MRI Studies of Brain Function and Metabolism

脑功能和代谢的 MRI 研究

• 批准号: 7594523
• 负责人: Daniel Martin Weinberger
• 金额: $ 432.66万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 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/7594523
• 关键词: Affect; Affective; Age; Alleles; Amino Acids; Amygdaloid structure; Anatomy; Anterior; Arousal; Attention; Back; Behavior; Bilateral; Biology; Brain; Brain Diseases; Carrier Proteins; Catechols; Clinical; Cognitive; Cognitive deficits; Complex; Computer information processing; Corpus striatum structure; DNA; Data; Development; Dextroamphetamine; Disease; Dopamine; Elderly; Emotional; Emotions; Environment; Event; Exhibits; Face; Failure; Financial compensation; Functional Magnetic Resonance Imaging; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Haplotypes; Health; Hippocampal Formation; Hippocampus (Brain); Human; Human Genetics; Hyperactive behavior; Image; Incentives; Lateral; Lead; Learning; Link; Locales; Magnetic Resonance Imaging; Measures; Mediating; Memory; Mental Depression; Mental Processes; Mental disorders; Metabolism; Methaqualone; Methionine; Methyltransferase; Methyltransferase Gene; Molecular Biology; Neurology; Noise; Nucleic Acid Regulatory Sequences; Oral; Patients; Performance; Phenotype; Physics; Play; Predisposition; Prefrontal Cortex; Process; Psychiatry; Psychometrics; Range; Regulation; Research; Resources; Risk; Role; Schizophrenia; Serotonin; Short-Term Memory; Signal Transduction; Specialist; Stimulus; Structure; Subgroup; Susceptibility Gene; System; Task Performances; Techniques; Therapeutic Effect; Time; Validation; Valine; Variant; Violence; age effect; base; brain research; clinical effect; cognitive function; emotion regulation; experience; frontal lobe; gray matter; improved; inhibitor/antagonist; interest; methionylmethionine; multidisciplinary; negative mood; neuroimaging; neurophysiology; neuropsychiatry; neurotransmission; relating to nervous system; response; senescence; serotonin transporter; tolcapone; valylvaline

Interesting findings have emerged from our studies this year. First, we began to tackle the problem of ill-defined phenotypes then we examined the contribution of several potentially functional variants in the gene catechol-o-methyltransferase (COMT) and haplotypes to the risk of schizophrenia (SCZ). Imaging genetics allowed us to evaluate the functional impact of these haplotypes on a neural system-level intermediate phenotype in normals during a working memory (WM) task. Our data shows that complex genetic variation can be validated functionally in humans and linked to prefrontal inefficiency. In a recent review looking at subtle gene effects which may be invisible through traditional clinical and psychometric measures, imaging-genetics has elucidated the contribution of COMT, GRM3, G72, DISC1, and BDNF to cognitive deficits in SCZ. These data suggest that there are common mechanisms underlying susceptibility for SCZ associated with complex genetic variations. Our study which explored the effects a genetic variation in the brain-derived necrotrophic factor (BDNF) gene on hippocampal (HP) gray matter volume found bilateral reductions of HP gray matter volumes in methionine carriers (met) compared with valine carriers (val) subjects. The met-BDNF carriers exhibited additional reduced gray matter volumes predominately in the lateral portion of the frontal lobes. These findings are consistent with the cellular and clinical effects of the BDNF val to met polymorphism and suggest that this change of an amino acid also affects the anatomy of the HP and prefrontal cortex (PFC), identifying a genetic mechanism of variation in brain form and structure related to learning and memory. In another study, which explored the effects of a functional polymorphism in a regulatory region of the human serotonin transporter gene, we found that s-carriers (short protein-carriers), had significantly reduced bilateral gray matter volumes in both the amygdala and the subgenual anterior cingulate. We also found that the serotonin s-allele effect on subgenual cingulate volume is dramatically