Clinical trial NCT06977178: Adverse Adolescent Pathways to Substance Use
Official title: Adverse Adolescent Pathways to Substance Use
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Anxiety
Adolescent Development
Substance Use
Lead sponsor: University of North Carolina, Chapel Hill
Sponsor class: OTHER
Collaborators: name: National Institute on Drug Abuse (NIDA)
name: RTI International
First posted: 2025-05-18
Enrollment: 180
Sex: ALL
Minimum age (years): 12
Maximum age (years): 14
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: The Trier Social Stress Test for Children (TSST-C 61)-- a social stressor involving story telling in front of two neutral judges, preparation time and a cognitive stressor involving mental arithmetic-counting backward from 1023 by 13s--will be used to elicit physiological stress responses.
Primary purpose: BASIC_SCIENCE

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Reaction time during the functional magnetic resonance imaging (FMRI) Stop Signal Task
timeFrame: baseline, 12-months, 24-months
measure: Percent signal change during the FMRI Stop Signal Task
timeFrame: baseline, 12-months, 24-months
measure: Percent signal change activation during the No-stimuli, Predictable-stimuli, and Unpredictable-stimuli (NPU) task
timeFrame: baseline, 12-months, 24-months
measure: Percent signal change during the Attentional Load Paradigm (ALP) task
timeFrame: baseline, 12-months, 24-months
measure: Percent signal change during Emotional Face N-Back (EFNBack)
timeFrame: baseline, 12-months, 24-months
measure: Sympathetic and Parasympathetic nervous system ECG activation or heart rate variability (HRV) during a psychosocial stressful task (Trier Social Stress Test - TSST)
timeFrame: at baseline, 12-month and 24-month
measure: Endocrine (cortisol) measures during a psychosocial stressful task (Trier Social Stress Test - TSST)
timeFrame: at baseline, 12-month and 24-month
measure: Assessment of Liability and Exposure to Substance Use and Antisocial Behavior, Revised (ALEXSA-R)
timeFrame: at baseline, 12-month and 24-month
measure: Neurocognitive testing and executive functioning through NIH Toolbox
timeFrame: at baseline, 12-month and 24-month
measure: Multidimensional Anxiety Scale for Children 2 (MASC2)
timeFrame: at baseline, 12-month and 24-month
measure: State-Trait Anxiety Inventory for Children (STAI-C)
timeFrame: at baseline, 12-month and 24-month
measure: Tobacco Alcohol and Drug Use Survey
timeFrame: 12-month and 24-month
Secondary outcomes:
measure: Age
timeFrame: at baseline, 12-month and 24-month
measure: Adverse Life Experiences
timeFrame: at baseline, 12-month and 24-month
Other outcomes:
Locations:
city: Chapel Hill
country: United States
facility: The University of North Carolina at Chapel Hill School of Medicine
state: North Carolina
Study officials:
affiliation: University of North Carolina, Chapel Hill
name: Aysenil Belger, PhD
role: PRINCIPAL_INVESTIGATOR
References: