL CONDUCT FDA-REQUIRED STUDIES TO READY AEF0117 FOR PHASE 3 TRIALS. THIS PROJECT HAS THE POTENTIAL FOR HIGH IMPACT, YIELDING THE NECESSARY RESULTS TO ADVANCE AEF0117 CLOSER TO FDA APPROVAL AS THE FIRST MEDICATION TO TREAT CUD.

TREATING SUICIDAL BEHAVIOR AND SELF-MUTILATION IN BPD

IMPROVED STRATEGIES FOR OUTPATIENT OPIOID DETOXIFICATION

COMMUNITY I-STAR MOZAMBIQUE: COMMUNITY IMPLEMENTATION OF SBIRT USING TECHNOLOGY FOR ALCOHOL USE REDUCTION IN MOZAMBIQUE

DECONSTRUCTING THE CELLULAR CONTROL OF HIPPOCAMPAL FUNCTIONS RELATED TO MENTAL HEALTH: A ROLE FOR BIRTH ORDER.

SLEEP AND WELL-BEING IN HIGH RISK YOUTH

MAPPING INTERINDIVIDUAL VARIATION IN THE AGING CONNECTOME

DEVELOPMENTAL ORIGINS OF AGGRESSIVE AND IMPULSIVE BEHAVIOR - PROJECT SUMMARY. SEPTAL-HYPOTHALAMIC NEURONAL ACTIVITY CENTRALLY MEDIATES AGGRESSIVE BEHAVIOR, WHILE THE MONOAMINE NEUROTRANSMITTERS DOPAMINE AND SEROTONIN PLAY STRONG AND MOSTLY OPPOSING MODULATORY ROLES. HOWEVER, RELATED CIRCUIT MECHANISMS AND ONTOGENY ARE LARGELY UNKNOWN. MAKING PROGRESS TOWARDS CIRCUIT MECHANISM, WE FOUND IN MICE THAT DOPAMINE INPUT FROM THE VENTRAL TEGMENTAL AREA TO THE LATERAL SEPTUM IS SUFFICIENT FOR PROMOTING AGGRESSION AND NECESSARY FOR ESTABLISHING BASELINE AGGRESSION. WITHIN THE LATERAL SEPTUM, DOPAMINE ACTS ON D2 RECEPTORS TO INHIBIT GABA NEURONS THAT PROJECT TO THE HYPOTHALAMUS. THESE FINDINGS EFFECTIVELY LINK THE CLINICALLY PERTINENT HYPER-DOPAMINE MODEL OF AGGRESSION WITH THE CLASSIC SEPTAL- HYPOTHALAMIC AGGRESSION AXIS. MAKING PROGRESS TOWARDS ONTOGENY, WE IDENTIFIED A SENSITIVE DEVELOPMENTAL WINDOW DURING ADOLESCENCE WHERE DOPAMINE TRANSPORTER BLOCKADE PERMANENTLY INCREASES ADULT AGGRESSION, IMPULSIVITY, AND BEHAVIORAL STIMULANT RESPONSE, AND IN PARALLEL LEADS TO A HYPERACTIVE DOPAMINE SYSTEM. CONVERSELY, PERIADOLESCENT SEROTONIN TRANSPORTER BLOCKADE REDUCES AGGRESSION AND BEHAVIORAL STIMULANT RESPONSE IN ADULTHOOD, AND IN PARALLEL LEADS TO A HYPOACTIVE DOPAMINE SYSTEM. HERE WE WILL CONTINUE THIS LINE OF RESEARCH AND STUDY THE OVERARCHING HYPOTHESIS THAT DEVELOPMENTAL DA AND 5-HT SIGNALING TUNES DA INPUT INTO THE LS AND NAC TO IMPACT AGGRESSION-RELATED BEHAVIORS IN ADULTHOOD. IN AIM 1, WE INVESTIGATE THE CAUSAL ROLE OF DOPAMINE INPUT INTO THE NUCLEUS ACCUMBENS IN AGGRESSION-RELATED BEHAVIOR. AGGRESSION IS BEHAVIORALLY CLASSIFIED INTO REACTIVE AGGRESSION WHICH OCCURS IMPULSIVELY IN RESPONSE TO PERCEIVED EXTERNAL THREAT AND PROACTIVE AGGRESSION THAT IS PREMEDITATED AND DIRECTLY MOTIVATED BY A DRIVE FOR APPETITIVE REWARD. WE HYPOTHESIZE THAT NUCLEUS ACCUMBENS INPUT CONTRIBUTES TO THE APPETITIVE VALUE IN PROACTIVE AGGRESSION. IN AIM 2, WE TEST THE HYPOTHESIS THAT D2 RECEPTORS OF THE LATERAL SEPTUM CONTRIBUTE TO SEXUAL DIMORPHIC DIFFERENCES IN AGGRESSIVE BEHAVIOR. WE ALREADY FOUND D2 RECEPTORS MEDIATE DOPAMINE-PROMOTED AGGRESSION IN MALE MICE AS WELL AS SEXUAL DIMORPHISM FOR D2 RECEPTOR EXPRESSION. FURTHERMORE, DOPAMINE INPUT INTO THE LATERAL SEPTUM IS NOT SUFFICIENT TO TRIGGER AGGRESSION IN FEMALES. IN AIM 3, WE INVESTIGATE THE CAUSAL ROLE OF SEROTONIN INPUT INTO THE LATERAL SEPTUM AND NUCLEUS ACCUMBENS IN AGGRESSION-RELATED BEHAVIOR. FINALLY, IN AIM 4, WE INVESTIGATE IF PERMANENTLY ALTERED DAERGIC INPUT INTO THE LS AND NAC DRIVES THE AGGRESSION PHENOTYPES AFTER DOPAMINE AND SEROTONIN TRANSPORTER BLOCKADE DURING DEVELOPMENT, BY MONITORING PATHWAY-SPECIFIC DOPAMINERGIC ACTIVITY DURING BEHAVIOR, PAIRED WITH OPTOGENETIC RESCUE EXPERIMENTS. BY MAPPING CIRCUITS TO BEHAVIOR IN THE CONTEXT OF SENSITIVE DEVELOPMENTAL PERIOD INTERFERENCE, WE WILL ADVANCE OUR UNDERSTANDING OF NORMAL AS WELL AS DISRUPTED BRAIN DEVELOPMENT AND FUNCTION. SUCH INFORMATION WILL IMPACT THE UNDERSTANDING OF HUMAN RISK FACTORS FOR MALADAPTIVE AGGRESSION AND DOPAMINE DYSFUNCTION. WITH THE NOVEL MECHANISTIC AND TRANSLATIONAL INSIGHT, WE SEEK TO INFORM CLINICAL AND EPIDEMIOLOGICAL STUDIES AND IMPROVE DIAGNOSIS, PREVENTION AND TREATMENT STRATEGIES FOR IN PSYCHIATRY.

RAPID HOME TEST TO REDUCE SEXUAL RISK BEHAVIOR IN MSM AND TRANSGENDER WOMEN

NEUROBEHAVIORAL MECHANISMS OF CHOICES TO SMOKE CANNABIS IN CANNABIS USE DISORDER

MASIVUKENI: A MULTIMEDIA ART ADHERENCE INTERVENTION FOR RESOURCE-LIMITED SETTINGS

IDENTITY DEVELOPMENT, RISK, AND RESILIENCE AMONG GENDER DIVERSE POPULATIONS

PSYCHOTHERAPIES FOR CHRONIC POSTTRAUMATIC STRESS DISORDER

CHILDHOOD MASS TRAUMA EXPOSURE, INFLAMMATORY PROGRAMMING, AND PSYCHOPATHOLOGY IN YOUNG ADULTHOOD

ANTECEDENTS AND CONSEQUENCES OF COCAINE TAKING: IMPACT OF OXYTOCIN

NEW YORK SERVING ADOLESCENTS IN NEED OF TREATMENT (NY SAINT)

RECAST BUFFALO - THE NYS OFFICE OF MENTAL HEALTH (OMH) RECAST BUFFALO PROGRAM'S POPULATION OF FOCUS IS BLACK AFRICAN AMERICANS RESIDING IN OR ATTENDING SCHOOL IN FIVE BUFFALO EAST SIDE NEIGHBORHOODS, WITH A SPECIAL FOCUS ON HIGH-RISK YOUTH AND THEIR FAMILIES. THESE NEIGHBORHOODS ARE HIGHLY IMPACTED BY THE RACIALLY MOTIVATED MASS SHOOTING THAT OCCURRED ON MAY 14, 2022. BLACK/AFRICAN AMERICAN YOUTH IN THESE NEIGHBORHOODS EXPERIENCE MULTIPLE RISK FACTORS INCLUDING THE IMPACTS OF STRUCTURAL RACISM, THE COVID PANDEMIC AND SCHOOL DISRUPTION, AND THE TRAUMA OF THE BUFFALO AND UVALDE SHOOTINGS WITH IN 10 DAYS. IN THESE NEIGHBORHOODS, YOUTH AND FAMILIES EXPERIENCE POWERLESSNESS AND SIGNIFICANT BARRIERS TO ACCESSING HIGH-QUALITY EDUCATION AND HOUSING, ADEQUATE HEALTH AND MENTAL HEALTH CARE, AND GOOD JOBS WITH FAIR PAY. CURRENT RESOURCES NEEDS AND GAPS AND CHALLENGES ASSOCIATED WITH ACCESS TO OR QUALITY OF SERVICES IN THESE COMMUNITIES ARE LONG-TERM AND COMPOUNDED BY THE MASS SHOOTING. THE NYS OMH SERG PROGRAM FOR BUFFALO HAS CATALYZED A ONE-YEAR PROCESS OF COMMUNITY PLANNING AND HEALING, WHICH WILL BE SUSTAINED BY RECAST. NYS OMH'S RECAST PROGRAM WILL INCLUDE A COALITION OF DIVERSE COMMUNITY STAKEHOLDERS TO ENSURE THAT COMMUNITY VOICE AND PARTNERSHIP IS INVOLVED IN ALL ASPECTS OF THE GRANT PROJECT, WHICH WILL SUPPORT RECOVERY-ORIENTED, TRAUMA-INFORMED, AND EQUITY-BASED BEHAVIORAL HEALTH AND WELLNESS. THE PROPOSED PROGRAM INCLUDES THREE RECAST FUNDED TRAUMA-INFORMED BEHAVIORAL HEALTH SERVICES:1) A BLACK MENTAL HEALTH RESPONSE TEAM LED BY BESTSELF BEHAVIORAL HEALTH WILL CONTINUE OUTREACH AND ENHANCEMENT WITH YOUTH AND FAMILIES IN THE EAST SIDE; 2) UNIVERSITY PSYCHIATRIC PRACTICE, IN COLLABORATION WITH SAYYES BUFFALO AND THE BUFFALO PUBLIC SCHOOLS, WILL PROVIDE CLINICAL SUPPORTS FOR STUDENTS STRUGGLING WITH COMMUNITY TRAUMA AND TRAINING FOR EDUCATORS; AND 3) BUFFALO COMMUNITY NON-TRADITIONAL MENTAL WELLNESS PROGRAMS WILL CONTINUE A FOCUS ON RESPECTING AND INTEGRATING BLACK/AFRICAN AMERICAN TRADITIONS AND CULTURE TO INCLUDE ARTS-BASED THERAPIES, COORDINATION WITH LOCAL HOUSES OF WORSHIP AND SPIRITUAL-BASED HEALING. IN ADDITION, AFTER PROJECT HOPE CRISIS COUNSELING SERVICES (FEMA-4480-DR-NY) END ON DECEMBER 12, 2022, THE BUFFALO URBAN LEAGUE AND SPECTRUM HEALTH WILL PARTICIPATE IN RECAST TO CONTINUE DELIVERING NYS OMH IN-KIND CRISIS COUNSELING OUTREACH AND ENGAGEMENT SERVICES TO BLACK/AFRICAN AMERICAN FAMILIES AND YOUTH RESIDING IN OR ATTENDING SCHOOLS IN THE EAST SIDE. TRAINING IN TRAUMA-INFORMED CARE AND APPROACHES WILL BE PROVIDED IN -KIND THROUGH THE NYS TRAUMA-INFORMED NETWORK AND VIA INDVIDUALS IN THE COMMUNITY TRAINED BY THE NYS OMH SERG PSYCHOLOGICAL FIRST AID TRAIN-THE-TRAINER. RECAST FUNDING IS REQUESTED FOR YOUTH AND FAMILY PEER SERVICES THAT WILL BE INTEGRATED INTO THIS WORK. GIVEN THE SHORTAGE OF BLACK/AFRICAN AMERICAN YOUTH AND FAMILY PEER ADVOCATES IN BUFFALO, NYS OMH WILL PARTNER WITH PEER-RUN ORGANIZATIONS TO BUILD WORKFORCE PIPELINES FOR BLACK/AFRICAN AMERICAN FAMILIES AND YOUTH TO BECOME CREDENTIALED. THE PROPOSED RECAST PROJECT GOALS ARE: GOAL 1: BUILD A COMMUNITY COALITION REPRESENTING BUFFALO'S BLACK/AFRICAN AMERICAN COMMUNITY THAT IS EMPOWERED TO ASSESS AND PLAN FOR HIGH-RISK YOUTH AND FAMILIES IMPACTED BY THE MASS SHOOTING. GOAL 2: INCREASE LOCAL MH CAPACITY FOR TRAUMA-INFORMED AND CULTURALLY COMPETENT BEHAVIORAL HEALTH SERVICES, INCLUDING YOUTH AND FAMILY PEER SERVICES, IN BUFFALO'S EAST SIDE THROUGH TRADITIONAL WELLNESS APPROACHES IN SCHOOLS AND THE COMMUNITY. GOAL 3: INCREASE ACCESS TO TRAUMA-INFORMED TRAINING TO EMPOWER LOCAL COMMUNITY TO RESPOND TO NEEDS OF BLACK/AFRICAN AMERICAN YOUTH FAMILIES, AND COMMUNITY MEMBERS IN A TRAUMA-INFORMED AND CULTURALLY COMPETENT MANNER. EACH RECAST GOAL HAS A SET OF MEASURABLE OBJECTIVES IDENTIFIED BY TIMEFRAMES. WE ESTIMATE THAT APPROXIMATELY 3,806 UNDUPLICATED INDIVIDUALS WILL BE SERVED DURING THE FOUR YEARS OF THE PROJECT. Y1-370; Y2-967; Y3-1,242; Y4-1,227; TOTAL 3,806

NEUROPSYCHOLOGICAL PROFILE AND NEUROCOGNITIVE BIOMARKERS OF ATTENTION AND MEMORY IN TRAUMA-EXPOSED RESPONDERS AT RISK OF PREMATURE COGNITIVE DECLINE

