Development of MRI Techniques for Drug-Abuse Applications

药物滥用领域 MRI 技术的发展

• 批准号: 7593278
• 负责人: Yihong Yang
• 金额: $ 266.52万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593278
• 关键词: Accounting; Affect; Age; Allegra; Amygdaloid structure; Anesthetics; Animal Model; Animals; Anisotropy; Anterior; Area; Bilateral; Blood Vessels; Blood Volume; Brain; Brain region; Cerebellum; Cerebrum; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine Users; Contrast Media; Control Groups; Corpus Callosum; Creatine; Data; Detection; Development; Diffusion; Diffusion Magnetic Resonance Imaging; Dimensions; Dorsal; Dose; Drug Addiction; Education; Electrodes; Electrophysiology (science); Enzymes; Experimental Designs; Fiber; Frequencies; Frontal gyrus; Functional Magnetic Resonance Imaging; Functional disorder; Gender; Glutamate Carboxypeptidase II; Glutamates; Glutamine; Hand; Hippocampus (Brain); Human; Imaging Techniques; Individual; Inferior; Inferior frontal gyrus; Instruction; Internal Capsule; Iron; Lead; Limb structure; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Medial; Metabolism; Methods; Neuronal Dysfunction; Neurons; Neurotransmitters; Numbers; Output; Parahippocampal Gyrus; Paraterminal gyrus; Patients; Pattern; Pharmaceutical Preparations; Pontine structure; Precentral gyrus; Predisposition; Prefrontal Cortex; Rate; Rattus; Regression Analysis; Research Project Grants; Rest; Rewards; Seeds; Self Administration; Signal Transduction; Somatosensory Cortex; Specificity; Spectrum Analysis; Structure of middle temporal gyrus; Structure of superior frontal gyrus; Substantia nigra structure; Superior temporal gyrus; Synapses; System; Techniques; Temporal Lobe; Testing; Thalamic structure; Thinking; Time; Tissues; Ventral Striatum; Weight; angular gyrus; aspartylglutamate; base; cingulate cortex; cognitive function; density; gamma-Aminobutyric Acid; gray matter; healthy volunteer; hemodynamics; insight; interest; mathematical model; neuroimaging; neuromechanism; novel; research study; response; reward circuitry; tool; white matter

1. Reduction of Functional Brain Connectivity in Chronic Cocaine Users Previous neuroimaging studies have shown significant reductions in metabolism, functional activity and/or gray matter density in several brain regions including prefrontal cortex (PFC), anterior cingulate cortex (ACC), ventral striatum, and meso-temporal lobes of human cocaine addicts. However, whether chronic use of cocaine affects the interactions among these brain regions is not known. In the present study, we use resting-state fMRI to test the hypothesis that system specific functional connectivity is altered in cocaine addicts compared to healthy controls. Resting-state fMRI experiments were performed on 20 cocaine users and 20 gender, age and education matched healthy controls. Regions of interest (ROIs) were selected in the amygdala, anterior cingulate, hippocampus, medial-dorsal thalamus, and sensorimotor cortex corresponding to the hand. Mean time courses were obtained from these seed ROIs and were utilized as templates for calculating cross-correlation coefficients (CC) for all voxels across the brain. A general reduction in functional connectivity was seen in cocaine addicts compared with matched control subjects. For example, when the seed point was in the amygdala, significant reductions in functional connectivity was found in a large area of the medial prefrontal cortices (mPFC), inferior prefrontal cortex (iPFC), orbital cortex, posterior cingulate cortices (PCC) in the cocaine group. The reduced connections among brain regions in the reward circuitry may help explain brain deficits associated with chronic cocaine addiction, and point to a powerful new tool to study cocaine-induced neuronal dysfunction or dysregulation. 2. Lower Glutamate Levels in the Anterior Cingulate Cortex of Chronic Cocaine Users In this study, we used a recently developed MRS technique (TE-averaged PRESS) to determine the consequences of long term, chronic cocaine use on Glu and other metabolites in the anterior cingulate cortex (ACC) of human brain. Fifteen healthy volunteers and seventeen age-matched chronic cocaine users participated in this study. Data were acquired on a Siemens Allegra 3T scanner, and were quantified using LCModel. Since creatine (Cr) has been shown to be stable in the frontal gray matter of cocaine users and healthy controls, statistical analyses were conducted on the ratios of NAA/Cr, Cho/Cr, Glu/Cr, and Ins/Cr between the two groups. Our results showed that Glu/Cr ratio was significantly lower (12%) in the cocaine-user group compared with the controls (F1,29=4.2; p < 0.05). Additionally, while the NAA/Cr significantly decreased with age (F1,29=9.1; p < 0.005), there was no significant difference as a function of group (F1,29=1.5, n.s.). Regression analyses showed a significant positive correlation between Glu/Cr and NAA/Cr (t29=2.2; p<0.05), accounting for age. A decrease in Glu is consistent with evidence from animal studies that showed chronic cocaine self-administration significantly decreases the turnover rate of Glu in many reward-related brain regions including the NAc and cingulate cortex, suggesting a possible reduction in synaptic density or neurotransmitter synthetic capacity. As NAA is thought to be a marker of neuronal integrity, the correlation between Glu/Cr and NAA/Cr may reflect decreased ability of ACC neurons to produce Glu. A decrease in the enzyme glutamate carboxypeptidase II (CGPII) or III (CGPIII), which catabolizes N-acetyl-aspartylglutamate (NAAG) to NAA and Glu, could also lead to a reduction in Glu. In either case, a loss of ACC glutaminergic output may provide a mechanistic explanation for the impaired cognitive functions previously seen in cocaine addicts. 3. Reduction of White Matter Integrity in Cocaine Uses Revealed by Diffusion MRI In this study, we tested the hypothesis that white matter integrity is altered in cocaine addicts compared to healthy controls using a voxelwise group analysis on diffusion tensor imaging (DTI) data. DTI data were acquired from 12 cocaine dependent individuals and 12 matched healthy controls on a Siemens 3T Allegra scanner. Fractional anisotropy (FA), mean diffusivity (MD), and 3 eigenvalues (1, 2, and 3) of the diffusion tensor were calculated in each voxel. Comparing DTI data of a cocaine group (n=12) with a control group (n=12), a number of brain regions demonstrated a reduction of FA in cocaine addicts compared, and theses regions generally appeared in a bilateral pattern. In Talairach coordinates (LPI), significant reduction of FA was found in pontine crossing tract, substantia nigra, subcallosal gyrus, superior cerebella peduncle, anterior cingulate, middle temporal gyrus, inferior frontal gyrus, medial frontal gyrus, superior frontal gyrus, anterior limb of internal capsule, amygdala, parahippocampal gyrus, corpus callosum, precentral gyrus, and superior occipital gyrus. A few regions of FA increase were also found, including in middle cerebella peduncle, posterior limb of internal capsule, superior temporal gyrus, middle occipital gyrus and angular gyrus. Meanwhile, a global increase of mean diffusivity (MD) was found in the cocaine users. These results suggest that chronic cocaine abuse may affect the white matter integrity in brain regions associated with drug addition. 4. Quantification of BOLD Effect in CBV-Weighted fMRI at 9.4T In CBV-weighted fMRI employing superparamagnetic contrast agent, iron dose and BOLD contamination are two important issues for experimental design and CBV quantification. Bothe BOLD and CBV-weighted fMRI are based upon the susceptibility effect, to which spin-echo and gradient-echo MRI sequence have different sensitivities. In the present study, CBV-weighted fMRI was conducted using spin echo and gradient echo sequences at 9.4T by systematically changing the doses of contrast agent. Results suggest that BOLD contamination is a significant component in CBV-weighted fMRI at high field, particularly when relatively low dose of contrast agent is administered. A mathematical model was developed to quantify the extra-vascular (EV) BOLD effect. With a TE of 35ms, the EV BOLD effect was estimated to account for 76 12% of the observed spin echo fMRI signal at 9.4T. These data suggest that correcting BOLD effect may be necessary for accurately quantifying activation-induced CBV changes at high field. 5. Mechanisms of Resting-State fMRI: Electrophysiology and fMRI on Rats Synchronized spontaneous fluctuations of the fMRI signal have been applied to reveal large-scale neuronal networks of the brain in the absence of specific task instructions. However, the underlying neural mechanisms of these fluctuations in fMRI remain largely unknown. We have recently developed an animal model to investigate these mechanisms by integrating electrophysiological and fMRI signals at the resting rat brain. By employing cerebral blood volume(CBV)-weighted fMRI with a superparamagnetic contrast agent, we achieved enhanced sensitivity and functional specificity, and were able to detect, for the first time, region-specific and anesthetic dose-dependent synchronized fMRI fluctuations in the primary somatosensory cortex (S1FL) of the resting rat brain. Epidural electroencephalographic (EEG) signals were recorded from bilateral S1FL electrodes using the same animal model. Results demonstrate that, unlike the evoked fMRI response that correlates with power changes in high frequency bands, power coherence in low frequency bands, particularly the delta band, correlates with the resting-state fMRI signal, and does so in a region-specific and dose-dependent fashion. These results add a novel dimension and new insight into the linkage between neuronal activity and hemodynamic response-based fMRI signal.

