Purpose: This 5-year R01 study will elucidate the role of maturational change across adolescence in neural connectivity and physiological stress responses in the relationship between anxiety and adverse pathways to substance use (APSU). Participants: Children (N=200) aged 12-14 with symptoms of anxiety and their legal caregiver will be recruited from clinical and community sources. Procedures: Youth participants will complete several questionnaires and interviews, undergo neuroimaging while performing cognitive tasks, and have their heart rate and skin conductance monitored during a mildly stressful task. Caregivers will complete several questionnaires.

The conceptual model proposes that the relationship between anxiety symptomatology and Adverse Patterns of Substance Use (APSU: age of onset, cumulative exposure, severity, and polydrug use) is a function of acute stress reactivity that is underpinned by specific neurobiological and neurocognitive factors measurable at a drug- and alcohol-naïve baseline. Youth at high risk for APSU will be over-sampled using parent and child-reported screeners that include items relating to emotion dysregulation, behavioral impulsivity, susceptibility to peer pressure, friends' conduct problems, and other risk-relevant characteristics to define a high-APSU-risk prodrome. Risk status will be measured as a continuous trait using well-tested thresholds for high and low risk for APSU, and the recruitment strategy will ensure sufficient variability on this axis. This approach ensures a sufficient number of youth will initiate and escalate SU within the time frame of the study, allowing the investigators to assess precursors APSU in high risk youth as a function of anxiety symptomatology and acute stress reactivity, using feasible and adequately powered methods.

To test hypotheses, the investigators will prospectively assess acute stress responsivity, anxiety symptoms, specific neural connectivity patterns, and APSU in a sample of 180 substance-naïve youth beginning in early adolescence (age 12-14, Tanner Stage >3) and two additional 12 month waves of data collection. Participants will complete an acute stress task outside the scanner with psychophysiological monitoring and a resting and performance based MRI session using impulsivity (fronto-striatal-thalamic circuitry), negative valence (threat circuitry), and attention bias (shifting from threat to frontal circuitry) tasks. At each wave, all surveys, cognitive tests, stress physiological, clinical and neuroimaging measures will be assessed. A final online exit survey in year 5 will be conducted simultaneously for all participants to evaluate clinical symptoms and end-point APSU.

The proposed prospective, longitudinal design is novel, creative, and timely. Brain imaging studies of this type are typically quite small, often due to cost limitations, and are only able to accurately model a small subset of factors and covariates. The investigators plan to evaluate the complexity of the problem with targeted variables that will be well-defined in the sample and tracked over time in relation to APSU in an atypically large sample for neuroimaging. This design will enable within- and between-subject comparisons that prospectively: (1) characterize substance use pathways (e.g., nature and extent of use over time) in the context of neurobiological and neurocognitive mechanisms associated with physiological responses to acute stress that underlie anxiety symptoms, (2) tracks developmental change in these processes, and (3) differentiates between potentially distinctive neural pathways that influence progression to APSU.

Inclusion Criteria:

• Male or female
• 12-14 years old,
• Report symptoms of anxiety
• Understand and sign an assent, and parents will sign a permission and a consent document in English
• Meets study hearing and vision requirements
• Substance use naïve

Exclusion Criteria:

• Has any foreign metal objects or implants as determined by the safety questionnaires (e.g., bone screws, shunts or body piercing that can't be removed, etc.)
• Has been diagnosed with psychosis or a severe emotional disturbance.
• Has used alcohol, tobacco, or marijuana more than 3 times.
• Is pregnant. Girls who self-report pregnancy may not participate in the stress evaluation or the MRI scan.
• Is taking any medications that directly alter cardiovascular function (e.g., propranolol or other beta blockers).
• Any current or lifetime treatment with antipsychotic medication.
• Has had a head injury that resulted in a loss of consciousness for more than 5 minutes.
• Is planning to get non-removable metal braces.
• Impaired intellectual functioning (full-scale intelligence quotient <70).
• Past or current history of a clinically significant central nervous system that could confound brain imaging evaluations.

As part of the federal funding for this grant, participant's de-identified data will be uploaded to the NIMH data archive. The NIH-funded research data repository aims to accelerate progress in clinical research through data sharing, data harmonization, and the reporting of research results. It also serves as a scientific community platform and portal to multiple other research repositories, allowing for aggregation and secondary analysis of data. NDA is a data repository run by the National Institute of Mental Health (NIMH) that allows researchers studying mental health problems to collect and share de-identified information with each other.

The data will become available by 18 months past the study completion date. After uploading, the data will be available in the NDA long term, but must be kept on the NDA for at least three years after the funding period ends.

De-identified data will be submitted to the National Institute of Mental Health Data Archive (NDA). To obtain access to the NDA, researchers follow the established procedures within NDA, and the NDA Data Access Committee will determine the approvals for these requests. Access will be given for any legitimate scientific purpose, as determined by NDA Access Committee.