reduced in met-BDNF allele carriers in comparison to val/val-BDNF carriers. Together, these results suggest that the val to met BDNF polymorphism may be a modifying genetic factor for depression, because it affects development and plasticity of critical brain systems involving serotonin related to the experience of negative mood and may lead, together with abnormal serotonin function (s-allele), to an anatomical substrate reflecting an increased vulnerability for depression. We have assembled DNA plates for analyses of candidate psychiatric susceptibility genes using neuroimaging as a functional validation strategy. We have over 650 normal subjects with high quality imaging data, both functional and structural, with which to explore genetic mechanisms of association. Abnormalities in dopamine (DA) neurotransmission contribute to a broad range of psychiatric disorders, like SCZ. DA plays a critical role in hippocampal processing, which is implicated in emotion regulation. This study examined genotype effect of COMT Val158Met on corticolimbic circuitry and functional connectivity during processing of salient stimuli and the relationship to novelty seeking. Using fMRI we found that the Met allele was associated with increases in hippocampal formation (HF) and ventrolateral prefrontal cortex (VLPFC) activation during viewing of faces displaying negative emotion. The ability of COMT Met/Met subjects to focus attention on a set of stimuli and inhibit interference may have deleterious effects in environments requiring rapid and flexible processing. Our studies in patients with SCZ explored the integrity of brain structures underlying cognitive function and affective behavior. We examined the phenomenon of low activity and hyperactivity of the DLPFC in SCZ. Groups were subdivided on the basis of performance on the WM task into high or low performing subgroups. Results show that in high-performing SCZ there were locales of greater PFC activation as well as locales of less activation. While only locales of low PFC activation were found in the low performing patients. These findings suggest that SCZ whose performance on the N-back WM task is similar to that of healthy comparison subjects, but they use greater PFC resources and achieve lower accuracy (i.e., inefficiency). Other patients with SCZ fail to sustain the PFC network that processes the information, achieving even lower accuracy as a result. These findings add to other evidence that abnormalities of prefrontal cortical function in SCZ are not reducible to simply too much or too little activity but, rather, reflect a compromised neural strategy for handling information mediated by the DLPFC. The group also examined the effects of genetic variations on cognitive performance. One study found that healthy subjects with the COMT met/met and the DAT 10 repeat alleles had more focused WM response than those with COMT val and DAT 9 repeat alleles. This suggests, for the first time, an additive genetic effect of two DA regulating genes. As previously described, genetic variations of COMT impacts the level of PF dopamine. DA plays a critical role in determining the level of PF signal to noise during information processing. In our study, we found that genetic variation in the COMT gene may affect the efficiency by which DA is inactivated resulting in diminished BOLD fMRI response and increased noise in Val carriers. We also studied the impact of a genetic variation in MAOA and found that the low level variant increased risk for violent behavior and predicted structural and functional changes in the PF-amygdala-hippocampal system for emotional regulation. The group has also been exploring the effects of neuropharmacological manipulation on brain information processing. Evidence suggests that COMT may play a unique role in regulating DA flux in the PFC, the group explored if Tolcapone, a COMT inhibitor can improve efficiency in PFC function. Preliminary results from this study suggest that TOL does enhance the efficiency of PF cortical information processing, and add evidence that COMT plays a significant role in modulating DA tone