1. 长期吸食可卡因的大脑功能连接减少 先前的神经影像学研究表明，人类可卡因成瘾者的几个大脑区域的新陈代谢、功能活动和/或灰质密度显着降低，包括前额叶皮层（PFC）、前扣带皮层（ACC）、腹侧纹状体和中颞叶。然而，长期使用可卡因是否会影响这些大脑区域之间的相互作用尚不清楚。在本研究中，我们使用静息态功能磁共振成像来测试可卡因成瘾者与健康对照者相比，系统特定功能连接发生改变的假设。对 20 名可卡因使用者和 20 名性别、年龄和教育程度相匹配的健康对照者进行了静息态功能磁共振成像实验。在与手对应的杏仁核、前扣带回、海马、内侧背侧丘脑和感觉运动皮层中选择感兴趣区域（ROI）。从这些种子 ROI 中获得平均时间进程，并将其用作计算大脑中所有体素的互相关系数 (CC) 的模板。与匹配的对照受试者相比，可卡因成瘾者的功能连接普遍减少。例如，当种子点位于杏仁核时，可卡因组的内侧前额叶皮层（mPFC）、下前额叶皮层（iPFC）、眼眶皮层、后扣带皮层（PCC）的大面积功能连接显着减少。奖励回路中大脑区域之间的连接减少可能有助于解释与慢性可卡因成瘾相关的大脑缺陷，并为研究可卡因引起的神经元功能障碍或失调提供了一个强大的新工具。 2. 长期可卡因使用者前扣带皮层谷氨酸水平降低 在这项研究中，我们使用最近开发的 MRS 技术（TE 平均 PRESS）来确定长期、慢性使用可卡因对人脑前扣带皮层 (ACC) 中的 Glu 和其他代谢物的影响。十五名健康志愿者和十七名年龄匹配的长期可卡因使用者参与了这项研究。数据在西门子 Allegra 3T 扫描仪上采集，并使用 LCModel 进行量化。由于肌酸（Cr）已被证明在可卡因使用者和健康对照者的额叶灰质中稳定，因此对两组之间的 NAA/Cr、Cho/Cr、Glu/Cr 和 Ins/Cr 的比率进行了统计分析。我们的结果表明，与对照组相比，可卡因使用者组的 Glu/Cr 比率显着降低 (12%) (F1,29=4.2；p < 0.05)。 此外，虽然 NAA/Cr 随着年龄的增长而显着降低（F1,29=9.1；p < 0.005），但作为组别函数没有显着差异（F1,29=1.5，n.s.）。回归分析显示，考虑到年龄，Glu/Cr 和 NAA/Cr 之间存在显着正相关（t29=2.2；p<0.05）。 Glu 的减少与动物研究的证据一致，动物研究表明，长期自我服用可卡因会显着降低许多与奖励相关的大脑区域（包括 NAc 和扣带皮层）中 Glu 的周转率，这表明突触密度或神经递质合成能力可能会降低。由于 NAA 被认为是神经元完整性的标志物，因此 Glu/Cr 和 NAA/Cr 之间的相关性可能反映了 ACC 神经元产生 Glu 的能力下降。 谷氨酸羧肽酶 II (CGPII) 或 III (CGPIII) 将 N-乙酰基-天冬氨酰谷氨酸 (NAAG) 分解代谢为 NAA 和 Glu，其减少也可能导致 Glu 减少。无论哪种情况，ACC 谷氨酰胺能输出的丧失都可以为先前在可卡因成瘾者中观察到的认知功能受损提供机制解释。 