LONGITUDINAL FOLLOW-UP OF 9/11 DIRECTLY EXPOSED CHILDREN IN THEIR AGE OF TRANSITION: INDEPENDENCE, OCCUPATION AND MORBIDITY

SCALING UP ECONNECT IN JUVENILE PROBATION SETTINGS: A HYBRID IMPLEMENTATION-EFFECTIVENESS TRIAL OF A DIGITAL SUICIDE RISK/BEHAVIOR IDENTIFICATION AND LINKAGE-TO-TREATMENT SYSTEM - AMONG US ADOLESCENTS, SUICIDE IS THE SECOND LEADING CAUSE OF DEATH1. SUICIDE RISK IS NOT UNIFORM ACROSS YOUTH, AND THOSE INVOLVED IN THE JUVENILE JUSTICE (JJ) SYSTEM ARE AT EVEN GREATER RISK FOR SUICIDAL BEHAVIOR (SB) GIVEN THEIR INCREASED PREVALENCE OF MOOD AND SUBSTANCE USE DISORDERS, TRAUMA EXPOSURE, AND ACCESS TO FIREARMS. WHILE SB SCREENING AND SERVICE PROVISION FOR YOUTH IN SECURE JJ SETTINGS OCCURS MORE SYSTEMATICALLY, SUCH PRACTICES ARE RARER FOR YOUTH WHO ARE SUPERVISED IN THEIR COMMUNITY (I.E., PROBATION SETTINGS). THE PROPOSED STUDY WILL EXAMINE STRATEGIES TO BOLSTER THE SUCCESSFUL SCALE-UP OF E-CONNECT, ONE OF THE FEW EVIDENCE-BASED SUICIDE BEHAVIOR IDENTIFICATION AND CROSS-SYSTEM LINKAGE PROGRAMS FOR YOUTH ON UNDER COMMUNITY SUPERVISION. THIS PROPOSAL IS FROM TWO PIS WITH COMPLIMENTARY EXPERTISE IN THE JUSTICE SYSTEM, IMPLEMENTATION SCIENCE, CLINICAL DECISION SUPPORT SYSTEMS, AND USE OF LARGE ADMINISTRATIVE DATA SETS, AND IS SUPPORTED BY A STRONG MULTI- DISCIPLINARY TEAM TO ACHIEVE STUDY AIMS. GUIDED BY THE GATEWAY PROVIDER MODEL (GPM) AND THE EXPLORATION, PREPARATION, IMPLEMENTATION SUSTAINMENT (EPIS) IMPLEMENTATION FRAMEWORK, WE NOW PROPOSE TO EXTEND OURWORK OF E-CONNECT, TO DEVELOP AND TEST A “PURVEYOR MODEL” OF IMPLEMENTATION SCALE-UP (I.E., E-CONNECT-SCALEUP). IN E- CONNECT-SCALEUP, RESEARCHTEAMLEADERSHIPWILL SERVEAS EXTERNAL FACILITATORSTO SUPPORT LOCAL FACILITATORS TO ENSURE THE SUCCESSFUL TRANSFER OF KNOWLEDGE, SKILL AND EXPERTISE IN DELIVERING E-CONNECT IN A NEW JJ SYSTEM AND GEOGRAPHIC CONTEXT, UTILIZING IMPLEMENTATION STRATEGIES TO SUPPORT THE MORE WIDESPREAD, SUSTAINED AND RIGOROUS ADOPTION OF E-CONNECT. WORKING IN 9 INDIANA COUNTIES, RANDOMLY ASSIGNED TO ONE OF THREE WAVES IN A STEPPED- WEDGE, IMPLEMENTATION-EFFECTIVENESSHYBRID TYPE-2 DESIGN ,THE SPECIFICAIMS ARE TO EXAMINE THE CLINICAL AND COST- EFFECTIVENESS OF E-CONNECT-SCALEUP ON (I) IDENTIFICATION OF YOUTH SERVICE NEED (SB AND BH CORRELATES) IN JUVENILE PROBATIONERS; (II) CROSS-SYSTEM (PROBATION-BH AGENCY) REFERRAL; AND (III) YOUTH BH SERVICE USE (INITIAL BH CONTACT; PRIMARY OUTCOME) BY COMPARING THE PERFORMANCE OF E-CONNECT TO (A) STANDARD PROBATION OFFICER PRACTICE (BASELINE) AND (B) TO RATES ACHIEVED IN THE PRIOR EFFICACY TRIAL OF E-CONNECT (AIM 1). WE WILL EXAMINE POTENTIAL MEDIATING OR MODERATING EFFECTS OF EPIS/GPM INNER AND OUTER CONTEXT FACTORS. WE WILL ALSO DETERMINE WHETHER E-CONNECT-SCALEUP CAN REDUCE RACE OR GENDER HEALTH DISPARITIES IN SB/BH SERVICE NEED IDENTIFICATION, CROSS- SYSTEM REFERRAL AND YOUTH SB/BH SERVICE USE (E.G. AS COMPARED TO STANDARD PROBATION PRACTICE (BASELINE), WHICH WOULD REPLICATE THE DISPARITY-REDUCING PERFORMANCE OF E-CONNECT IN NYS (AIM 2). FINALLY, WE WILL EXAMINE THE IMPLEMENTATION OF E-CONNECT-SCALEUP IN TERMS OF FIDELITY AND ACCEPTABILITY AND COMPARE ADVANCEMENT THROUGH THE STAGES OF IMPLEMENTATION THROUGH TO SUSTAINMENT ACROSS THE 9 COUNTIES IN ORDER TO DEMONSTRATE THE FEASIBILITY OF SCALING-UP E-CONNECT IN PROBATION SETTINGS BEYOND NYS (AIM 3). WE WILL ELUCIDATE THE INNER- AND OUTER-LEVEL EPIS- AND GPM- DERIVED FACTORS THAT PROMOTE OR HINDER DELIVERY OF IMPLEMENTATION STRATEGIES AND PRACTICE CHANGE TO INFORM SCALE UP ACROSS A VARIETY OF CONTEXTS.

RDOC DOMAINS UNDERLYING EMOTIONAL HEALTH AND TRAJECTORIES OF PSYCHOPATHOLOGY IN FAMILIES OF WTC FIRST RESPONDERS AND EVACUEES: A GENOME-WIDE GXE STUD

STATE MEDICAL MARIJUANA LAWS AND MTF TEEN MARIJUANA USE AND ATTITUDES SINCE 1991

9/11 TRAUMA AND TOXICITY IN CHILDHOOD: LONGITUDINAL HEALTH AND BEHAVIORAL OUTCOMES

IMPROVING ASSESSMENT FOR NEUROCOGNITIVE IMPAIRMENT AMONG PERINATALLY HIV INFECTED YOUTH

A LONGITUDINAL MULTIMODAL MRI STUDY OF ADOLESCENTS WITH BULIMIA NERVOSA

ASTROCYTES AS THE INTEGRATORS OF NEUROMODULATOR SIGNALS - THIS TRANSFORMATIVE AWARD APPLICATION IS DESIGNED TO TEST AN INTEGRATIVE HYPOTHESIS ABOUT ASTROCYTE FUNCTION ACROSS THE BRAIN WHILE EXTENDING THE CURRENT LIMITS OF STATE-OF-THE-ART TECHNOLOGIES IN CELLULAR IMAGING AND SPATIAL TRANSCRIPTOMICS. THE TEAM OF INVESTIGATORS WITH CELLULAR, MOLECULAR, SYSTEMS, THEORETICAL/COMPUTATIONAL NEUROSCIENCE AND BIOMEDICAL ENGINEERING EXPERTISE WILL TAKE A MULTIPRONGED APPROACH TO TEST THE CENTRAL HYPOTHESIS THAT ASTROCYTES SERVE THE FUNCTION OF INTEGRATING NEUROMODULATOR SIGNALS IN CIRCUITS ACROSS THE BRAIN. ASTROCYTES ARE BY SOME ACCOUNTS THE MOST COMMON CELL IN THE BRAIN. THEY HAVE BEEN HISTORICALLY VIEWED AS SUPPORT CELLS FOR NEURAL CIRCUITS, BUT EMERGING EVIDENCE SUGGESTS THAT THEY ARE ACTIVE PARTICIPANTS IN CIRCUIT FUNCTIONS. THIS IS ESPECIALLY INTERESTING BECAUSE ASTROCYTES ARE AFFECTED BY STRESS, AGING, AND MANY DISEASES OF THE CENTRAL NERVOUS SYSTEM. REMARKABLY, ASTROCYTES EXPRESS RECEPTORS FOR SEROTONIN, NOREPINEPHRINE, DOPAMINE, AND ACETYLCHOLINE; THE FOUR NEUROMODULATOR SYSTEMS THAT ARISE FROM DEEP STRUCTURES AND INNERVATE MOST BRAIN CIRCUITS. THESE NEUROMODULATOR SYSTEMS HAVE CONSIDERABLE OVERLAPPING CIRCUIT FUNCTIONS SUGGESTING THAT A MECHANISM FOR INTEGRATING THEIR INPUTS IS IMPORTANT FOR DISAMBIGUATING HOW EACH NEUROMODULATOR EXERTS ITS CONTRIBUTION TO THE CIRCUIT FUNCTIONS. THIS PROJECT WILL TEST THE POSSIBILITY THAT ASTROCYTES PROVIDE SUCH AN INTEGRATOR FUNCTION. THE INVESTIGATORS WILL USE STATE OF THE ARTS TECHNIQUES AND DEVELOP NEW ONES TO TEST HOW ASTROCYTES ARE AFFECTED BY NEUROMODULATORS AND HOW THESE EFFECTS IMPACT CIRCUIT FUNCTIONS AND BEHAVIOR IN TWO BRAIN SYSTEMS. IN VIVO STUDIES WILL TEST THE HYPOTHESIS ON A CELL POPULATION LEVEL MANIPULATING EACH OF THE NEUROMODULATOR CIRCUITS WHILE TESTING ASTROCYTE RESPONSES TO ALL FOUR, CIRCUIT PHYSIOLOGY, AND BEHAVIOR. EX VIVO STUDIES WILL FOCUS ON SINGLE CELL DIFFERENCES IN ASTROCYTES BY COMBINING FUNCTIONAL STUDIES THAT PARALLEL IN VIVO ONES. THESE SPATIALLY RESOLVED FUNCTIONAL STUDIES WILL BE ALIGNED WITH SPATIAL SINGLE CELL TRANSCRIPTOMICS PROVIDING GENE EXPRESSION DATA TO PARALLEL FUNCTIONAL DATA AT SCALE. STRESS AND AGING ARE KNOWN TO IMPACT ASTROCYTES AND NEUROMODULATOR FUNCTIONS AND ADVERSELY AFFECT MANY NEUROPSYCHIATRIC DISEASES. THE TEAM WILL LASTLY ESTABLISH HOW STRESS AND AGING IMPACT THE ABILITY OF ASTROCYTES TO INTEGRATE NEUROMODULATOR SIGNALS USING THEIR CUTTING EDGE TECHNIQUES. COMPLETING THESE AMBITIOUS STUDIES WILL UNEQUIVOCALLY TEST A TRANSFORMATIVE IDEA FOR AN ORGANIZING PRINCIPLE AROUND ASTROCYTE FUNCTION THROUGHOUT THE BRAIN AND INFORM HOW DYSFUNCTION OF THESE CELLS CAN BE CONTRIBUTING TO DISEASES OF THE CENTRAL NERVOUS SYSTEM.

EFFECTS OF PRENATAL MATERNAL DEPRESSION AND ANTIDEPRESSANT EXPOSURES ON OFFSPRING NEURODEVELOPMENTAL TRAJECTORIES: A BIRTH COHORT STUDY

COMPARISON OF NORMAL AGING WITH ALZHEIMER'S DISEASE: CELLULAR, SYNAPTIC, AND VASCULAR INDICES AFFECTING BRAIN PLASTICITY AND NEUROGENESIS - ADULT HIPPOCAMPAL NEUROGENESIS (AHN) AND ANGIOGENESIS OCCUR TOGETHER IN THE NEUROGENIC NICHE OF THE HIPPOCAMPUS DENTATE GYRUS (DG) AND SUPPORT COGNITIVE FUNCTIONS AND BEHAVIORAL RESPONSES TO STRESS IN RODENTS. CONNECTIVITY BETWEEN NEWBORN AND EXISTING GRANULE NEURONS IS FUNDAMENTAL FOR THESE FUNCTIONS. WE FOUND THAT NORMALLY AGING (NA) SUBJECTS INTO THEIR EIGHTH DECADE OF LIFE HAVE A STABLE NUMBER OF PROGENITOR CELLS (NPCS) AND IMMATURE NEURONS, BUT ANGIOGENESIS AND NEUROPLASTICITY ARE DECREASED WITH AGING AND DIRECTLY CORRELATED WITH EACH OTHER, SUGGESTING THAT, EVEN IF AHN OCCURS IN OLDER ADULTS, THE VASCULAR SUPPORT AND CONNECTIVITY OF NEWBORN NEURONS MIGHT BE REDUCED. MOREOVER, WE DO NOT KNOW IF MORE NPCS DIFFERENTIATE INTO GLIA IN OLDER INDIVIDUALS, AS IT HAPPENS IN AGING RODENTS. AHN IS LOWER IN ALZHEIMER’S DISEASE (AD), AND IF NPCS PREFERENTIALLY DIFFERENTIATE INTO GLIA OR DO NOT, DIVIDE, DIFFERENTIATE AND MATURE EFFICIENTLY, REMAINS UNKNOWN. WE INVESTIGATED EXPRESSION OF KRUPPEL LIKE FACTOR 9 (KLF9), A TRANSCRIPTION FACTOR NECESSARY FOR NEUROGENESIS-DEPENDENT SYNAPTIC PLASTICITY, AND WE FOUND AN AGE-ASSOCIATED DECLINE IN KLF9 EXPRESSION. WE FURTHER TESTED IF THE OBSERVED AGE-ASSOCIATED ANGIOGENESIS DECLINE COULD BE DUE TO REDUCED EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR 2 (VEGFR2), WHICH REGULATES BOTH ANGIOGENESIS AND AHN. OUR PILOT DATA SHOW THAT NUMBER OF INTRA- AND EXTRA- VASCULAR CELLS EXPRESSING VEGFR2 ARE FEWER WITH AGING. ALTERED VASCULAR AND DENDRITE/SPINE PLASTICITY COULD CONTRIBUTE TO NA AND AD, AND ISOLATING KEY MOLECULAR REGULATORS COULD LEAD TO DESIGNING NEW TREATMENTS FOR AD. HERE WE PROPOSE TO ASSESS HYPOTHESIS-GENERATED MOLECULAR TARGETS, AND IN A PARALLEL PROJECT (1R01AG076949), WE HAVE PROPOSED TO PERFORM, IN THE SAME 140 SUBJECTS AND BRAIN REGION, PROTEOMICS, SINGLE NUCLEUS AND SPATIAL MULTIOMICS (RNA AND ATAC) SEQUENCING, USING DATA DRIVEN APPROACHES WHICH COULD REVEAL UNANTICIPATED MOLECULAR UNDERPINNINGS OF BRAIN AGING AND AD. THE APPROACH PROPOSED HERE ALLOWS COMBINED VISUALIZATION OF SELECTED MOLECULAR TARGETS AT THE SINGLE CELL LEVEL, AND DETAILED ANATOMICAL MAPPING OF CELL, CAPILLARY, DENDRITE AND SPINE STRUCTURE AND CONNECTIVITY. OUR RIGOROUS METHODS ASSURE DETAILED CLINICAL ASSESSMENT, BRAIN TISSUE QUALITY, UNIFORM TISSUE PROCESSING, USE OF TOXICOLOGY AND NEUROPATHOLOGY, AND STRICT INCLUSION/EXCLUSION CRITERIA. WE WILL STUDY HIPPOCAMPI FROM NIMH, COLUMBIA UNIVERSITY TAUB INSTITUTE BRAIN BANK (SEE LETTER), AND THE COLUMBIA/NYSPI BRAIN COLLECTION. WE WILL ASSESS AGING EFFECTS IN NA SUBJECTS (N=100, AGE 14-90 YEARS, 57 MALES AND 43 FEMALES), AND WILL ASSESS HOW NA DIFFERS FROM AD COMPARING NA SUBJECTS AGED 60 AND OLDER WITH AGE- AND SEX-MATCHED AD SUBJECTS (N=40, BRAAK STAGES 1 THROUGH 4). AIMS ARE TO QUANTIFY: (1) NEURONAL AND GLIAL DIFFERENTIATION OF NPCS. (2) DENDRITES, SPINES AND SYNAPSES, AND THEIR MOLECULAR REGULATORS: 2A. GOLGI- STAINED DENDRITES AND SPINES; 2B. NEUROFILAMENT-IMMUNOREACTIVE DENDRITES; 2C. SPINE AND SYNAPTIC PROTEINS SPINOPHILIN, SYN1 AND PSD95; 2D. KLF9 MRNA. (3) ANGIOGENESIS AND VEGFR2. (4) RELATIONSHIPS BETWEEN CELLULAR AND MORPHOLOGICAL DATA FROM AIMS 1-3, AND AD BRAAK STAGES, STRESS EXPOSURE, EDUCATION LEVEL AND SEX.

