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

焦虑青少年不良物质使用模式的发育病理生理学

• 批准号: 10566213
• 负责人: Aysenil Belger
• 金额: $ 70.68万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566213
• 关键词: Acute; Adolescence; Adolescent; Affective; Age; Amygdaloid structure; Anxiety; Behavioral; Biological Markers; Brain; Characteristics; Clinic; Cognitive; Data; Data Collection; Detection; Development; Diagnosis; Disease; Emotional; Equipment and supply inventories; Etiology; Exhibits; Exposure to; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Heterogeneity; Hydrocortisone; Impulsivity; Informal Social Control; Intervention; Link; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Medial; Modeling; Monitor; Neural Pathways; Neurobiology; Neurons; Outcome; Pathway interactions; Pattern; Physiological; Physiology; Process; Regulation; Reporting; Rest; Risk; Role; Salivary; Sampling; Severities; Sex Differences; Stress; Substance Use Disorder; Support System; Surveys; Symptoms; System; Task Performances; Temporal Lobe; Testing; Time; Work; Youth; acute stress; adolescent substance use; anxiety symptoms; behavioral outcome; biological adaptation to stress; biomarker identification; clinical diagnosis; cognitive control; design; efficacious intervention; eligible participant; externalizing behavior; graph theory; heart rate variability; high risk; high-risk adolescents; improved; information processing; longitudinal course; longitudinal, prospective study; multimodality; neural; neural network; neurodevelopment; neuroimaging; personalized approach; predictive marker; programs; prospective; recruit; reduce symptoms; response; risk prediction; secondary analysis; social stress; stress reactivity; stressor; substance use; substance using adolescents; support network; therapy design

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 relationship between anxiety and APSU. We propose to chart the developmental progression of neural and stress physiological factors that confer risk for APSU in adolescents with anxiety symptoms by conducting a prospective, longitudinal study of adolescents (N=180, age 12-14), including three 12 month waves of data collection. Eligible participants will report anxiety symptoms and substance use naïvete and will be oversampled (50%) on the basis of high risk for adolescent SUD using an established cut-off on a well- established risk inventory. Graph theory will be applied to functional connectivity estimates of MRI data at rest and during cognitive control, inhibition, and threat processing tasks to test an integrative, multi-modal model with physiological, behavioral and survey measures to track trajectories of neurodevelopment. Identifying biomarkers predictive of APSU in at-risk adolescents is critical to the design of program components more precisely targeted to neural and physiological systems that support self-regulation, with potential to achieve more than the small to modest effect sizes currently produced by even our most efficacious interventions.

拟议的5年R01研究将检查生物标志物的成熟途径（神经连通性和 压力生理学）至有焦虑症状的青少年的药物使用（APSU）的不利模式 改善基于精度的，有针对性的干预。焦虑仍然是最常见的临床 青少年症状结构域，是药物使用障碍的潜在先驱，并加剧， 尽管结局存在很大的异质性。因此，仅检测动画症状 提供有关可预测性，病理生理学，进步和预防性的有限信息 动画链接的APSU。了解动画症状如何增加APSU的风险的关键 神经通路的破坏，这些神经通路是对威胁信息处理的执行认知调制的破坏 和回应。我们建议当地威胁处理电路的改变（例如，中央扩展 杏仁核）在预期或不可预测的威胁性和压力身体失调（心率）期间 在社会压力任务中，可变性和唾液皮质醇）是内部症状的基础。但是，本地 网络内的改变可能无法完全解释从内在症状（焦虑）到 外在行为（APSU）。这是我们进一步提出的，认知能力之间的协调崩溃 控制电路（额叶和cingulo-obercular）和威胁处理电路都将在两者中表达 弱化的神经连通性和较差的任务表现，这将预测青少年的APSU SUD高风险的焦虑符号。在整个发展中，我们期望这些神经元和生理学 功能将变得更加明显，性别差异将变得越来越突出。 我们的目标是阐明整个青少年在神经连通性中的成熟变化的作用 在关系中，额 - 束缚子系统和对急性压力源的身体压力反应之间 在焦虑和APSU之间。我们建议绘制神经和压力的发育进展 通过进行动画症状的青少年中APSU风险的物理因素，通过进行 青少年的前瞻性，纵向研究（n = 180，年龄12-14岁），包括三个12个月的数据浪潮 收藏。符合条件的参与者将报告动画符号和物质使用幼稚，将是 在青少年SUD的高风险基础上，使用已建立的临界值进行过采样（50％） 已建立的风险清单。图理论将应用于REST的MRI数据的功能连通性估计 在认知控制，抑制和威胁处理任务期间，以测试一个综合的多模式模型 采用身体，行为和调查措施来跟踪神经发育的轨迹。识别 在高危青少年中预测APSU的生物标志物对于计划组件的设计至关重要 精确针对支持自我调节的神经和物理系统，并有可能实现 即使是我们最有效的干预措施，目前还产生的小到适中的效应大小。