MRS Changes in Marijuana Using Adolescents: 2D MRS with Prior Knowledge Fitting

描述（由申请人提供）：本项目的总体目标是开发和实施一种新的磁共振波谱（MRS）技术，用于测量青少年慢性大麻吸烟者和匹配的健康对照受试者的大脑代谢物，以研究在大脑发育的这一关键阶段慢性大麻暴露的影响。众所周知，大麻中的主要精神活性化合物（9-四氢大麻酚（THC））会激活位于谷氨酸和（-氨基丁酸（GABA）神经元和轴突末端的大麻素1型（CB 1）受体。CB 1受体通过抑制Ca 2+电流和调节K+通道门控来减少谷氨酸或GABA的释放。谷氨酸和GABA在整个青春期的皮质重塑中起着关键作用。然而，目前可用于测量这些代谢物的MRS方法受到可靠性差的限制，因此通常采用仅测量生化化合物的子集的高度代谢物选择性MRS方法。需要改进对慢性大麻暴露引起的GABA能和多巴胺能张力扰动的量化，以了解其对发育中大脑的影响。我们建议应用在体内局部二维（2D）质子（1H）MRS研究神经化学的改变在26个青少年慢性大麻吸烟者和26个匹配的控制。我们将开发和实施2D 1H MRS方法，以提高有效的光谱分辨率，通过分离所有代谢物质子MR信号在2D表面。所有2D 1H MRS数据集将使用先验知识拟合（ProFit）进行拟合，这是一种光谱拟合算法，使用单个2D代谢物基础光谱迭代拟合整个2D表面。与ProFit结合使用的所提出的2D 1H MRS方法的显著优点是同时定量GABA和谷氨酸，其精确度显著高于传统的1D 1H MRS方法。这种方法的另一个重要优势是同时和可靠地测量脑谷氨酰胺，一种星形胶质细胞前体，是谷氨酸能和GABA能神经传递的中心。重要的是，保留了关于N-乙酰天冬氨酸、含胆碱化合物、总肌酸和肌醇的额外代谢信息，尽管使用2D 1H MRS和ProFit具有更高的精度。我们相信，新提出的先进的MRS方法将使我们能够检查与以前不可能的大量使用大麻相关的生化变化，并将产生对早期干预和治疗具有重要意义的发现。 公共卫生相关性：青少年大麻消费很普遍，构成了一个重大的公共卫生问题。拟议的研究将实施一种新的磁共振波谱（MRS）方法，以检查慢性大麻使用对青少年大脑成熟过程中大脑化学的影响。这项研究的结果将有助于更好地了解青少年在大脑发育的脆弱时期使用大麻的影响，并有可能帮助确定更有效的预防和治疗策略。

DESCRIPTION (provided by applicant): The overall aim of this project is to develop and implement a new magnetic resonance spectroscopy (MRS) technique for measuring brain metabolites in adolescent chronic marijuana smokers and matched healthy control subjects, in order to investigate the effects of chronic marijuana exposure during this critical phase of brain development. It is well established that the primary psychoactive compound within marijuana, (9-tetrahydrocannabinol (THC), activates the cannabinoid type-1 (CB1) receptor located on glutamate and (-amino butyric acid (GABA) neuron and axon terminals. CB1 receptors decrease glutamate or GABA release through the inhibition of Ca2+ currents and modulation of K+ channel gating. Both glutamate and GABA play pivotal roles in cortical remodeling throughout adolescence. However, the MRS approaches currently available to measure these metabolites are limited by poor reliability as a result highly metabolite-selective MRS approaches that measure only a subset of biochemical compounds are often adopted. Improved quantification of the perturbation of GABAergic and glutamatergic tone induced by chronic marijuana exposure is needed to understand its impact on the developing brain. We propose to apply in vivo localized two-dimensional (2D) proton (1H) MRS to study neurochemical alterations in 26 adolescent chronic marijuana smokers and 26 matched controls. We will develop and implement 2D 1H MRS methods in order to enhance the effective spectral resolution by separating all metabolite proton MR signals over a 2D surface. All 2D 1H MRS datasets will be fitted using prior knowledge fitting (ProFit), a spectral fitting algorithm that iteratively fits the whole 2D surface using individual 2D metabolite basis spectra. A significant advantage of the proposed 2D 1H MRS method used in combination with ProFit is the concomitant quantification of GABA and glutamate with a significantly higher level of precision than conventional 1D 1H MRS methods. A further important advantage of this approach will be the simultaneous and reliable measure of brain glutamine, an astrocytic precursor that is central to glutamatergic and GABAergic neurotransmission. Importantly, additional metabolic information concerning N-acetyl aspartate, choline-containing compounds, total creatine and myo-inositol is retained albeit with higher precision using 2D 1H MRS and ProFit. We believe the newly advanced MRS methods proposed would allow us to examine the biochemical changes associated with heavy cannabis use at level not previously possible and will produce findings with important implications for early intervention and treatment. PUBLIC HEALTH RELEVANCE: Adolescent cannabis consumption is widespread and constitutes a significant public health concern. The proposed study will implement a new magnetic resonance spectroscopy (MRS) method to examine the impact of chronic cannabis use on brain chemistry during adolescent brain maturation. Findings from this research will lead to an improved understanding of the effects of adolescent cannabis use during this vulnerable period of brain development and have the potential to aid in the identification of more effective prevention and treatment strategies.