FUNCTIONAL CONNECTOME ANALYSIS OF AMPHETAMINE ACTION AT DOPAMINE NEURON SYNAPSES

IMPULSIVITY IN COCAINE ABUSERS: RELATIONSHIP TO DRUG TAKING AND TREATMENT OUTCOME

LOW-FREQUENCY SINE-WAVE NEUROSTIMULATION THERAPY FOR EPILEPSY

PRENATAL ENDOCRINE-DISRUPTING CHEMICALS AND SOCIAL/COGNITIVE RISK IN MOTHERS AND INFANTS: POTENTIAL BIOLOGIC PATHWAYS

AN INTEGRATIVE COMPUTATIONAL INTERROGATION OF CIRCUIT DYSFUNCTION INSCHIZOPHRENIA VIA NEURAL TIMESCALES - SUMMARY/ABSTRACT SCHIZOPHRENIA IS A DEVASTATING AND BURDENSOME ILLNESS THE MECHANISMS OF WHICH REMAIN ELUSIVE. CONTRIBUTING TO THEIR ELUSIVENESS ARE A HIGHLY COMPLEX SET OF GENETIC FACTORS, PROPOSED ETIOLOGICAL AND PATHOPHYSIOLOGICAL PATHWAYS, AND PHENOTYPIC MANIFESTATIONS. TO ADDRESS THIS COMPLEXITY, WE PROPOSE A HYBRID METHOD COMBINING DATA-DRIVEN APPROACHES TO LARGE-SCALE MULTIMODAL DATASETS AND THEORY-DRIVEN COMPUTATIONAL APPROACHES IN ORDER TO PROVIDE A THEORETICALLY CONSTRAINED FRAMEWORK BRIDGING GENETICS, DEVELOPMENT, CIRCUIT FUNCTION, COGNITION, AND PHENOMENOLOGY OF SCHIZOPHRENIA. TO THAT END, AND IN RESPONSE TO ‘NOTICE OF SPECIAL INTEREST REGARDING THE USE OF HUMAN CONNECTOME DATA (HCP) FOR SECONDARY ANALYSIS’, WE WILL USE DATA FROM UP TO 64,000 INDIVIDUALS, INCLUDING HEALTHY INDIVIDUALS AND PATIENTS WITH SCHIZOPHRENIA AND OTHER DISORDERS, FROM VARIOUS HCP-RELATED PROJECTS AS WELL AS THE UK BIOBANK. WE SPECIFICALLY PROPOSE MEASURING INTRINSIC NEURAL TIMESCALES (INT) FROM RESTING-STATE FMRI DATA AS A THEORY-DRIVEN INDEX OF EXCITATION/INHIBITION (E/I) IMBALANCE IN CORTICAL MICROCIRCUITS. FIRST, EXTENDING OUR PRIOR WORK WE AIM TO CONFIRM AND FURTHER CHARACTERIZE INT ALTERATIONS IN SCHIZOPHRENIA (WIDESPREAD TRAIT-LIKE INT REDUCTIONS AND LOCAL HIERARCHY-DEPENDENT INT MODULATIONS IN RELATION TO PSYCHOTIC SYMPTOMS) AND TO TEST THEIR SPECIFICITY RELATIVE TO OTHER DISORDERS. SECOND, WE WILL EVALUATE THE DEVELOPMENTAL TRAJECTORIES OF INT AND CHARACTERIZE THE GENETIC PROFILE OF THIS FMRI MEASURE AND ITS OVERLAP WITH THE GENETIC PROFILE FOR SCHIZOPHRENIA RISK. THIRD, GIVEN THE ROLE OF E/I RATIO IN CORTICAL MICROCIRCUITS IN SUPPORTING WORKING-MEMORY COMPUTATIONS, WE WILL EXAMINE THE RELATIONSHIP BETWEEN INT AND WORKING-MEMORY ACTIVATION AND PERFORMANCE. WE WILL FURTHER SEEK TO ESTABLISH INT AS A CIRCUIT-LEVEL MEDIATOR OF POLYGENIC RISK FOR SCHIZOPHRENIA ON COGNITIVE DEFICITS. THROUGHOUT, WE WILL USE WELL-POWERED, RIGOROUS, STATE-OF-THE-ART FMRI AND STATISTICAL DATA-DRIVEN METHODS SUITABLE FOR LARGE-SCALE STUDIES AND HCP-STYLE FMRI SEQUENCES, INCLUDING CROSS- VALIDATION AND TESTS OF GENERALIZABILITY. TOGETHER WITH A STRONG THEORETICAL FOUNDATION AND USING BIOPHYSICAL MODELING TO COMPLEMENT FMRI ANALYSES, THIS HYBRID—THEORY- AND DATA-DRIVEN—APPROACH WILL FACILITATE AN INTEGRATED UNDERSTANDING OF THE CIRCUIT-LEVEL MECHANISMS BRIDGING DISTAL GENETIC-RISK FACTORS AND PROXIMAL MANIFESTATIONS OF SCHIZOPHRENIA. IN PARTICULAR, THE COMBINATION OF CUTTING-EDGE CELL-TYPE ENRICHMENT ANALYSES OF GWAS (WHICH IN SCHIZOPHRENIA HAVE SUGGESTED CONVERGING ENRICHMENT IN EXCITATORY AND INHIBITORY CORTICAL CELLS) AND BIOPHYSICAL MODELING AT THE LEVEL OF CORTICAL MICROCIRCUITS OF INTERACTING EXCITATORY AND INHIBITORY CELLULAR POPULATIONS WILL PROVIDE AN INTERPRETATION OF DISPARATE DATA IN TERMS OF CONVERGENT CELL- AND CIRCUIT-LEVEL PATHWAYS. IN DOING SO, THIS PROJECT WILL VALIDATE A THEORETICALLY INFORMATIVE, INTERPRETABLE, TRANSLATABLE, AND SCALABLE RESTING-STATE FMRI MEASURE—INT—THAT MAY BE RELEVANT ACROSS SEVERAL DISORDERS AND, WHICH ADDITIONALLY OWING TO ITS HIGH RELIABILITY AND EASE OF ACQUISITION, HAS HIGH POTENTIAL AS A CANDIDATE BIOMARKER.

TREATMENT OF PSYCHOSIS AND AGITATION IN ALZHEIMERS DISEASE

HEALTHCALL: BRIEF INTERVENTION TO REDUCE DRUG USE IN HIV PRIMARY CARE

VENTROSTRIATAL DOPAMINE RELEASE AND REWARD MOTIVATION IN MDD

VTA-NAC GABAERGIC COMMUNICATION UNDERLYING STRESS-INDUCED REWARD DEFICITS - MILLIONS OF AMERICANS SUFFER FROM DEFICITS IN REWARD-SEEKING, IN THE CONTEXT OF PSYCHIATRIC DISORDERS, SUCH AS MAJOR DEPRESSIVE DISORDER, SCHIZOPHRENIA, AND SUBSTANCE USE DISORDERS. STRESS CAN BOTH EXACERBATE THESE DISORDERS AND DIRECTLY CAUSE REWARD-SEEKING DEFICITS. MICE SUBJECTED TO CHRONIC STRESS ALSO DEVELOP REWARD-SEEKING DEFICITS. HOWEVER, IT REMAINS UNCLEAR HOW STRESS DISRUPTS REWARD-SEEKING. REWARD-SEEKING IS A COMPLEX PROCESS THAT INCLUDES ANTICIPATORY MOTIVATION TO OBTAIN REWARDS, AN ASSESSMENT OF THE HEDONIC VALUE OF REWARDS, AND LEARNING TO ASSOCIATE REWARD-PREDICTING CUES WITH REWARDING OUTCOMES. COMMUNICATION BETWEEN THE VENTRAL TEGMENTAL AREA (VTA) AND THE NUCLEUS ACCUMBENS (NAC) PLAYS A CENTRAL ROLE IN THESE PROCESSES. DOPAMINE (DA) RELEASED FROM THE VTA TO THE NAC SUPPORTS COMPONENTS OF REWARD-SEEKING, INCLUDING ANTICIPATION AND LEARNING. YET EFFORTS TO SHOW THAT VTA-NAC DA DEFICITS UNDERLIE STRESS-INDUCED REWARD-SEEKING DEFICITS HAVE YIELDED MIXED RESULTS. RECENTLY, RESEARCHERS HAVE IDENTIFIED THAT INHIBITORY VTA GABA NEURONS ARE ALSO KEY FOR SETTING EXPECTATIONS THAT BOTH GUIDE REWARD ANTICIPATION AND ASSOCIATIVE LEARNING. WE HAVE FOUND THAT DURING ACUTE STRESS, THESE VTA GABA NEURONS INDUCE RHYTHMIC NAC ACTIVITY AND THAT THIS ACTIVITY PREDICTS SUBSEQUENT TRANSIENT REDUCTIONS IN REWARD-SEEKING. MOREOVER, RHYTHMICALLY STIMULATING NAC PROJECTING VTA GABA NEURONS SUFFICES TO RECAPITULATE BOTH STRESS-INDUCED NAC RHYTHMIC ACTIVITY AND SUBSEQUENT REWARD-SEEKING DEFICITS. THESE DATA RAISE THE POSSIBILITY THAT CHRONIC STRESS CAUSES REWARD-SEEKING DEFICITS VIA VTA-NAC GABA ACTIVITY. SINCE VTA GABA NEURONS HAVE KNOWN ROLES IN ANTICIPATION AND LEARNING, THESE DATA ALSO SUGGEST THAT CHRONIC STRESS MIGHT DISRUPT ENCODING OF SPECIFIC ASPECTS OF REWARD-SEEKING. THIS PROPOSAL TESTS THESE IDEAS AND DIRECTLY LINKS CHRONIC STRESS- INDUCED VTA-NAC GABAERGIC ACTIVITY TO SUBSEQUENT DEFICITS IN THE ENCODING OF REWARD-SEEKING. SPECIFIC AIM 1 WILL TEST WHETHER TWO CHRONIC STRESS DISRUPTS SPECIFIC ASPECTS OF REWARD-SEEKING USING TASKS THAT ASSESS ASSOCIATIVE LEARNING, ANTICIPATORY MOTIVATION AND HEDONIC VALUATION AND CONSIDER MICE ALONG THE SUSCEPTIBLE- RESILIENT SPECTRUM. SPECIFIC AIM 2 WILL USE OPTOGENETICS AND CHRONIC IN VIVO MULTI-SITE ELECTROPHYSIOLOGY IN AWAKE, BEHAVING MICE TO TEST WHETHER VTA-NAC GABAERGIC ACTIVITY CAUSES CHRONIC STRESS-INDUCED REWARD-SEEKING DEFICITS BY RECORDING THE IN VIVO FIRING ACTIVITY OF VTA-NAC GABA PROJECTIONS DURING CHRONIC STRESS AND SUBSEQUENT REWARD-SEEKING. WE WILL ALSO DETERMINE WHETHER CHRONIC OPTOGENETIC STIMULATION OF THIS PATHWAYS SUFFICES TO INDUCE PERSISTENT REWARD-SEEKING DEFICITS. FINALLY, SPECIFIC AIM 3 WILL USE PATHWAY-SPECIFIC CHEMOGENETIC BLOCKADE TO TEST WHETHER BLOCKING VTA-NAC GABAERGIC ACTIVITY CAN PREVENT CHRONIC STRESS-INDUCED REWARD- SEEKING DEFICITS. WE WILL ALSO USE CAL-LIGHT (CALCIUM AND LIGHT-ACTIVATED GENE EXPRESSION) TO EXPRESS AN INHIBITORY OPSIN IN STRESS-ACTIVATED VTA NEURONS. THIS TECHNIQUE WILL ALLOW US TO TEST WHETHER INHIBITING STRESS-ACTIVATED NEURONS DURING REWARD-SEEKING CAN REVERSE THE EFFECTS OF CHRONIC STRESS. WITH THIS APPROACH, WE WILL DEVELOP PATHWAY AND CELL-TYPE SPECIFIC UNDERSTANDING OF HOW CHRONIC IMPAIRS REWARD-SEEKING WITH THE GOAL OF FINDING NOVEL TREATMENTS FOR REWARD-SEEKING DEFICITS.

