# Developmental Pathophysiology of Adverse Patterns of Substance Use in Adolescents with Anxiety

> **NIH DA R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2026 · $644,398

## Abstract

The proposed 5-year R01 study will examine maturational pathways of biomarkers (neural connectivity and
stress physiology) to adverse patterns of substance use (APSU) in adolescents with anxiety symptoms to
improve precision-based, targeted intervention. Anxiety remains one of the most commonly diagnosed clinical
symptom domains in adolescence and is a potent precursor to and exacerbator of substance use disorder,
although there is substantial heterogeneity in outcomes. As such, detection of anxiety symptoms alone
provides limited information about the predictability, pathophysiology, progression, and preventability of
anxiety-linked APSU. Key to understanding how anxiety symptoms increase risk for APSU may be found in a
disruption of neural pathways that subserve executive cognitive modulation of threat information processing
and response. We propose that local alterations in threat processing circuitry (e.g., the central extended
amygdala) during anticipation or unpredictability of threat, and stress physiological dysregulation (heart rate
variability and salivary cortisol) during a social stress task, underpin internalizing symptoms. However, local
intra-network alterations likely do not fully explain pathways from internalizing symptoms (anxiety) to
externalizing behaviors (APSU). Thus, we further propose that a breakdown in coordination between cognitive
control circuity (frontoparietal and cingulo-opercular) and threat processing circuitry will be expressed in both
weakened neural connectivity and poorer task performance, which will predict APSU in adolescents with
anxiety symptoms at high risk for SUD. Across development, we expect these neuronal and physiological
features will become even more pronounced and sex differences will become increasingly prominent.
 Our objective is to elucidate the role of maturational change across adolescence in neural connectivity
between fronto-limbic subsystems and physiological stress responses to an acute stressor in the r

## Key facts

- **NIH application ID:** 11334318
- **Project number:** 5R01DA057312-04
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Aysenil  Belger; DIANA H FISHBEIN; TY A RIDENOUR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** DA
- **Fiscal year:** 2026
- **Award amount:** $644,398
- **Award type:** 5
- **Project period:** 2023-07-01T00:00:00 → 2028-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11334318

## Citation

> US National Institutes of Health, RePORTER application 11334318, Developmental Pathophysiology of Adverse Patterns of Substance Use in Adolescents with Anxiety (5R01DA057312-04). Retrieved via AI Analytics 2026-06-26 from https://api.ai-analytics.org/grant/nih/11334318. Licensed CC0.

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