Adolescent Cannabis Use, Complex Brain Network Connectivity & Schizophrenia Risk

本研究的总体目标是确定大麻（MJ）对青少年大脑连接的影响，并确定这种对复杂神经网络的影响是否在精神分裂症（SZ）患者的生物亲属中更为明显。这一建议意义重大，因为它将提供有关青少年MJ暴露对公共卫生构成的潜在危害的新信息。青少年使用MJ是SZ的已知环境风险因素。MJ也是美国青少年中最常用的非法药物，首次接触MJ通常发生在青春期中期。最近的年轻人调查报告说，MJ的使用率不断上升，MJ持续容易获得，并且MJ有害的看法不断下降。大麻素受体的激活在调节神经细胞存活、大脑发育和神经可塑性方面至关重要。动物研究提供了明确的证据表明，MJ中存在的四氢大麻酚对大脑有害，特别是在青少年大脑成熟的敏感时期。然而，人类神经影像学研究一直是矛盾的，部分原因是缺乏人类青少年的纵向数据。为了解决这些知识的差距，我们将进行一项前瞻性的MRI研究，健康的青少年志愿者没有家族史的SZ（HNV），和一个匹配的样本的SZ患者的一级亲属。入组研究时，受试者既往未使用过MJ。将采用有针对性的招募策略和密切关注以促进受试者保留。脑解剖，弥散加权磁化传递率，和静息态功能磁共振成像数据，在摄入量和3年后获得。每隔6个月使用可靠且经过充分验证的评估方案，监测受试者紧急使用MJ的发生和严重程度（预计为摄入样本的25%）。这项前瞻性研究设计将产生4个信息丰富的比较组（按MJ使用和SZ家族史分层），提供明确的测试，以揭示青少年MJ暴露和家族SZ风险对纵向脑变化的独特影响。具体目标1和2利用最先进的统计分析来评估紧急使用MJ对脑结构完整性受试者内变化的影响，以及对SZ亲属的差异效应。他的假设是，有紧急MJ使用的青少年将表现出大脑结构完整性的缺陷。在SZ遗传脆弱性的背景下，生物亲属将更容易受到MJ的有害影响。具体目标3使用新的图论方法来量化大脑结构和功能连接的拓扑特性。青少年MJ使用对大脑网络组织变化的影响将在HNV和SZ亲属之间进行对比。具体目标4探讨神经认知，人格特质和前驱症状的次要结果，以开发综合模型来解释青少年MJ-SZ联系。因此，这项建议的纵向研究设计和创新的网络连接措施将推进知识的影响，青少年MJ暴露对公共卫生和SZ的易感性。

DESCRIPTION (provided by applicant): The overall aim of this research is to determine the effects of marijuana (MJ) on brain connectivity in adolescents, and to establish whether such influences on complex neural networks are more pronounced in biological relatives of schizophrenia (SZ) patients. This proposal is significant because it will provide new information about the potential hazards adolescent MJ exposure poses to public health. Adolescent MJ use is a known environmental risk factor for SZ. MJ is also the most commonly used illicit drug among adolescents in the U.S. where first MJ exposure often occurs in mid-adolescence. Recent youth surveys report rising MJ usage, persistent easy MJ access, and declining perception that MJ is harmful. Activation of cannabinoid receptors is vital in regulating neural cell survival, brain development and neuroplasticity. Animal studies provide clear evidence that tetrahydrocannabinol present in MJ is deleterious to the brain, especially during the sensitive period of adolescent brain maturation. However, human neuroimaging studies have been contradictory partly due to the absence of longitudinal data on human adolescents. To address these gaps in knowledge, we will conduct a prospective MRI study of healthy adolescent volunteers without family history of SZ (HNV), and a matched sample of first-degree relatives of SZ patients. At study entry, subjects have no prior MJ use. Targeted recruitment strategies and close attention to promote subject retention will be utilized. Brain anatomic, diffusion-weighted magnetization transfer ratio, and resting-state functional MRI data are obtained at intake and 3 years later. Using reliable and well-validated assessment protocols at 6-monthly intervals, subjects will be monitored for onset and severity of emergent MJ use (expected to be 25% of intake sample). This prospective study design will yield 4 informative comparison groups (stratified by MJ use and SZ family history) providing an explicit test to reveal the unique effect of adolescent MJ exposure and of familial SZ risk on longitudinal brain changes. Specific Aims 1 and 2 utilize state-of-the-art statistical analyses to assess the impact of emergent MJ use on within-subject changes in brain structural integrity, and on differential effects in SZ relatives. he hypothesis is that adolescents with emergent MJ use will show deficits in structural brain integrity. Against a background of genetic vulnerability for SZ, biological relatives will be more susceptible to MJ's deleterious effects. Specific Aim 3 uses novel graph theory methods to quantify the topographical properties of brain structural and functional connectivity. The influence of adolescent MJ use on changes in brain network organization will be contrasted between HNV and SZ relatives. Specific Aim 4 explores secondary outcomes of neurocognition, personality traits and prodromal symptoms to develop integrative models to explain the adolescent MJ-SZ link. Thus, this proposal with its longitudinal study design and innovative network connectivity measures will advance knowledge regarding the impact adolescent MJ exposure has on public health and on SZ susceptibility.