UNCOVERING THE RISK ARCHITECTURE OF SUICIDAL BEHAVIORS: A REPRESENTATIVE SAMPLE AT HIGH RISK

TARGETING COTRANSMISSION FOR CIRCUIT-SPECIFIC PHARMACOTHERAPY

MATERNAL ADVERSITY, INFLAMMATION, AND NEURODEVELOPMENT: HOW INTERGENERATIONAL PROCESSES PERPETUATE DISADVANTAGE IN A LOW-RESOURCE SETTING

TRAINING MOTIVATIONAL INTERVIEWING USING LIVE SUPERVISION

IMPACT OF MINORITY STRESS ON CARDIOVASCULAR DISEASE RISK AND RESILIENCE - 7. PROJECT SUMMARY/ABSTRACT THIS PROJECT IS RESPONSIVE TO NOT-MD-19-001 NOTICE OF SPECIAL INTEREST IN RESEARCH ON THE HEALTH OF SEXUAL AND GENDER MINORITY (SGM) POPULATIONS. GENDER MINORITY POPULATIONS ARE AT INCREASED RISK FOR CARDIOVASCULAR DISEASE (CVD) MORBIDITY AND MORTALITY. SPECIFICALLY, BEHAVIORAL RISK FACTOR SURVEILLANCE SYSTEM DATA SUGGEST THAT, COMPARED TO CISGENDER PEOPLE, GENDER MINORITIES ARE AT MORE THAN DOUBLE THE RISK FOR MYOCARDIAL INFARCTION AND REPORT GREATER DEPRESSION, PHYSICAL INACTIVITY, AND ELEVATED BODY MASS INDEX (BMI), AS WELL AS POORER ACCESS TO HEALTHCARE, ALL OF WHICH INCREASE CVD RISK. FURTHER, MANY GENDER MINORITY INDIVIDUALS TAKE HORMONES, WHICH MAY FURTHER INCREASE THEIR RISK OF CVD. ACCORDING TO MINORITY STRESS THEORY, THE NEGATIVE IMPACT OF PREJUDICE AND DISCRIMINATION IS ONE CONTRIBUTOR TO CVD RISK DISPARITIES. ALTHOUGH PREVIOUS STUDIES HAVE FOUND ASSOCIATIONS BETWEEN GENDER MINORITY STRESS AND POORER SELF-REPORTED MENTAL HEALTH, THE IMPACT OF MINORITY STRESS ON PHYSICAL HEALTH OUTCOMES, INCLUDING CVD RISK, HAS NOT BEEN EXAMINED IN GENDER MINORITY POPULATIONS. THE GOAL OF THIS STUDY IS TO ADVANCE OUR UNDERSTANDING OF HOW MINORITY STRESS AND RESILIENCE AFFECT CVD RISK. IN AN ESTABLISHED LONGITUDINAL, MULTISITE COHORT OF GENDER MINORITY INDIVIDUALS IN THREE U.S. CITIES (N=390), WE AIM TO: (1) DETERMINE THE ASSOCIATION OF MINORITY STRESS WITH MENTAL HEALTH AND CVD RISK; (2) DETERMINE THE IMPACT OF SOCIAL SUPPORT, ACCESS TO CARE, AND IDENTITY DEVELOPMENT ON MENTAL HEALTH AND CVD RISK; AND (3) IDENTIFY MODIFIABLE RESILIENCE FACTORS THAT MAY INFLUENCE THE RELATIONSHIP OF MINORITY STRESS TO MENTAL HEALTH AND CVD RISK IN THIS HEALTH DISPARITY POPULATION. IN ADDITION TO STRUCTURED INTERVIEWS AND ECOLOGICAL MOMENTARY ASSESSMENTS (EMA) OF STRESS AND RESILIENCE AT BASELINE AND 2-YEAR FOLLOW-UP, WE WILL COLLECT 2-WEEK BURSTS OF OBJECTIVE MEASUREMENTS OF BLOOD PRESSURE, SLEEP AND PHYSICAL ACTIVITY. THE PROPOSED RESEARCH WILL PROVIDE THE BEST EVIDENCE TO DATE TO GUIDE RESEARCHERS AND CLINICIANS WORKING TO DEVELOP INTERVENTIONS TO REDUCE CVD DISPARITIES IN GENDER MINORITY POPULATIONS, AND PROMOTE THEIR LONG-TERM HEALTH AND WELLBEING.

CONTROL AND REWARD CIRCUITS AS TARGETS FOR REPETITIVE THOUGHTS AND BEHAVIORS

TRANSLATIONAL RESEARCH ON EATING DISORDERS: REWARD SYSTEMS

IMPROVING THE EFFECTIVENESS OF TREATMENT FOR DEPRESSION IN HISPANICS

STRENGTHENING MENTAL HEALTH AND SUBSTANCE USE DISORDER TREATMENT, RECOVERY SUPPORT AND CRISIS CARE TO ADDRESS THE IMPACT OF THE COVID-19 PANDEMIC ON RESIDENTS OF NEW YORK CITY AND LOWER HUDSON VALLE

PAR04-122 SATELLITE ANIMAL FACILITY CONSTRUCTION PROJECT

KETAMINE VS MIDAZOLAM: TESTING RAPID RELIEF OF SUICIDE RISK IN DEPRESSION

INDIVIDUALIZED RISK PREDICTION IN PERSONS AT CLINICAL HIGH-RISK FOR PSYCHOSIS USING NEUROMELANIN-SENSITIVE MRI.

EFFICACY OF BUPRENORPHINE AND XR-NALTREXONE COMBINATION FOR RELAPSE PREVENTION IN OPIOID USE DISORDER

TESTING A DIATHESIS-STRESS MODEL OF ADOLESCENT SUICIDE: DOPAMINERGIC, SOCIAL, AND INHIBITORY MECHANISMS - PROJECT SUMMARY SUICIDE IS A MAJOR PUBLIC HEALTH CRISIS AND, CURRENTLY, IS THE SECOND LEADING CAUSE OF DEATH AMONG 10-24- YEAR-OLDS. SUICIDAL THOUGHTS AND BEHAVIORS (STB) INCREASE DRASTICALLY DURING ADOLESCENCE AND ARE PARTICULARLY COMMON AMONG DEPRESSED ADOLESCENTS. HOWEVER, DEFINITIVE MARKERS TO IDENTIFY WHICH DEPRESSED ADOLESCENTS ARE MOST AT-RISK FOR SUICIDAL BEHAVIORS HAVE NOT BEEN DEVELOPED. INNOVATIVE, MULTIMODAL STUDIES PROBING BIOLOGICAL AND SOCIOEMOTIONAL MECHANISMS MAY ELUCIDATE POTENTIAL TARGETS TO IMPROVE PREDICTION OF YOUTH SUICIDE AND REDUCE THE NEEDLESS LOSS OF LIFE. CURRENT DIATHESIS-STRESS MODELS OF STB POSIT INTERACTIONS BETWEEN DISTAL DIATHESES THAT PREDISPOSE INDIVIDUALS TO STB AND PROXIMAL STRESSORS, PARTICULARLY SOCIAL REJECTION AND INTERPERSONAL LOSS. RECENT REVIEWS HIGHLIGHT POTENTIAL NEURAL DIATHESES FOR STB, YET FINDINGS ARE LIMITED, PARTICULARLY FOR HIGH-RISK ADOLESCENTS. THE CURRENT PROJECT TARGETS THREE DISTAL NEURAL MECHANISMS–DOPAMINERGIC, SOCIAL, AND INHIBITORY DEFICITS–IN A SAMPLE OF 14-17-YEAR-OLD ADOLESCENTS: DEPRESSED ADOLESCENTS EITHER SUICIDAL IDEATION (N=55) OR A RECENT SUICIDE ATTEMPT (N=55) AND DEMOGRAPHICALLY MATCHED HEALTHY CONTROLS (N=35). FIRST, POST-MORTEM WORK HAS IMPLICATED DOPAMINERGIC DEFICITS IN ADULT SUICIDE, BUT EXAMINING DOPAMINE FUNCTION IN VIVO IS CRITICAL TO UNDERSTAND PROSPECTIVE RISK FOR ADOLESCENT STB. THUS, WE WILL LEVERAGE A NOVEL MAGNETIC RESONANCE IMAGING (MRI) ACQUISITION SENSITIVE TO NEUROMELANIN AS A NON-INVASIVE PROXY FOR DOPAMINE IN KEY MIDBRAIN PROJECTION REGIONS. GIVEN THE CONTRIBUTION OF DOPAMINE TO REWARD AND ANHEDONIC DEFICITS IN DEPRESSION, WE HYPOTHESIZE THAT DOPAMINERGIC REDUCTIONS WILL BE PROMINENT IN ADOLESCENT STB, PARTICULARLY AMONG ATTEMPTERS. SECOND, SUICIDE ATTEMPTERS EXPERIENCE MORE INTERPERSONAL STRESS THAN IDEATORS, AND THUS, THE PROPOSED PROJECT WILL CLARIFY WHETHER ALTERATIONS IN SOCIAL PROCESSING NEURAL CIRCUITRY CONFER HEIGHTENED RISK FOR SUICIDAL BEHAVIORS. WE HYPOTHESIZE THAT, DURING AN ECOLOGICALLY VALID CHATROOM MRI TASK, ATTEMPTERS WILL EXHIBIT BLUNTED STRIATAL RESPONSE TO ACCEPTANCE AND INCREASED INSULA RESPONSE TO REJECTION BY SAME-AGE PEERS RELATIVE TO IDEATORS. THIRD, NEGATIVE URGENCY, THE TENDENCY TO ACT IMPULSIVELY FOLLOWING NEGATIVE EMOTIONS, IS IMPLICATED IN ADOLESCENT SUICIDAL BEHAVIORS. WE HYPOTHESIZE THAT ATTEMPTERS WILL EXHIBIT FRONTAL, STRIATAL, AND INSULAR INHIBITION DEFICITS DURING AN EMOTIONAL GO/NO-GO MRI PARADIGM, FOLLOWING A SOCIAL-EVALUATIVE STRESSOR TO INDUCE A NEGATIVE MOOD STATE. ADOLESCENT IDEATORS AND ATTEMPTERS WILL BE RECRUITED FROM A PEDIATRIC EMERGENCY DEPARTMENT AND FOLLOWED FOR A HIGH-RISK 3-MONTH PERIOD, AS 10% OF ADOLESCENTS WILL ATTEMPT SUICIDE WITHIN 90 DAYS OF HOSPITAL DISCHARGE. INTERPERSONAL STRESS WILL BE CHARACTERIZED OVER FOLLOW-UP VIA PROSPECTIVE ECOLOGICAL MOMENTARY ASSESSMENT AND IN-DEPTH RETROSPECTIVE INTERVIEWS. COLLECTIVELY, THESE NOVEL MULTIMODAL MRI AND STRESS MEASURES HOLD GREAT PROMISE TO ELUCIDATE THE PATHWAY TO ADOLESCENT SUICIDAL BEHAVIORS, A KEY NIMH RESEARCH PRIORITY.

RANDOMIZED, CONTROLLED TRIAL OF PROPRANOLOL FOR AGGRESSION, SELF-INJURY, AND SEVERE DISRUPTIVE BEHAVIOR IN ADOLESCENTS AND ADULTS WITH A DIAGNOSIS OF AUTISM

CO-REGULATION OF STRIATAL DOPAMINE AND ACETYLCHOLINE DURING FLEXIBLE LEARNING - PROJECT SUMMARY THE NEUROMODULATORS ACETYLCHOLINE (ACH) AND DOPAMINE (DA) PLAY IMPORTANT ROLES IN LEARNING. IN THE STRIATUM CHOLINERGIC INTERNEURONS (CINS) ARE MODULATED CO-INCIDENT WITH THE RELEASE OF DA IN RESPONSE TO UNPREDICTED REWARDS AND REWARD PREDICTING CUES AND BOTH SIGNALS HAVE BEEN IMPLICATED IN CODING PREDICTION ERROR SIGNALS. WHEREAS DA NEURONS ARE MOSTLY ACTIVATED BY THESE SALIENT EVENTS, CINS OFTEN SHOW A MULTIPHASIC RESPONSE WITH A PROMINENT PAUSE IN ACTIVITY. THE TIME LOCKED OCCURRENCE OF BOTH SIGNALS SUGGEST THAT THEY ARE COORDINATED BUT IT IS STILL UNCLEAR WHETHER THEY ARE REGULATED INDEPENDENTLY FROM EACH OTHER OR WHETHER THEY MUTUALLY REGULATE EACH OTHER. MOREOVER, WHETHER THEIR TEMPORAL CO-INCIDENCE IS IMPORTANT FOR LEARNING STILL NEEDS TO BE DETERMINED. SUPPORT FOR A MUTUAL CO-REGULATION COMES FROM BOTH STIMULATION AND LESION STUDIES. IN THE SLICE, DA RELEASED FROM DA TERMINALS INHIBITS THE ACTIVITY OF CINS VIA ACTIVATION OF D2 RECEPTORS. STRIKINGLY, CLASSICAL 6-OHDA LESION STUDIES IN NON-HUMAN PRIMATES SUGGEST THAT THE PAUSE IN TONICALLY ACTIVE NEURONS (TANS), THE PRIMATE COUNTERPARTS OF CINS, IS FULLY DEPENDENT ON DA; ALTHOUGH THIS HYPOTHESIS HAS BEEN CHALLENGED BY DATA IMPLICATING THALAMIC OR OTHER PROJECTIONS IN THE PAUSE GENERATION. SLICE PHYSIOLOGY AND IN VIVO STIMULATIONS STUDIES HAVE FURTHER SHOWN THAT ACH RELEASED FROM CINS LOCALLY INDUCES DA RELEASE. ONE LIMITATION OF STIMULATION STUDIES IS THAT THEY DO NOT MEASURE NATURALLY EVOKED ACH OR DA LEVELS. THUS, THE IMPORTANCE OF THIS MUTUAL CO-REGULATION DURING LEARNING MUST BE DETERMINED UNDER NATURAL CONDITIONS. AN IDEAL WAY TO ACHIEVE THIS IS TO SIMULTANEOUSLY MEASURE BEHAVIORALLY-EVOKED CHANGES IN DA AND ACH LEVELS IN THE SAME ANIMAL. SINCE STRIATAL ACH HAS BEEN FOUND TO BE IMPORTANT WHEN BEHAVIOR NEEDS TO BE ADAPTED TO NEW TASK RULES THE APPLICATION WILL FOCUS ON UNDERSTANDING THE IMPORTANCE OF THE MUTUAL CO-REGULATION OF DA AND ACH FOR COGNITIVE FLEXIBILITY. TO THIS END, WE PROPOSE TO SIMULTANEOUSLY RECORD TASK-EVOKED DA AND ACH TRANSIENTS IN THE MOUSE DURING TWO FLEXIBLE LEARNING BEHAVIORS, GO/NOGO AND REVERSAL LEARNING. OUR PRELIMINARY DATA SHOW THAT BOTH BEHAVIORS ARE AFFECTED BY STRIATAL CIN FUNCTION. WE THEN WILL ISOLATE THE DA-DEPENDENT COMPONENT OF THE ACH SIGNAL BY ENHANCING OR ABOLISHING THE ABILITY OF DA TO INHIBIT CINS. CONVERSELY, WE WILL ABOLISH THE ABILITY OF CINS TO RELEASE ACH OR INHIBIT CIN ACTIVITY WITH HIGH TEMPORAL RESOLUTION. DETERMINING HOW THESE MANIPULATIONS AFFECT TASK-EVOKED CHANGES IN ACH/DA LEVELS AND PERFORMANCE WILL ESTABLISH THE IMPORTANCE OF MUTUAL CO-REGULATION OF DA AND ACH SIGNALS FOR FLEXIBLE LEARNING. OUR STUDIES WILL PROVIDE MECHANISTIC INSIGHTS INTO DA AND ACH CO-REGULATION IN THE STRIATUM. THIS HAS CLINICAL RELEVANCE AS BOTH NEUROTRANSMITTERS ARE DYSREGULATED IN THE STRIATUM OF PATIENTS WITH BRAIN DISORDERS INCLUDING SCHIZOPHRENIA AND PARKINSON DISORDER, WHERE BOTH NEUROMODULATOR SYSTEMS ARE TARGETED BY CURRENT THERAPEUTIC TREATMENTS.