3. 扩散 MRI 揭示可卡因使用中白质完整性的降低 在这项研究中，我们使用扩散张量成像 (DTI) 数据的体素分组分析来测试可卡因成瘾者的白质完整性与健康对照相比发生改变的假设。 DTI 数据是通过西门子 3T Allegra 扫描仪从 12 名可卡因依赖者和 12 名匹配的健康对照获得的。计算每个体素中的分数各向异性 (FA)、平均扩散率 (MD) 和扩散张量的 3 个特征值（1、2 和 3）。比较可卡因组（n=12）与对照组（n=12）的DTI数据，可卡因成瘾者的多个大脑区域显示FA减少，并且这些区域通常出现双侧模式。在 Talairach 坐标（LPI）中，脑桥交叉束、黑质、胼胝体下回、小脑上脚、前扣带回、颞中回、额下回、额内侧回、额上回、内囊前肢、杏仁核、海马旁回显着减少 脑回、胼胝体、中央前回和枕上回。也发现少数区域FA增加，包括小脑中脚、内囊后肢、颞上回、枕中回和角回。与此同时，可卡因使用者的平均扩散率（MD）在全球范围内有所增加。这些结果表明，长期滥用可卡因可能会影响与药物添加相关的大脑区域的白质完整性。 4. 9.4T CBV 加权 fMRI 中 BOLD 效应的量化 在使用超顺磁性造影剂的 CBV 加权 fMRI 中，铁剂量和 BOLD 污染是实验设计和 CBV 定量的两个重要问题。 BOLD和CBV加权fMRI都是基于磁敏感效应，自旋回波和梯度回波MRI序列对此具有不同的敏感性。 在本研究中，通过系统地改变造影剂的剂量，使用9.4T的自旋回波和梯度回波序列进行CBV加权fMRI。结果表明，BOLD 污染是高场 CBV 加权 fMRI 的重要组成部分，特别是在使用相对较低剂量的造影剂时。我们开发了一个数学模型来量化血管外 (EV) BOLD 效应。 TE 为 35ms 时，EV BOLD 效应估计占 9.4T 观察到的自旋回波 fMRI 信号的 76±12%。这些数据表明，为了准确量化高场下激活引起的 CBV 变化，校正 BOLD 效应可能是必要的。 5. 静息态 fMRI 的机制：大鼠的电生理学和 fMRI 功能磁共振成像信号的同步自发波动已被应用于在没有特定任务指令的情况下揭示大脑的大规模神经元网络。然而，功能磁共振成像这些波动的潜在神经机制仍然很大程度上未知。我们最近开发了一种动物模型，通过在静息大鼠大脑中整合电生理学和功能磁共振成像信号来研究这些机制。通过将脑血容量（CBV）加权功能磁共振成像与超顺磁性造影剂结合使用，我们实现了增强的灵敏度和功能特异性，并且首次能够检测到静息大鼠大脑初级体感皮层（S1FL）中区域特异性和麻醉剂量依赖性同步功能磁共振成像波动。使用相同的动物模型从双侧 S1FL 电极记录硬膜外脑电图 (EEG) 信号。结果表明，与高频段功率变化相关的诱发 fMRI 响应不同，低频段（尤其是 delta 频段）的功率相干性与静息态 fMRI 信号相关，并且以区域特异性和剂量依赖的方式进行。这些结果为神经元活动和基于血流动力学反应的功能磁共振成像信号之间的联系增加了一个新的维度和新的见解。