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（神经连接和 压力生理学）对青少年焦虑症状的不良物质使用模式（APSU）的影响， 改进以精确为基础、有针对性的干预。焦虑仍然是最常见的临床诊断之一 症状领域，是物质使用障碍的潜在前兆和加重因素， 尽管结果存在很大的异质性。因此，仅检测焦虑症状 提供了关于可预测性、病理生理学、进展和可预防性的有限信息， 焦虑相关的APSU了解焦虑症状如何增加APSU风险的关键可能在一个 破坏有助于威胁信息处理的执行认知调节的神经通路 和回应。我们建议威胁处理电路的局部改变（例如，中心延伸 杏仁核）和应激生理失调（心率 变异性和唾液皮质醇）在社会压力任务，巩固内化症状。但当地 网络内的改变可能不能完全解释从内化症状（焦虑）到 外化行为（APSU）。因此，我们进一步提出，在认知之间的协调故障， 控制回路（额顶叶和扣带-鳃盖）和威胁处理回路将在两种语言中表达。 神经连接减弱和任务表现较差，这将预测青少年的APSU， 焦虑症状是SUD的高风险。在整个发育过程中，我们预计这些神经和生理 特征将更加明显，性别差异将日益突出。 我们的目标是阐明在整个青春期的成熟变化在神经连接中的作用 额边缘子系统和生理应激反应之间的关系 焦虑症和APSU之间的联系我们建议绘制神经和压力的发展进程， 通过对有焦虑症状的青少年进行一项研究， 青少年（N = 180，年龄12 - 14）的前瞻性纵向研究，包括3个12个月的数据波 收藏.合格的参与者将报告焦虑症状和药物使用幼稚，并将 基于青少年SUD的高风险，使用一个良好的既定临界值进行过采样（50%）， 建立风险清单。图论将被应用于MRI数据在休息时的功能连接估计 以及在认知控制、抑制和威胁处理任务中测试一个综合的多模态模型 通过生理、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的生物标志物对项目组成部分的设计至关重要。 精确针对支持自我调节的神经和生理系统，有可能实现 甚至比我们目前最有效的干预措施所产生的小到中等的效果更大。