USING MULTIPLE DATASETS TO EXAMINE YOUTH PSYCHIATRIC DIAGNOSIS

2/2 - FAMILIAL EARLY-ONSET SUICIDE ATTEMPT BIOMARKERS

NEURAL SUBSTRATES OF DEFICITS IN NATURALISTIC SOCIAL COGNITION IN SCHIZOPHRENIA

INVESTIGATION OF EAAT3 IN OCD PATHOPHYSIOLOGY

A DATA SCIENCE FRAMEWORK FOR EMPIRICALLY EVALUATING AND DERIVING REPRODUCIBLE AND TRANSFERRABLE RDOC CONSTRUCTS IN YOUTH

DISCOVERY SCIENCE OF HUMAN BRAIN FUNCTION ACROSS THE LIFESPAN

PATHOLOGICAL AND FUNCTIONAL IMPACT OF TAUOPATHY IN VIVO

RISK AND BENEFITS OF OVERDOSE EDUCATION AND NALOXONE PRESCRIBING TO HEROIN USERS

REAL TIME RELAPSE RISK SCORING FOR OPIOID USE DISORDER (OUD) FROM CLINICAL TRIAL DATASETS - REAL TIME RELAPSE RISK SCORING FOR OPIOID USE DISORDER (OUD) FROM CLINICAL TRIAL DATASETS PROJECT SUMMARY ANY CLINICIAN TREATING A PATIENT WITH OPIOID USE DISORDER (OUD) WOULD LIKE TO KNOW WHETHER THIS PATIENT WOULD RELAPSE IN THE NEXT WEEK OR MONTH. SUCH A SCORE, ANALOGOUS TO A CREDIT SCORE IN CONSUMER FINANCE, MAY BE SIMILARLY OBTAINED FROM LONGITUDINAL DATA STREAMS DERIVED FROM PATIENT BEHAVIOR DURING SUD TREATMENT. THERE ARE SEVERAL COMMON DATA SOURCES THAT EVERY OUD PATIENT IN TREATMENT PRODUCES: A BINARY, LONGITUDINAL DATA SURVEY OF USE PATTERNS FOR A SET OF PRE-DETERMINED SUBSTANCES OF ABUSE, TREATMENT SESSION ATTENDANCE RECORDS, AND MEDICATION RECORDS. IN PARTICULAR, URINE DRUG SCREENS (UDS) OR ALCOHOL AND NICOTINE BREATHALYZERS AND STANDARD TIMELINE FOLLOW BACK (TLFB) QUESTIONNAIRES ARE UNIVERSAL SURVEYS IN EVERY TREATMENT DELIVERY CONTEXT, INCLUDING LARGE PRAGMATIC CLINICAL TRIALS. WHILE THESE DATA STREAMS ARE INCOMPLETE, OF DIFFERENT LENGTHS AND SAMPLING FREQUENCIES, AND CORRELATE IN COMPLEX WAYS, CONTEMPORARY MACHINE LEARNING METHODS ALLOW US TO OVERCOME THESE CHALLENGES. WE AIM TO BUILD A TOOLBOX THAT WOULD ALLOW FOR THE FOLLOWING: 1) STANDARDIZED METHODS FOR RISK SCORING AND VISUALIZATION FROM UDS AND TLFB DATASETS IN EXISTING LARGE CLINICAL TRIALS; 2) STANDARD METHODS FOR INFERENCES OF RISK SCORES: PROCEDURE FOR HYPOTHESIS TESTING WHETHER AN INTERVENTION MADE A DIFFERENCE IN THE RISK SCORES AND THEIR TRAJECTORIES. 3) USER-FRIENDLY SOFTWARE MODULES AIMED TOWARD RESEARCHERS AND ADMINISTRATORS FOR QUALITY IMPROVEMENT PROJECTS AND CUSTOMIZED PREDICTIVE MODELING PIPELINES, AND INTERPRETABLE WEB PORTAL FOR CLINICIANS, ANALOGOUS TO A CREDIT REPORT. THIS PROPOSAL WILL ALSO INCORPORATE USABILITY SURVEY AND EVALUATION FOR ALGORITHMIC BIAS. THESE APPLICATIONS WILL PROVIDE A COMPUTATIONAL FRAMEWORK FOR FUTURE REAL TIME PREDICTIVE MODELING WORK FOR MANY OTHER DIFFERENT SUBSTANCE USE DISORDERS.

CIRCUIT-SPECIFIC, CHEMOGENETIC NEUROMODULATION IN NONHUMAN PRIMATES. - ABSTRACT UG3/UH3 DEEP BRAIN STIMULATION (DBS), APPLIED TO AREAS LIKE THE SUBTHALAMIC NUCLEUS (STN), IS A STANDARD TREATMENT FOR PARKINSON DISEASE (PD), HOWEVER, DBS HAS INHERENT SURGICAL RISKS AS WELL AS POTENTIAL FOR INFECTIONS AND ADVERSE SIDE EFFECTS. OUR OVERARCHING GOAL IS TO ESTABLISH NOVEL CHEMOGENETIC NEUROMODULATION STRATEGIES IN NONHUMAN PRIMATES (NHPS) THAT UTILIZE AND BUILD UPON THE STRENGTHS OF DBS BUT RESOLVE MANY DBS LIMITATIONS, AND ULTIMATELY TO TRANSLATE THESE TO CLINICAL THERAPIES IN HUMANS. WE FOCUS ON DESIGNER RECEPTORS EXCLUSIVELY ACTIVATED BY DESIGNER DRUGS (DREADDS), WHICH WORK VIA SPECIALIZED EXCITATORY OR INHIBITORY RECEPTORS GENETICALLY INSERTED INTO NEURONS. OUR RESEARCH PLAN, WHICH INTEGRATES A ROBUST PLAN TO ENHANCE DIVERSE PERSPECTIVES, HAS A TOOL DEVELOPMENT (UG3) PHASE FOLLOWED BY A PRE-CLINICAL TRIAL (UH3) PHASE. THE MAIN OBJECTIVE OF THE UG3 IS TO: A) DEVELOP MORE EFFECTIVE AND SPECIFIC DREADD INDUCTION IN NHPS: A) USING A CIRCUIT-SPECIFIC RETRO-INFECTION METHOD TO SELECTIVELY INFECT THE NEURONS COMPRISING STNGP PATHWAY, BELIEVED TO BE KEY TO MOTOR SYMPTOMS IN PD, AND B) USE FOCUSED ULTRASOUND PRIOR TO SURGICAL DELIVERY OF VIRAL CONSTRUCTS TO AUGMENT DREAD EXPRESSION IN THE STNGP CIRCUIT. WE WILL USE POSITRON EMISSION TOMOGRAPHY (PET) AND BEHAVIORAL ASSESSMENTS TO GAUGE THE STRENGTH OF VIABLE DREADD RECEPTOR EXPRESSION, AND POST-MORTEM HISTOLOGY TO SCREEN FOR NEUROPATHOLOGY AND TO ASSESS THE DENSITY AND ANATOMICAL DISTRIBUTION OF TRANSDUCED NEURONS. THE GO/NO-GO FOR DECISION FOR MOVING TO THE UH3 WILL BE BASED ON: 1) EVIDENCE OF MOTOR ABNORMALITIES OR BEHAVIORAL CHANGE DUE TO DREADD ACTIVATION WITH AN EFFECT SIZE =0.80, AND/OR 2) HISTOLOGICAL EVIDENCE OF DREADD EXPRESSION IN =35% OF NEURONS IN THE STN. THE MAIN OBJECTIVE OF THE UH3 IS TO DETERMINE IF ACTIVATION OF DREADDS IN STN NEURONS, USING THE ORAL DREADD AGONIST DESCHLOROCLOZAPINE (DCZ), REDUCES MOTOR ABNORMALITIES NHPS TREATED WITH A NEUROTOXIN TO INDUCE A PD-LIKE CONDITION. WE WILL START (AIM 1) BY DETERMINING THE OPTIMAL ORAL AGONIST DOSAGE AND EFFICACY FOR DREADD ACTIVATION IN MPTP NHPS. WE WILL THEN (AIM 2) DETERMINE THE LONG-TERM EFFICACY AND SAFETY OF ORAL DREADD ACTIVATION IN MPTP NHPS, WITH CLINICAL/BEHAVIORAL ANALYSES EMPHASIZING CLINICAL BENEFITS, AND MOTOR/NON-MOTOR SIDE EFFECTS. WE WILL USE PET IN THE SAME NHPS TO MONITOR THE STABILITY OF DREADD EFFECTS ON STN CIRCUITS AND FOLLOW UP WITH HISTOLOGICAL ANALYSIS TO CONFIRM DREADD DISTRIBUTION ACROSS STN CIRCUITS, TO LOOK FOR POTENTIAL TISSUE DAMAGE AND TO CONFIRM STRIATAL DOPAMINE DEPLETION DUE TO THE NEUROTOXIN TREATMENT. FINALLY (AIM 3) WE WILL EXPLORE THE USE OF PET IN THE SAME NHPS AS A NONINVASIVE A GAUGE FOR THE EFFICACY OF THE DREADD AGONIST ALONE OR AS PART OF A COMBINED THERAPY TO GUIDE DOSAGE ADJUSTMENT IN FUTURE HUMAN STUDIES. TO ENHANCE THE RIGOR AND REPRODUCIBILITY, KEY UH3 EXPERIMENTS WILL BE INDEPENDENTLY VALIDATED. SUCCESS IN THIS WORK AND ITS HUMAN TRANSLATION MAY BE GAME-CHANGING FOR THE TREATMENT OF PD AND OTHER NEUROLOGICAL/PSYCHIATRIC DISORDERS.

A NATIONAL BIRTH COHORT STUDY OF PRENATAL FACTORS AND NEURODEVELOPMENTAL PSYCHIATRIC DISORDERS

MAXIMIZING TREATMENT OUTCOME IN OCD

IMAGING STIMULANT EFFECTS ON EMOTIONAL LABILITY IN CHILDREN WITH ADHD

MECHANISMS DRIVING SEX DIFFERENCES IN COGNITIVE OUTCOMES FOLLOWING EARLY LIFE STRESS

PHARMACOLOGICAL FACILITATION OF BEHAVIORAL MODIFICATION FOR COCAINE USE DISORDERS

REAL-TIME FMRI NEUROFEEDBACK BASED STRATIFICATION OF DEFAULT NETWORK REGULATION

ADOLESCENCE, MOTIVATION AND THE MATURATION OF THE PREFRONTAL CORTEX.

INTERPERSONAL THERAPY FOR DEPRESSION IN BREAST CANCER

NEW YORK STATE ENHANCING THE QUALITY AND INTEGRATION OF TREATMENT FOR YOUTH (NYS EQUITY) - THE NEW YORK STATE OFFICE OF ADDICTION SERVICES AND SUPPORTS (NYS OASAS) YOUTH AND FAMILY TREE PROJECT, TITLED ENHANCING THE QUALITY AND INTEGRATION OF TREATMENT FOR YOUTH (EQUITY), WILL EXPAND AND ENHANCE THE SUBSTANCE USE SERVICE CONTINUUM FOR TRANSITION AGE YOUTH (AGES 16-25) WITH A SUBSTANCE USE DISORDER (SUD) AND/OR CO-OCCURRING SUBSTANCE USE AND MENTAL HEALTH DISORDERS (COD) AND THEIR FAMILIES. NYS OASAS WILL INCREASE THE ABILITY TO PROVIDE A FULL CONTINUUM OF ACCESSIBLE AND EFFECTIVE TRAUMA-INFORMED TREATMENT, EARLY INTERVENTION, AND RECOVERY SERVICES FOR THIS POPULATION AND THEIR FAMILIES BY PROMOTING THE USE OF EVIDENCE-BASED PRACTICES AND SERVICE ENHANCEMENTS TO FAMILY THERAPY, SCREENING AND ASSESSMENT, TOBACCO CESSATION, RECOVERY HOUSING, AND WRAP AROUND SERVICES. OVER THE COURSE OF FIVE YEARS, OASAS WILL PARTNER WITH PROVIDER SITES ACROSS NEW YORK STATE TO IMPLEMENT A TRAUMA-INFORMED AND PERSON-CENTERED APPROACH TO PROVIDING MOTIVATIONAL ENHANCEMENT THERAPY/COGNITIVE BEHAVIORAL THERAPY (MET/CBT), MULTIDIMENSIONAL FAMILY THERAPY (MDFT), SCREENING, BRIEF INTERVENTION, AND REFERRAL TO TREATMENT (SBIRT), AND ENHANCING THE USE OF MEDICATION ASSISTED TREATMENT (MAT), ESPECIALLY FOR OPIOID AND ALCOHOL USE. THE SAMHSA TOOLKIT FOR SMOKING CESSATION WILL ALSO BE USED TO SCREEN YOUTH AND THEIR FAMILIES FOR TOBACCO USE DISORDER (TUD) AND EXPAND ACCESS TO SMOKING CESSATION MEDICATIONS. IT IS EXPECTED THAT SERVICES THROUGH THE YOUTH AND FAMILY TREE GRANT WILL BE PROVIDED TO A MINIMUM OF 50 TRANSITION AGE YOUTH (TAY) IN YEAR 1 AND 100 TAY IN EACH SUBSEQUENT YEAR, TOTALING 450 YOUTH SERVED. OASAS WILL DEVELOP SYSTEMS AND PROCEDURES DEEMED NECESSARY TO SUSTAIN THESE PROPOSED SERVICES BEYOND THE FIVE-YEAR GRANT PERIOD, INCLUDING EXTENSIVE STAFF TRAINING ON THE AFOREMENTIONED EVIDENCE-BASED PRACTICES AND SCREENINGS. SPECIFIC GOALS OF YOUTH AND FAMILY TREE INCLUDE: (1) INCREASE ACCESS TO EVIDENCE-BASED SUBSTANCE USE TREATMENT SERVICES FOR YOUTH AND THEIR FAMILIES, (2) INTRODUCE THE USE OF A COMPREHENSIVE, FAMILY-CENTERED TREATMENT PROGRAM FOR TAY WITH SUBSTANCE USE AND/OR CO-OCCURRING MENTAL HEALTH DISORDERS, (3) PROMOTE THE USE OF RECOVERY SUPPORT SERVICES FOR YOUTH, (4) IMPROVE ACCESS, SERVICE DELIVERY AND OUTCOMES FOR YOUTH VULNERABLE TO HEALTH DISPARITIES, (5) EXPAND SUSTAINABLE RECOVERY HOUSING FOR YOUTH, (6) EMPHASIZE FEMALE AND ETHNIC MINORITY ACCESS TO SERVICES, AND (7) INCREASE ACCESS TO PRIMARY CARE, MENTAL HEALTH, AND OTHER SUPPORTIVE SERVICES.

