R01MH126979

PUBERTY-RELATED DEVELOPMENT OF FRONTO-AMYGDALA CIRCUITRY IN ANXIOUS YOUTH: A MULTIMODAL NEUROIMAGING STUDY WITH ULTRA-HIGH RESOLUTION MRI SCANNER (7T) - SUMMARY

ANXIETY DISORDERS, WHICH ONSET DURING CHILDHOOD OR ADOLESCENCE, OFTEN PERSIST INTO ADULTHOOD, AND INCREASE THE RISK OF DEPRESSION AND SUICIDE. EARLY ADOLESCENCE, WITH THE ONSET OF PUBERTY, IS AN IMPORTANT PERIOD FOR THE DEVELOPMENT AND/OR EXACERBATION OF ANXIETY SYMPTOMS – I.E., GENERALIZED ANXIETY DISORDER (GAD) AND SOCIAL ANXIETY DISORDER (SAD) – WITH HIGHER LEVELS OF SYMPTOMS IN GIRLS THAN BOYS.

DURING THIS TIME, FRONTO-AMYGDALA CIRCUITRY, WHICH SUPPORTS EMOTION REGULATION, UNDERGOES IMPORTANT MATURATIONAL CHANGES. ALTHOUGH ALTERATIONS IN THIS CIRCUITRY HAS BEEN REPORTED IN ANXIETY DISORDERS, THE NEURODEVELOPMENTAL MECHANISMS UNDERLYING THE SEX DIFFERENCES IN LEVELS OF ANXIETY SYMPTOMS REMAIN POORLY UNDERSTOOD.

COMPARED TO NON-ANXIOUS YOUTH, ANXIOUS YOUTH EXHIBIT GREATER AMYGDALA ACTIVATION AND REDUCED FRONTO-AMYGDALA FUNCTIONAL CONNECTIVITY WHEN PROCESSING THREAT-RELATED STIMULI. SUCH REDUCED TOP–DOWN MODULATION OF AMYGDALA ACTIVITY TO THREAT HAS BEEN LINKED IN ANXIOUS ADULTS TO ELEVATED CONCENTRATIONS IN -AMINOBUTYRIC ACID (GABA) AND GLUTAMATE IN THE VENTROMEDIAL PREFRONTAL CORTEX (VMPFC) AND AMYGDALA, RESPECTIVELY. IT HAS ALSO BEEN LINKED, INCLUDING IN ANXIOUS YOUTH, TO REDUCED INTEGRITY OF WHITE MATTER TRACTS CONNECTING VMPFC AND AMYGDALA (I.E., UNCINATE FASCICULUS AND CINGULUM).

WHILE VMPFC INHIBITION OF AMYGDALA ACTIVITY INCREASES WITH AGE, WE AND OTHERS HAVE SHOWN IN HEALTHY AND AT- RISK YOUTH THAT INCREASES IN PUBERTAL HORMONES, PARTICULARLY TESTOSTERONE, ARE ASSOCIATED WITH REDUCED VMPFC- AMYGDALA FUNCTIONAL CONNECTIVITY TO THREAT. WE WILL TEST THE MODEL THAT INCREASES IN PUBERTAL HORMONES DURING EARLY ADOLESCENCE WILL EXACERBATE ALTERATIONS IN FRONTO-AMYGDALA CIRCUITRY IN ANXIOUS YOUTH AND CONTRIBUTE TO GREATER THREAT REACTIVITY AND INCREASES IN ANXIETY SYMPTOMS, ESPECIALLY IN GIRLS.

WE TEST THIS HYPOTHESIS IN A SAMPLE OF MEDICATION-FREE 140 ADOLESCENTS (50% FEMALE), VARYING IN LEVELS OF ANXIETY, WITH 2/3 OVERSAMPLED FOR CLINICAL LEVELS OF GAD AND SAD SYMPTOMS. WE WILL REPEATEDLY ASSESS PARTICIPANTS AT FIVE TIMEPOINTS.

AT BASELINE AND APPROXIMATELY 2 YEARS LATER, WE WILL ASSESS ANXIETY (CLINICAL INTERVIEWS, QUESTIONNAIRES), PUBERTAL STATUS (TANNER, SELF-REPORT), PUBERTAL HORMONES (DHEA, TESTOSTERONE, AND ESTRADIOL), THREAT REACTIVITY IN A REAL-WORLD CONTEXT WITH PHYSIOLOGICAL AND SUBJECTIVE MEASURES OF THREAT REACTIVITY, AND NEURAL INDICES OF VMPFC-AMYGDALA CIRCUITRY (FMRI DURING THREAT PROCESSING AND AT REST, WHITE MATTER CONNECTIVITY, AND MAGNETIC RESONANCE SPECTROSCOPY (MRS) MEASURES OF GABA AND GLUTAMATE).