in the PFC. In another study, using event-related fMRI, we examined the effects of oral dextroamphetamine treatment on brain activity and during active mental processing. We found that by enhancing tonic over phasic activation, dextroamphetamine treatment equalized levels of ventral striatal activity and positive arousal during anticipation of both gain and loss. These findings suggest that therapeutic effects of dextroamphetamine on incentive processing may involve reducing the difference between anticipation of gains and losses. The group also explored the neurophysiological correlates of altered brain function associated with senescence. In a study aimed at exploring the neurophysiological correlates of reduced WM capacity with age we found that within WM capacity (as in 1-Back) when the elderly performed as well as the younger subjects, they showed greater prefrontal cortical (BA 9) activity bilaterally. At higher WM loads (as in 2-Back and 3-Back), however, when they performed worse then the younger subjects, the elderly showed relatively reduced activity in these prefrontal regions. These data suggest that within capacity, compensatory mechanisms such as additional prefrontal cortical activity are called upon to maintain proficiency in task performance. As cognitive demand increases, however, they are pushed beyond a threshold beyond which any compensation can be made probably from a failure to engage such compensatory mechanisms. This leads to a decline in performance. Studies are being pursued to explore the effect of aging on other brain systems, and the role of genetics on these changes.

我们今年的研究得出了有趣的发现。首先，我们开始解决不明确的表型问题，然后我们研究了儿茶酚邻甲基转移酶（COMT）基因和单倍型中几个潜在功能变异对精神分裂症（SCZ）风险的贡献。成像遗传学使我们能够评估这些单倍型在工作记忆（WM）任务期间对正常人神经系统水平中间表型的功能影响。我们的数据表明，复杂的遗传变异可以在人类中进行功能验证，并与前额叶效率低下有关。在最近的一篇综述中，研究了通过传统临床和心理测量方法可能看不见的微妙基因效应，成像遗传学阐明了 COMT、GRM3、G72、DISC1 和 BDNF 对 SCZ 认知缺陷的影响。这些数据表明，SCZ 易感性存在与复杂遗传变异相关的共同机制。我们的研究探讨了脑源性坏死营养因子 (BDNF) 基因的遗传变异对海马 (HP) 灰质体积的影响，发现与缬氨酸携带者 (val) 受试者相比，蛋氨酸携带者 (met) 受试者的 HP 灰质体积双侧减少。 met-BDNF 携带者表现出额外减少的灰质体积，主要集中在额叶的外侧部分。这些发现与 BDNF val 对满足多态性的细胞和临床影响一致，并表明氨基酸的这种变化也会影响 HP 和前额皮质 (PFC) 的解剖结构，从而确定与学习和记忆相关的大脑形式和结构变异的遗传机制。在另一项研究中，探讨了人类血清素转运蛋白基因调控区域功能多态性的影响，我们发现 s 载体（短蛋白载体）显着减少了杏仁核和膝下前扣带回的双侧灰质体积。我们还发现，与 val/val-BDNF 携带者相比，met-BDNF 等位基因携带者的血清素 s 等位基因对膝下扣带回体积的影响显着降低。总之，这些结果表明，满足 BDNF 多态性的 val 可能是抑郁症的一个修饰遗传因素，因为它影响涉及与负面情绪体验相关的血清素的关键大脑系统的发育和可塑性，并且可能与异常的血清素功能（s 等位基因）一起导致反映抑郁症脆弱性增加的解剖学基础。 我们组装了 DNA 板，使用神经影像学作为功能验证策略来分析候选精神病易感基因。我们拥有超过 650 名正常受试者，拥有高质量的功能和结构成像数据，可用于探索关联的遗传机制。多巴胺 (DA) 神经传递异常会导致一系列精神疾病，例如 SCZ。 DA 在海马处理过程中发挥着关键作用，而海马处理与情绪调节有关。本研究探讨了 COMT Val158Met 在处理显着刺激过程中对皮质边缘回路和功能连接的基因型影响以及与寻求新奇事物的关系。使用功能磁共振成像，我们发现 Met 等位基因与观看表现出负面情绪的面孔时海马结构 (HF) 和腹外侧前额叶皮层 (VLPFC) 激活的增加有关。 COMT Met/Met 受试者将注意力集中在一组刺激上并抑制干扰的能力可能会在需要快速灵活处理的环境中产生有害影响。 我们对 SCZ 患者的研究探讨了认知功能和情感行为背后的大脑结构的完整性。我们检查了 SCZ 中 DLPFC 的低活性和高活性现象。根据 WM 任务的表现将各组细分为高表现或低表现亚组。结果表明，在高性能 SCZ 中，存在 PFC 激活较高的区域和激活较少的区域。而在表现不佳的患者中仅发现了低 PFC 激活的区域。这些发现表明，SCZ 在 N-back WM 任务上的表现与健康对照受试者相似，但他们使用了更多的 PFC 资源并实现了较低的准确性（即效率低下）。其他 SCZ 患者无法维持处理信息的 PFC 网络，从而导致准确性更低。这些发现补充了其他证据，表明 SCZ 前额皮质功能的异常不能简单地归结为活动过多或过少，而是反映了处理由 DLPFC 介导的信息的神经策略受损。 该小组还研究了遗传变异对认知能力的影响。一项研究发现，具有 COMT met/met 和 DAT 10 重复等位基因的健康受试者比具有 COMT val 和 DAT 9 重复等位基因的健康受试者具有更集中的 WM 反应。这首次表明两个 DA 调节基因具有累加遗传效应。如前所述，COMT 的遗传变异会影响 PF 多巴胺的水平。 DA 在信息处理过程中确定 PF 信噪比水平方面起着至关重要的作用。在我们的研究中，我们发现 COMT 基因的遗传变异可能会影响 DA 失活的效率，导致 Val 携带者中 BOLD fMRI 反应减弱和噪音增加。我们还研究了 MAOA 遗传变异的影响，发现低水平变异会增加暴力行为的风险，并预测 PF-杏仁核-海马系统用于情绪调节的结构和功能变化。 该小组还一直在探索神经药理学操作对大脑信息处理的影响。有证据表明，COMT 可能在调节 PFC 中的 DA 通量方面发挥独特的作用，该小组探讨了 COMT 抑制剂托卡朋 (Tolcapone) 是否可以提高 PFC 功能的效率。这项研究的初步结果表明，TOL 确实提高了 PF 皮质信息处理的效率，并补充了 COMT 在调节 PFC 中 DA 音调中发挥重要作用的证据。在另一项研究中，我们使用事件相关的功能磁共振成像检查了口服右旋苯丙胺治疗对大脑活动和主动心理处理过程的影响。我们发现，通过增强强直性而非阶段性激活，右旋苯丙胺治疗可以均衡腹侧纹状体活动水平和预期获得和损失期间的积极唤醒水平。这些发现表明，右旋苯丙胺对激励处理的治疗作用可能涉及减少预期收益和损失之间的差异。 该小组还探讨了与衰老相关的大脑功能改变的神经生理学相关性。在一项旨在探索 WM 能力随年龄下降的神经生理学相关性的研究中，我们发现，在 WM 能力范围内（如 1-Back），当老年人的表现与年轻受试者一样时，他们的双侧前额皮质 (BA 9) 活动更大。然而，在较高的 WM 负荷（如 2-Back 和 3-Back）下，当老年人的表现比年轻受试者差时，老年人的这些前额叶区域的活动相对减少。这些数据表明，在能力范围内，需要补偿机制（例如额外的前额皮质活动）来保持任务执行的熟练程度。然而，随着认知需求的增加，它们被推到了一个阈值之外，超过这个阈值，可能会因为未能启用这种补偿机制而获得任何补偿。这会导致性能下降。正在进行的研究旨在探索衰老对其他大脑系统的影响，以及遗传学在这些变化中的作用。