GOLGI STUDIES OF SCHIZOPHRENIA

HUMAN PLACENTAL MORPHOLOGY, FUNCTION, AND PATHOLOGY: RELATIONSHIP TO ENVIRONMENTAL EXPOSURES AND NEWBORN AND CHILD HEALTH

APOLIPOPROTEIN E GENOTYPE MODULATES BRAIN MITOVESICLE PRODUCTION, A COMPONENT OF MITOCHONDRIAL QUALITY CONTROL - ABSTRACT : GENERATION OF EXTRACELLULAR VESICLES AND THEIR RELEASE FROM A CELL CONTRIBUTES TO CELLULAR WASTE REMOVAL, MEDIATES THE TRANSPORT OF MATERIALS BETWEEN CELLS, AND PROPAGATES PATHOLOGY IN THE BRAIN. RECENTLY, WE CHARACTERIZED A PREVIOUSLY UNKNOWN TYPE OF EXTRACELLULAR VESICLE OF MITOCHONDRIAL ORIGIN, THE MITOVESICLE, WHICH WE HAVE SHOWN CONTAINS A HIGHLY SELECTIVE COMPILATION OF MITOCHONDRIAL PROTEINS, LIPIDS, RNA, AND DNA. ADDITIONALLY, WE HAVE GROWING EVIDENCE THAT MITOVESICLES – THEIR LEVELS, PRODUCTION, AND COMPOSITION – ARE ALTERED IN NEUROGENERATIVE DISEASES AND DURING AGING. IN SEVERAL SYSTEMS WHERE MITOPHAGY IS COMPROMISED WE HAVE SHOWN AN INCREASE IN MITOVESICLES NUMBERS. THESE FINDINGS HAVE LED US TO PROPOSE THAT MITOVESICLE SECRETION SUPPORTS MITOCHONDRIA HOMEOSTASIS BY ELIMINATING DETRIMENTAL MITOCHONDRIAL MATERIALS FROM THE CELL, ACTING AS AN IMPORTANT AND SELECTIVE MITOCHONDRIAL QUALITY CONTROL. FURTHER, WHEN MITOPHAGY IS INEFFICIENT AND MITOCHONDRIA ARE STRESSED, ENHANCED MITOVESICLE PRODUCTION MAY SUPPORT CELL SURVIVAL BY ELIMINATING OXIDIZED AND DAMAGED MITOCHONDRIAL COMPONENTS. WE HAVE EXCITING PRELIMINARY FINDINGS SHOWING THAT APOE GENOTYPE DIFFERENTIALLY REGULATES BOTH BRAIN MITOVESICLE LEVELS (IN THE FOLLOWING RANK ORDER APOE2>APOE3>APOE4) AND THEIR CONTENT. GIVEN OUR PROPOSED ROLE FOR MITOVESICLES AS AN IMPORTANT MITOCHONDRIAL QUALITY CONTROL, THIS PROJECT WILL ADDRESS OUR HYPOTHESIS THAT THE ENHANCED RELEASE OF MITOVESICLES IN APOE2 IS BENEFICIAL, PROTECTING THE CELL FROM MITOCHONDRIAL DAMAGE, WHEREAS THE LOWER MITOVESICLE BIOGENESIS IN APOE4 IS DELETERIOUS. TESTING WHETHER APOE GENOTYPE AND AGING MODULATES MITOVESICLE LEVELS AND CONTENT, AIM 1 WILL ELUCIDATE THE EFFECTS THAT APOE GENOTYPE HAS ON BRAIN MITOVESICLES IN HUMANIZED APOE MICE AT VARIOUS AGES, WITH MOUSE FINDINGS CONFIRMED IN HUMAN BRAIN TISSUE. AIM 2 WILL DETERMINE IN VITRO AND IN VIVO WHETHER MITOVESICLE PRODUCTION IS A PROTECTIVE COMPONENT OF MITOCHONDRIAL QUALITY CONTROL, ONE THAT IS ENHANCED BY APOE2 EXPRESSION AND COMPROMISED BY APOE4, AND WHETHER MITOCHONDRIAL STRESS IS MODERATED BY ROBUST MITOVESICLE PRODUCTION. IN ADDITION TO “WASTE REMOVAL” MEDIATING MITOCHONDRIAL HEALTH, WE HAVE PRELIMINARY FINDINGS SHOWING THAT MITOVESICLES ARE BIOLOGICALLY ACTIVE ONCE IN THE EXTRACELLULAR SPACE, INCLUDING EFFECTS ON LONG-TERM POTENTIATION (LTP). IN AIM 3, WE WILL DETERMINE THE IMPACT THAT BRAIN MITOVESICLES OF DIFFERING APOE GENOTYPES AND AGES HAVE ON LTP AND SYNAPTOTOXICITY, TESTING THE IDEA THAT APOE4 CAUSES A “DOUBLE-HIT”, WITH A REDUCED NUMBER OF MITOVESICLE COMPROMISING MITOVESICLE-MEDIATED MITOCHONDRIAL QUALITY CONTROL, WHILE THE SECRETED MITOVESICLES LEAD TO THE TRANSMISSION OF MITOVESICLE-DRIVEN TOXICITY TO OTHER CELLS. SPECIFICALLY, THIS AIM WILL INVESTIGATE HOW MITOVESICLE CONTENT DETERMINES THE NEURONAL AND SYNAPTIC IMPACT OF MITOVESICLES ONCE IN THE EXTRACELLULAR SPACE, EXAMINING THEIR UPTAKE BY TARGET CELLS, THEIR IMPACT ON MITOCHONDRIA ONCE INTERNALIZED, AND THEIR IMPACT ON SYNAPSES AND SYNAPTIC FUNCTION. THESE STUDIES WILL DEFINE THE NOVEL ROLE OF MITOVESICLES IN MITOCHONDRIAL HOMEOSTASIS, A QUALITY CONTROL PATHWAY FOR MITOCHONDRIA THAT WE PROPOSE IS MODULATED IN THE BRAIN BY APOE GENOTYPE.

EARLY CORTICAL PROCESSING IN SCHIZOPHRENIA

NEUROPHYSIOLOGY AND ANATOMY OF MULTISENSORY PROCESSING

A SCHIZOPHRENIA EXTENSION STUDY FOR THE NKI ROCKLAND SAMPLE II PROJECT: AN OPEN RESOURCE OF MULTIMODAL BRAIN, PHYSIOLOGY & BEHAVIOR FROM A COMMUNITY LIFESPAN SAMPLE - ABSTRACT SCHIZOPHRENIA (SZ) IS A SEVERE MENTAL DISORDER THAT AFFECTS ~.5% OF THE POPULATION WORLDWIDE AND IS ASSOCIATED WITH SIGNIFICANT INCREASES IN BOTH DISABILITY AND MORTALITY. DISABILITY IS ATTRIBUTABLE IN PART TO THE EFFECTS OF COGNITIVE IMPAIRMENTS AND EXPERIENTIAL NEGATIVE SYMPTOMS, WHILE EXCESS MORTALITY IS ATTRIBUTABLE IN PART TO THE EFFECTS OF INCREASED SUICIDALITY EARLY IN THE DISORDER AND OF NEGATIVE MODIFIABLE HEALTH RISK FACTORS LATER IN THE ILLNESS. EEG- AND FMRI-BASED METHODS HAVE BEEN USED EXTENSIVELY TO INVESTIGATE NEURAL MECHANISMS, BUT PARADIGMS AND METHODS DIFFER EXTENSIVELY ACROSS GROUPS. SMALL-SCALE STUDIES IMPLICATE INCREASED URGENCY AS A RISK FACTOR FOR BOTH AGGRESSION AND SUICIDALITY IN SCHIZOPHRENIA, AND OF LONELINESS AS A DRIVER OF INCREASED HEALTH RISK BUT AWAIT REPLICATION IN LARGER STUDIES. THE LACK OF AVAILABILITY OF LARGE SCALE, OPEN DATABASES THAT INCORPORATE BOTH BRAIN IMAGING AND HEALTH & WELLNESS INFORMATION IS THUS A MAJOR BARRIER TO SCIENTIFIC ADVANCE IN THE FIELD OF SZ. THE PRESENT STUDY LEVERAGES THE TECHNOLOGY AND DATA OF THE ONGOING NIMH-FUNDED (MH124045) ROCKLAND SAMPLE II (NKI-RSII) STUDY OF NORMAL DEVELOPMENT TO CREATE AN OPEN DATA SET OF MULTI-MODAL BRAIN, PHYSIOLOGY AND BEHAVIOR FOR SZ. AS THE NKI-RSII, BOTH RAW AND PROCESSED DATA WILL BE SHARED ONLINE ALONG WITH ANALYSIS ROUTINES AND WILL REPRESENT AN OPEN RESOURCE FOR CLINICAL INVESTIGATION. THE NKI-RSI (N=1400) AND RSII (N=600) STUDIES COLLECT AND SHARE EXTENSIVE NEUROIMAGING, NEUROPHYSIOLOGICAL, PHYSIOLOGICAL AND DEEP PHENOTYPING DATA FROM A COMMUNITY-ASCERTAINED, CROSS-SECTIONAL, LIFESPAN SAMPLE (AGES 6–85 YEARS OLD). DESIGN OF NKI-RSII WAS GUIDED BY THREE MAJOR THEMES: 1) MULTIMODAL MEASUREMENT AND INTEGRATION ACROSS FUNCTIONAL DOMAINS, 2) ECOLOGICAL SAMPLING (E.G., WEARABLES, SENSORS, SMARTPHONE APPS), AND 3) ENHANCED PHYSIOLOGICAL PHENOTYPING FOR CARDIOVASCULAR FITNESS AND OBESITY. SPECIFIC MULTI-MODAL MEASURES INCLUDE TASK-, RESTING-STATE (R-), AND NATURAL VISION (NV-) FMRI, DIFFUSION KURTOSIS IMAGING (DKI), AND NATURALISTIC EEG (NV- EEG) IMPLEMENTED THROUGH THE RECENTLY DEVELOPED MOBILE BODY/BRAIN IMAGING (MOBI)-EEG PLATFORM. RELATIVE BRAIN AGE (RBA) IS CALCULATED USING NOVEL MULTIMODAL ALGORITHMS. BEHAVIORAL ASSESSMENTS ARE DRAWN FROM THE NIH TOOLBOX LIBRARY AND INCLUDE MEASURES OF COMPANIONSHIP, LIFE SATISFACTION AND SOCIAL DISTRESS. IMPULSIVITY IS EVALUATED USING THE UPPS-P. DISABILITY IS EVALUATED USING THE WHO DISABILITY ASSESSMENT SCHEDULE. ECOLOGICAL SAMPLING IS USED TO SUPPLEMENT BEHAVIORAL ASSESSMENTS. CONSISTENT WITH NKI-RSII PROCEDURES, ALL DATA WILL BE SHARED PROSPECTIVELY VIA THE INTERNATIONAL NEUROIMAGING DATA-SHARING INITIATIVE (INDI) AND THE NIMH DATA ARCHIVE (NDA). DESPITE THE EXTENSIVE INVESTMENT IN THE NKI-RSI AND RSII INITIATIVES AND THE GOALS OF EVENTUAL NEUROPSYCHIATRIC USE, NO PATIENT DATA SETS ARE PRESENTLY COLLECTED. THIS PROJECT LEVERAGES THESE RESOURCES TO COLLECT A RICH DATA SET CAPABLE OF SUPPORTING INTEGRATED INVESTIGATION ACROSS NEURAL-, BEHAVIORAL- AND HEALTH-RELATED LEVELS, AND WILL ADDRESS KEY HYPOTHESES RELATED TO CAUSES AND TREATMENT TARGET IDENTIFICATION FOR THE EXTENSIVE DISABILITY AND EXCESS MORTALITY ASSOCIATED WITH SZ.