CHANGE IN SYMPTOMS WILL BE ASSESSED BI-ANNUALLY VIA ONLINE QUESTIONNAIRES OVER 2 YEARS POST BASELINE VISIT. WE USE AN ULTRA HIGH-FIELD MRI AT 7 TESLA, WHICH WILL YIELD UNPRECEDENTED CHARACTERIZATION OF VMPFC-AMYGDALA NEURODEVELOPMENT IN ANXIOUS YOUTH.

WE WILL ALSO EXPLORE THE EFFECTS OF PUBERTAL HORMONES, ANXIETY, AND THREAT REACTIVITY ON WHOLE BRAIN FUNCTIONAL NETWORKS AND EXAMINE HOW EACH OF THE NEURAL INDICES RELATE TO EACH OTHER OVER TIME.

OUR GOALS ARE CONSISTENT WITH THE RDOC INITIATIVE AND NIMH STRATEGY 2.2, ENCOURAGING IDENTIFICATION OF EARLY BIOLOGICAL AND ENVIRONMENTAL RISK AND PROTECTIVE FACTORS AND THEIR UNDERLYING MECHANISMS TO INFORM THE CONTINUED DEVELOPMENT OF PREVENTION AND INTERVENTION.

University Of Pittsburgh - Of The Commonwealth System Of Higher Education

THE MISSION OF THE NATIONAL INSTITUTE OF MENTAL HEALTH (NIMH) IS TO TRANSFORM THE UNDERSTANDING AND TREATMENT OF MENTAL ILLNESSES THROUGH BASIC AND CLINICAL RESEARCH, PAVING THE WAY FOR PREVENTION, RECOVERY, AND CURE. WE FULFILL THIS MISSION BY SUPPORTING AND CONDUCTING RESEARCH ON MENTAL ILLNESSES, HEALTH SERVICES, AND THE UNDERLYING BASIC SCIENCE OF THE BRAIN AND BEHAVIOR; SUPPORTING THE TRAINING OF SCIENTISTS TO CARRY OUT BASIC AND CLINICAL MENTAL HEALTH RESEARCH; AND COMMUNICATING WITH SCIENTISTS, PATIENTS, PROVIDERS, AND THE PUBLIC ABOUT MENTAL HEALTH RESEARCH ADVANCES AND PRIORITIES. IN MAY 2024, NIMH RELEASED ITS STRATEGIC PLAN FOR RESEARCH. THE STRATEGIC PLAN BUILDS ON THE SUCCESSES OF PREVIOUS NIMH STRATEGIC PLANS BY PROVIDING A FRAMEWORK FOR SCIENTIFIC RESEARCH AND EXPLORATION, AND ADDRESSING NEW CHALLENGES IN MENTAL HEALTH.THE NEW STRATEGIC PLAN OUTLINES FOUR HIGH-LEVEL GOALS: GOAL 1: DEFINE THE BRAIN MECHANISMS UNDERLYING COMPLEX BEHAVIORS GOAL 2: EXAMINE MENTAL ILLNESS TRAJECTORIES ACROSS THE LIFESPAN GOAL 3: STRIVE FOR PREVENTION AND CURES GOAL 4: STRENGTHEN THE PUBLIC HEALTH IMPACT OF NIMH-SUPPORTED RESEARCH THESE FOUR GOALS FORM A BROAD ROADMAP FOR THE INSTITUTES RESEARCH PRIORITIES OVER THE NEXT FIVE YEARS, BEGINNING WITH THE FUNDAMENTAL SCIENCE OF THE BRAIN AND BEHAVIOR, AND EXTENDING THROUGH EVIDENCE-BASED SERVICES THAT IMPROVE PUBLIC HEALTH OUTCOMES.

93.242 - Mental Health Research Grants

National Institute of Mental Health (NIMH) [HHS - NIH]

Pittsburgh, Pennsylvania 152133203 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 05/31/26 to 05/31/27 and the total obligations have increased 400% from $766,641 to $3,834,240.