PATHWAYS TO ENGAGEMENT IN HIV-CARE FOR NEWLY-DIAGNOSED SOUTH AFRICANS

IDENTIFYING BRAIN-BASED BIOMARKERS FOR ASD & THEIR BIOLOGICAL SUBTYPES

BUILDING A GRANULAR BRAIN-WIDE MAP OF THE SEROTONIN SYSTEM - PROJECT SUMMARY AS A BRAIN-WIDE NEUROMODULATOR, SEROTONIN REGULATES A VAST ARRAY OF COGNITIVE AND EMOTIONAL FUNCTIONS. IT CAN POTENTLY INDUCE PLASTICITY IN THE ADULT BRAIN. AND WITH THIS POWER, IT CAN PROMOTE LEARNING AND OPEN WINDOWS FOR CHANGE AND HEALING IN NEUROPSYCHIATRIC CONDITIONS. IT ALSO HAS IMPORTANT ROLES IN ADAPTIVE BEHAVIORAL RESPONSES TO STRESS, AFFILIATIVE SOCIAL BEHAVIOR, AGGRESSION, AND SLEEP. IT IS NO WONDER THAT SEROTONERGIC AGENTS ARE WIDELY USED IN PSYCHIATRY ACROSS SEVERAL DIAGNOSES. HOWEVER, CURRENT TREATMENTS HAVE MANY LIMITATIONS. MOST AFFECT THE SEROTONIN SYSTEM GLOBALLY WITHOUT REGARD TO ITS UNDERLYING HETEROGENEITY. TO MODULATE THE SYSTEM IN A TARGETED WAY, WE NEED TO UNDERSTAND HOW IT IS WIRED, AND WHAT EACH WIRE DOES. SEROTONERGIC NEURONS IN THE DORSAL AND MEDIAL RAPHE NUCLEI SEND AXONAL PROJECTIONS THROUGHOUT THE ENTIRE BRAIN. IN THIS PROJECT, WE WILL MAP THESE PROJECTIONS, WITH SINGLE CELL RESOLUTION BARCODING APPROACH, TO ALL THEIR MAJOR BRAIN TARGETS. WE WILL DETERMINE THE STRENGTH OF THE PROJECTION TO EACH TARGET, AND WE WILL DETERMINE WHICH TARGET AREAS ARE COREGULATED BY COLLATERAL PROJECTIONS, FORMING SUBNETWORKS. FURTHERMORE, WE WILL DETERMINE THE MOLECULAR AND FUNCTIONAL IDENTITY OF THE NEURONS IN EACH PROJECTION. IDENTIFYING THE ANATOMICAL, MOLECULAR, AND FUNCTIONAL BRAIN-WIDE SEROTONERGIC SUBNETWORKS COULD LEAD TO NEW APPROACHES FOR TARGETED THERAPIES.

IMPACT OF METABOTROPIC GLUTAMATE RECEPTOR HETEROMERIZATION ON SIGNALING AND PHARMACOLOGY - GLUTAMATE, THE MAJOR EXCITATORY NEUROTRANSMITTER IN THE BRAIN, ACTS AT EIGHT METABOTROPIC GLUTAMATE (MGLU) SUBTYPES, EXPRESSED IN A PARTIALLY OVERLAPPING FASHION IN DISTINCT BRAIN CIRCUITS. RECENT EVIDENCE INDICATES THAT SPECIFIC MGLU RECEPTOR PROTOMERS CAN HETERODIMERIZE AND EXHIBIT DRAMATICALLY DIFFERENT PHARMACOLOGY WHEN COMPARED TO THEIR HOMOMERIC COUNTERPARTS. THESE FINDINGS OPEN IMPORTANT POSSIBILITIES FOR MORE SELECTIVE LIGAND MODULATION OF MGLU RECEPTOR BIOLOGY IN THE BRAIN. TO DEFINE MGLU HETERODIMER-SPECIFIC PHARMACOLOGY, WE DEVELOPED A TECHNIQUE TERMED CODA-RET (COMPLEMENTED DONOR ACCEPTOR-RESONANCE ENERGY TRANSFER), IN WHICH ONLY A DEFINED DIMERIC PAIR OF RECEPTORS INDUCES A SIGNAL UPON RECEPTOR ACTIVATION. CODA-RET CAN BE USED IN EITHER HOMODIMER OR HETERODIMER MODE, SUCH THAT ACTIVATING LIGANDS WITH DIFFERENTIAL PHARMACOLOGY AT HOMO- VS. HETERODIMERS CAN BE REVEALED. WE HAVE USED CODA-RET IN THE CONTEXT OF AN MGLU2/4 HETEROMER TO DEMONSTRATE THAT AN MGLU2 NEGATIVE ALLOSTERIC MODULATOR (NAM) CAN BLOCK THE RESPONSE TO AN MGLU4-SPECIFIC AGONIST ACROSS THE DIMER INTERFACE. FURTHERMORE, WE SHOWED THAT, WHILE ONE STRUCTURAL CLASS OF MGLU4 POSITIVE ALLOSTERIC MODULATORS (PAMS) CAN POTENTIATE BOTH MGLU4/4 HOMOMERS AND MGLU2/4 HETERODIMERS, ANOTHER CLASS OF MGLU4 PAMS POTENTIATES ONLY MGLU4/4 HOMOMERS. WE USED THESE PHARMACOLOGICAL TOOLS TO IDENTIFY INPUT-SPECIFIC PHARMACOLOGY IN SPECIFIC NEURONAL CIRCUITS, WITH EFFECTS CONSISTENT WITH MGLU2/4 HETERODIMERS AT CORTICOSTRIATAL AND THALAMOCORTICAL SYNAPSES, VERSUS MGLU4/4 RECEPTORS AT STRIATOPALLIDAL SYNAPSES, PROVIDING AN OPPORTUNITY FOR MORE PRECISE PHARMACOLOGICAL INTERVENTION. IN MICE, EVOKED EXCITATORY CURRENTS AND INDUCTION OF LONG-TERM POTENTIATION (LTP) AT SCHAFFER COLLATERAL-CA1 (SC-CA1) SYNAPSES IN THE HIPPOCAMPUS ARE BLOCKED BY THE SELECTIVE MGLU7 NEGATIVE ALLOSTERIC MODULATOR (NAM), ADX71743. IN CONTRAST, THE MGLU7 NAM MMPIP, WITH A SIMILAR PROFILE TO ADX71743 IN HETEROLOGOUS CELLS EXPRESSING MGLU7 HOMOMERS, FAILS TO BLOCK THESE RESPONSES IN BRAIN SLICES. WE HYPOTHESIZED THAT THIS MIGHT RESULT FROM HETEROMERIZATION OF MGLU7 WITH ANOTHER MGLU RECEPTOR PROTOMER. SINCE AN MGLU8 PHARMACOLOGY HAS ALSO BEEN REPORTED AT SC-CA1 SYNAPSES, WE USED CODA-RET TO STUDY MGLU7/8 HETERODIMERS IN VITRO AND FOUND THAT ADX71743 BLOCKS RESPONSES OF BOTH MGLU7/7 HOMODIMERS AND MGLU7/8 HETERODIMERS, WHEREAS MMPIP ONLY ANTAGONIZES RESPONSES AT MGLU7/7 HOMODIMERS. USING THESE COMPOUNDS, AS WELL AS GENETIC KNOCKOUT OF MGLU8, WE WILL TEST THE HYPOTHESIS THAT A RECEPTOR WITH A PHARMACOLOGICAL SIGNATURE CONSISTENT WITH AN MGLU7/8 HETERODIMER IS FUNCTIONALLY EXPRESSED IN THE HIPPOCAMPUS. OUR AIMS ARE: 1) TO DEFINE THE PHARMACOLOGICAL PROFILES OF MGLU7 ALLOSTERIC LIGANDS AT GLUTAMATERGIC AND GABAERGIC SYNAPSES IN AREA CA1 OF THE HIPPOCAMPUS. 2) TO TEST THE HYPOTHESIS THAT MGLU7/8 HETERODIMERS LEAD TO THE MMPIP-INSENSITIVE PHENOTYPE IN SC-CA1 RESPONSES. 3) TO ELUCIDATE THE ACTIVATION MECHANISM AND SIGNALING PROPERTIES OF MGLU7/7 HOMODIMERS, MGLU8/8 HOMODIMERS, AND MGLU7/8 HETERODIMERS USING CODA-RET.

A NEW PERSPECTIVE ON THE ROLE OF EXTRACELLULAR VESICLES IN ALZHEIMER'S DISEASE - ABSTRACT: EXTRACELLULAR VESICLE (EV) GENERATION AND RELEASE IS INVESTIGATED AS A DEFAULT WASTE REMOVAL MECHANISM, A SOURCE OF POTENTIAL BIOMARKERS, FOR TRANSPORT OF MATERIAL BETWEEN CELLS, AND FOR PROPAGATION OF PATHOLOGY THROUGHOUT THE BRAIN. EVS ARE HIGHLY HETEROGENOUS, AND EACH EV SUBTYPE CONTRIBUTES TO BRAIN PHYSIOLOGY AND DISEASE DIFFERENTLY. OUR LABORATORY HAS DEVELOPED A TECHNIQUE TO FRACTIONATE EV SUBTYPES FROM MURINE AND HUMAN BRAIN TISSUE, IDENTIFYING A PREVIOUSLY UNKNOWN SUBTYPE OF BRAIN EVS OF MITOCHONDRIAL ORIGIN, NAMED MITOVESICLES. GIVEN THE NOVELTY, MITOVESICLE BIOLOGY AND FUNCTION(S) HAVE NEVER BEEN INVESTIGATED. WE HYPOTHESIZE THAT MITOVESICLE SECRETION INTO THE BRAIN EXTRACELLULAR SPACE ELIMINATES DETRIMENTAL MITOCHONDRIAL MATERIALS FROM THE CELL, ESPECIALLY WHEN OTHER MITOCHONDRIAL QUALITY CONTROL MECHANISMS, INCLUDING MITOPHAGY, ARE DISRUPTED. SHUTTLING FROM ONE CELL TO ANOTHER, DYSFUNCTIONAL MITOVESICLES CAN TRANSFER THIS MITOCHONDRIAL CONTENT FROM A SINGLE FOCAL SITE TO THE REST OF THE BRAIN, POTENTIALLY IMPAIRING RECIPIENT DISTAL CELLS. WE WILL TEST OUR NOVEL HYPOTHESES REGARDING CELLULAR MECHANISMS INVOLVING MITOVESICLES IN THE BRAIN, BOTH PHYSIOLOGICAL AND PATHOLOGICAL, IDEAS THAT ARE SUPPORTED BY OUR PRELIMINARY FINDINGS AND ARE CONSISTENT WITH MITOCHONDRIA BEING A POINT OF HEIGHTENED VULNERABILITY IN ALZHEIMER DISEASE (AD). WE PROPOSE IN VITRO AND IN VIVO STUDIES OF ALL ASPECTS OF MITOVESICLE LIFECYCLE, INCLUDING GENERATION, SECRETION, UPTAKE, AND INTRACELLULAR FATE IN RECIPIENT CELLS. FURTHERMORE, WE WILL EXPLORE WHETHER MITOVESICLES ISOLATED FROM BRAINS OF MURINE MODELS OF B-AMYLOIDOSIS TRIGGER ALTERATIONS IN OTHERWISE NORMAL TISSUES THAT ARE REMINISCENT OF AD, INCLUDING CHANGES IN MITOCHONDRIAL DYNAMICS, MITOPHAGY, REACTIVE OXYGEN SPECIES PRODUCTION, OXIDATIVE BALANCE, CELL SURVIVAL, NEUROINFLAMMATION, AND SYNAPTIC TRANSMISSION, LEADING TO BEHAVIORAL DEFICITS. OUR PROPOSED STUDIES WILL EXAMINE THE MECHANISM INITIATING CHANGES IN MITOVESICLES BIOGENESIS AND SECRETION AND THE DOWNSTREAM EFFECTS OF THESE CHANGES. WE WILL STUDY MITOVESICLES ISOLATED FROM THE BRAIN OF TWO AD-RELEVANT MOUSE MODELS OF B-AMYLOIDOSIS, THE KNOCK-IN APPNL-F/NL- F AND THE OVEREXPRESSING APP23, THAT PRELIMINARY STUDIES HAVE SHOWN TO BE ALTERED PRIOR TO ROBUST B-AMYLOIDOSIS. THE EFFECT OF SEX, AGE, AND AMYLOID B DEPOSITION WILL BE CONSIDERED BY ANALYZING BRAINS OF FEMALE AND MALE MICE AT DIFFERENT AGES, COMPARING A PRODROMAL STAGE, AN AGE WITH LIMITED PLAQUE PATHOLOGY, AND AN ADVANCED PATHOLOGY STAGE AGE WITH EXTENSIVE B-AMYLOIDOSIS. IN AIM 1 WE WILL INVESTIGATE MITOVESICLE BIOLOGY, INCLUDING INTRACELLULAR BIOGENESIS, TRANSPORT, RELEASE, AND UPTAKE OF PHYSIOLOGICAL MITOVESICLES IN CULTURED NEURONS, ASTROCYTES, AND MICROGLIA. IN AIM 2 WE WILL INVESTIGATE THE PATHOGENIC CHANGES IN MITOVESICLES IN THE TWO B- AMYLOIDOSIS MOUSE MODELS. FINDINGS WILL BE CONFIRMED IN MITOVESICLES ISOLATED FROM THE BRAIN OF AD PATIENTS, AS COMPARED WITH NON-DEMENTED CONTROLS. THE PROPOSED EXPERIMENTS WILL DETERMINE THE BALANCE OF BENEFICIAL AND PATHOGENIC EFFECTS OF MITOVESICLES AND HAVE THE POTENTIAL TO IDENTIFY PREVIOUSLY UNEXPLORED THERAPEUTIC DIRECTIONS TO RESTORE THE INTEGRITY OF MITOCHONDRIA, MINIMIZING THE NEURODEGENERATIVE CONSEQUENCES OF AD.

THALAMO-PREFRONTAL CIRCUIT MATURATION DURING ADOLESCENCE - ADOLESCENCE IS A WINDOW OF VULNERABILITY FOR THE DEVELOPMENT OF SCHIZOPHRENIA AND OTHER MENTAL DISORDERS. IN SCHIZOPHRENIA, IMAGING STUDIES HAVE FOUND THAT THALAMO-PREFRONTAL RESTING STATE CONNECTIVITY IS REDUCED DURING ADOLESCENCE PRIOR TO DISEASE ONSET. THIS DECREASE IN FUNCTIONAL CONNECTIVITY HAS BEEN LINKED TO COGNITIVE SYMPTOMS AND THE ETIOLOGY OF THE DISORDER. FOR MANY YEARS, AN ALTERED MATURATION OF THE PREFRONTAL CORTEX (PFC) HAS BEEN IMPLICATED IN THE COGNITIVE DEFICITS OF MENTAL DISORDERS YET THE MECHANISMS THAT DRIVE PFC MATURATION ARE LARGELY UNKNOWN. BECAUSE THALAMIC INPUT ACTIVITY IS IMPORTANT FOR CIRCUIT MATURATION IN SENSORY CORTICES, WE HYPOTHESIZE HERE THAT THALAMIC INPUT ACTIVITY IS ALSO IMPORTANT FOR PREFRONTAL CIRCUIT MATURATION. TO ADDRESS WHETHER ADOLESCENCE IS A SENSITIVE TIME-PERIOD DURING WHICH THALAMIC ACTIVITY REGULATES THE MATURATION OF PFC CIRCUITRY, WE USED MICE AND COMPARED THE EFFECTS OF REDUCING ACTIVITY IN THE THALAMIC NUCLEI PROJECTING TO THE PFC DURING POSTNATAL DAYS P20-50 WITH THAT IN ADULTHOOD (P90-120). WE FOUND THAT INHIBITING THE THALAMUS DURING ADOLESCENCE LEADS TO A LONG-LASTING DECREASE IN THE DENSITY OF THALAMO-MPFC PROJECTIONS AND A REDUCED EXCITATORY DRIVE TO MPFC NEURONS. ADOLESCENT THALAMIC INHIBITION FURTHER CAUSES COGNITIVE DEFICITS IN ATTENTIONAL SET SHIFTING DURING ADULTHOOD THAT ARE ASSOCIATED WITH DISRUPTED CORRELATED NEURONAL ACTIVITY AND TASK OUTCOME ENCODING IN THE MPFC. IN CONTRAST, THALAMIC INHIBITION DURING ADULTHOOD HAS NO LONG-LASTING CONSEQUENCES ON MPFC EXCITATION, CORRELATED ACTIVITY, OUTCOME ENCODING AND BEHAVIOR. STRIKINGLY, EXCITING THE THALAMUS IN ADULTHOOD DURING THE SET SHIFTING TASK RESCUES IN VIVO NEURONAL ACTIVITY AND COGNITIVE DEFICITS INDUCED BY ADOLESCENT INHIBITION. WHILE THESE DATA POINT TO ADOLESCENCE AS A SENSITIVE TIME WINDOW FOR PFC CIRCUIT MATURATION THE UNDERLYING MECHANISMS BY WHICH ADOLESCENT INHIBITION IMPAIRS MPFC MATURATION ARE STILL UNCLEAR. TO ADDRESS THIS, FIRST, THE DEVELOPMENT OF MPFC CIRCUITRY NEEDS TO BE CHARACTERIZED DURING ADOLESCENCE. SECOND, IT WILL BE IMPORTANT TO DETERMINE WHETHER ADOLESCENT INHIBITION INDUCES LONG-LASTING CHANGES IN INTRINSIC MPFC CIRCUITRY, AND WHICH SPECIFIC MPFC PROJECTIONS AND INTERNEURONS ARE REGULATED BY ADOLESCENT THALAMIC INHIBITION. THIRD, IT WILL BE IMPORTANT TO KNOW WHEN SUCH CHANGES ARISE AND HOW THEY RELATE TO THE CHANGES IN IN VIVO CROSS CORRELATED ACTIVITY AND OUTCOME ENCODING. OUR DATA FURTHER SUGGEST THAT BOOSTING THALAMIC ACTIVITY COULD PROVIDE A STRATEGY FOR RESCUING COGNITIVE DEFICITS IN NEURODEVELOPMENTAL DISORDERS. HOWEVER, AS PRESENTED, THE BENEFICIAL EFFECT ONLY OCCURS WHILE THE THALAMUS IS STIMULATED. THEREFORE, STRATEGIES WILL NEED TO BE IDENTIFIED THAT ALLOW FOR A LONGER LASTING RESCUE OF THE COGNITIVE ABILITIES. WE WILL ADDRESS THESE QUESTIONS USING THREE AIMS: AIM 1: TO DETERMINE WHEN AND WHERE ADOLESCENT THALAMIC ACTIVITY REGULATES THE DEVELOPMENT OF MPFC CIRCUIT CONNECTIVITY. AIM 2: TO DETERMINE WHETHER THE IMPACT OF ADOLESCENT THALAMIC INHIBITION ON COGNITION REQUIRES MATURATION OF THE MPFC. AIM 3. TO DETERMINE WHETHER THALAMIC EXCITATION CAN LEAD TO A LONG-LASTING RESCUE OF THE COGNITIVE DEFICIT.

CONTRIBUTION OF MATERNAL IMMUNE ACTIVATION, VIRAL INFECTION AND EPIGENETICS TO AUTISM--A COMMUNITY-BASED CASE CONTROL STUDY - PROJECT SUMMARY/ABSTRACT AUTISM SPECTRUM DISORDER (ASD) IS A BROAD RANGE OF RELATED NEURODEVELOPMENTAL DISORDERS THAT ARE EXPRESSED WITHIN THE FIRST 2 TO 3 YEARS OF LIFE AS STEREOTYPIC BEHAVIORS, AND LANGUAGE AND SOCIAL-EMOTIONAL IMPAIRMENTS. ASD AFFECTS ABOUT 1 IN 59 CHILDREN IN THE UNITED STATES AND CARRIES A HIGH ECONOMIC COST TO FAMILIES AND COMMUNITIES. WHILE THERE IS A CONTRIBUTION OF HEREDITY, A GROWING BODY OF RESEARCH SUGGESTS THAT ASD HAS ORIGINS IN UTERO. SPECIFICALLY, EVIDENCE IS ACCUMULATING THAT PRENATAL INFLAMMATION IS A CRITICAL EXPOSURE IN THE CAUSAL PATHWAY OF AT LEAST A SUBSET OF ASD. NOTABLY, THIS EXPOSURE MAY OPERATE THROUGH SEX-DIMORPHIC EFFECTS ON THE PLACENTA ON FETAL BRAIN DEVELOPMENT, CONSISTENT WITH THE HIGH ASD RISK FOR MALES RELATIVE TO FEMALES. IN OUR COMMUNITY-BASED HOSPITAL POPULATION, UNIQUE DUE TO MANDATED UNIVERSAL PLACENTAL HISTOPATHOLOGY ASSESSMENT AND LINKAGE TO PEDIATRIC COMMUNITY CARE, PILOT ANALYSES IDENTIFIED A 3-TO-7-FOLD INCREASED RISK OF CHILDHOOD ASD ASSOCIATED WITH PRENATAL EXPOSURE TO ACUTE AND/OR CHRONIC INFLAMMATION (AI, CI). THIS MARKER WAS SEEN IN ~25% OF LOW-RISK CHILDREN EVENTUALLY DIAGNOSED WITH ASD. THESE INFLAMMATORY PLACENTAL PATHOLOGIES WERE NOT MARKED BY ANY MATERNAL SIGNS OR SYMPTOMS DURING PREGNANCY. IN ADDITION, WE IDENTIFIED A 13-FOLD INCREASED ODDS OF ASD RISK WITH PLACENTAL VILLOUS MALDEVELOPMENT (PVM). WE PROPOSE HERE TO TEST PATHWAYS FROM THESE PLACENTAL HISTOPATHOLOGY DIAGNOSES TO EVENTUAL ASD DIAGNOSIS. WE WILL BEGIN WITH TARGETED FORMALIN-FIXED PARAFFIN-EMBEDDED (FFPE) PLACENTAL HISTOPATHOLOGY OF AI, CI, AND PVM. WE WILL THEN EMPLOY DETAILED AND QUANTITATIVE IMMUNOPHENOTYPING OF PLACENTAL-DECIDUAL TISSUE AT THE PLACENTAL-MATERNAL INTERFACE. WE CAN THOROUGHLY PROFILE CELL TYPE, CELL FUNCTION MARKERS, AND INFLAMMATION ACTIVATION/APOPTOSIS TARGETS AT THE SAME TIME BY USING COMPUTER-ASSISTED DEEP LEARNING THAT ALLOWS PRECISE TRACKING OF IMMUNOLABELING AND MINIMIZES CONCERNS OF LABEL OVERLAP THAT CAN CONFOUND INTERPRETATION OF IMMUNOFLUORESCENT PREPARATIONS. WE WILL NEXT ASSESS NEWBORN CIRCULATING LEVELS OF CYTOKINES, CHEMOKINES, AND GROWTH FACTORS, ALTERATIONS OF WHICH ARE KNOWN TO IMPACT NEURODEVELOPMENTAL PROCESSES KEY TO THE GENESIS OF NEURONAL DYSFUNCTION MANIFESTED IN ASD. WE WILL ALSO EXAMINE EPIGENETIC PATHWAYS BY ASSESSING DNA METHYLATION IN THE PLACENTA AND ITS LINK TO INFLAMMATION AND PVM. OUR ANALYSES WILL TEST THESE AS PATHWAYS FROM PLACENTAL/DECIDUAL TISSUE MARKERS OF INFLAMMATION AND/OR PVM TO ASD DIAGNOSIS. NO OTHER ASD CASE-CONTROL SAMPLE IN A COMMUNITY-BASED POPULATION HAS UNIVERSAL ACCESS TO FFPE TISSUE. THIS PROPOSED PROJECT WILL OPEN A UNIQUE WINDOW ON THE PRENATAL ENVIRONMENT UNDERLYING ASD. CLARIFICATION OF THE PATHWAYS OPERATING IN COMMUNITY-BASED ASD WILL ELUCIDATE THE MECHANISMS INVOLVED IN ASD RISK.

AMINO-TERMINAL ACETYLATION OF PROTEINS IN MAMMALIAN BIOLOGY AND DISEASE

USE OF NOVEL MOBILE TECHNOLOGY TO SCREEN SEXUAL PARTNERS FOR HIV AND STIS

AUDITORY EVENT-RELATED POTENTIALS AS IN VIVO PRECLINICAL ASSAYS OF CIRCUIT ENGAGEMENT FOR E/I-BASED THERAPEUTIC DEVELOPMENT - THIS APPLICATION RESPONDS TO PAR-22-170 BUILDING IN VIVO PRECLINICAL ASSAYS OF CIRCUIT ENGAGEMENT FOR APPLICATION IN THERAPEUTIC DEVELOPMENT. THE PROJECT WILL OPTIMIZE NON-HUMAN PRIMATE (NHP) AND RODENT ANALOGS OF HUMAN AUDITORY MISMATCH NEGATIVITY (MMN) FOR USE IN PRECLINICAL DEVELOPMENT PROGRAMS. DEFICITS IN MMN GENERATION HAVE BEEN EXTENSIVELY DESCRIBED IN SCHIZOPHRENIA (SZ) AND SHOWN TO CORRELATE WITH COGNITIVE IMPAIRMENT AND POOR FUNCTIONAL OUTCOME IN ESTABLISHED SZ, AND IN CONVERSION TO SZ AMONG INDIVIDUALS AT CLINICAL HIGH RISK (CHR), DEMONSTRATING CLINICAL RELEVANCE. MMN MAY ALSO DECREASE IN AMPLITUDE DURING THE INITIAL STAGES OF SZ, PROVIDING A TARGET FOR DEVELOPMENT OF TREATMENTS THAT MAY PREVENT NEURODEGENERATION DURING INITIAL STAGES OF THE DISORDER. MMN INDEXES THE INTEGRITY OF EARLY AUDITORY PROCESSING (EAP) SUCH AS DELAYED TONE MATCHING ABILITIES, WHICH ARE CRITICAL FOR PROCESSES SUCH AS AUDITORY EMOTION RECOGNITION, VERBAL MEMORY, AND PHONOLOGICAL READING ABILITY. DEFICITS IN THESE PROCESSES, IN TURN, SIGNIFICANTLY PREDICT OUTCOME. IN ADDITION, LOCAL CIRCUIT ABNORMALITIES THAT GIVE RISE TO MMN IMPAIRMENTS IN AUDITORY CORTEX MAY BE PRESENT ACROSS BRAIN REGIONS. INSIGHTS GLEANED FROM INVESTIGATION AND REMEDIATION OF MMN DEFICITS MAY THEREFORE BE RELEVANT ACROSS CORTICAL REGIONS. IN HUMANS, MMN GENERATION IS INHIBITED RELIABLY BY N-METHYL-D-ASPARTATE RECEPTORS (NMDAR), SUGGESTING INVOLVEMENT OF UNDERLYING GLUTAMATERGIC MECHANISMS AND LOCAL EXCITATORY/INHIBITORY (E/I) BALANCE. IN SPECTRAL ANALYSES, MMN SHOWS PRIMARY POWER WITHIN THE THETA FREQUENCY RANGE, SUGGESTING ADDITIONAL INVOLVEMENT OF SOMATOSTATIN (SOM)-TYPE GABA INTERNEURONS. MMN-LIKE ACTIVITY HAS BEEN DEMONSTRATED IN BOTH NHP AND RODENTS, AND IN BOTH SPECIES SHOWS SIMILAR SPECTRAL CONTENT AND NMDAR SENSITIVITY TO HUMAN MMN. THE PRESENT PROJECT WILL 1) FURTHER OPTIMIZE THESE MEASURES FOR USE IN EARLY-STAGE DRUG DEVELOPMENT, WHILE 2) ALSO EVALUATING THEIR SENSITIVITY AND SELECTIVITY TO COMPOUNDS THAT DO (E.G. NMDAR ANTAGONISTS) AND DO NOT (E.G. 5-HT2A ANTAGONISTS) AFFECT THEIR GENERATION IN HUMANS. THESE MEASURES WILL THEN 3) BE USED TO TEST SPECIFIC LOCAL AND DISTRIBUTED CIRCUIT COMPUTATIONAL MODELS TO PERMIT REFINEMENT IN USE OF MMN PARADIGMS ACROSS HUMANS, NHP AND RODENTS. AT THE DISTRIBUTED NETWORK LEVEL, MECHANISTIC TESTING WILL SEEK TO REFINE EMERGENT PREDICTION ERROR (PE) BASED THEORIES OF MMN GENERATION, WHICH POSIT SPECIFIC FEED-FORWARD AND FEED-BACK INFORMATION FLOW AMONG PRIMARY AUDITORY CORTEX (A1), SUPERIOR TEMPORAL GYRUS (STG) AND INFERIOR FRONTAL GYRUS (IFG), AND TO DEVELOP SPECTRAL SIGNATURES OF THIS INFORMATION FLOW. AT THE LOCAL CIRCUIT LEVEL, MECHANISTIC TESTING WILL ASSESS THE RELATIVE CONTRIBUTIONS OF SPECIFIC INTERNEURON POPULATIONS USING CELL-SPECIFIC GENETIC MANIPULATION. SEVERAL COMPOUNDS THAT TARGET NMDAR VIA THE GLYCINE/D-SERINE MODULATORY SITE (E.G. ICLEPERTIN, LUVADAXISAT) HAVE SHOWN PROMISE FOR TREATMENT OF COGNITIVE IMPAIRMENT ASSOCIATED WITH SZ (CIAS). THE PRESENT PIPELINE WILL ENABLE IDENTIFICATION AND VALIDATION OF ADDITIONAL TARGETS WITHIN THE E/I CIRCUIT AND DEVELOPMENT OF ADDITIONAL APPROACHES FOR ENHANCEMENT OF GLUTAMATERGIC FUNCTION AND RESTORATION OF E/I BALANCE ACROSS NEUROPSYCHIATRIC DISORDERS.

PILOT LONGITUDINAL DATA COLLECTION TO INFORM PUBLIC HEALTH_FRAGILE X SYNDROME