Multimodal imaging: genetic and environmental effects in neuropsychiatry

该小组继续在健康志愿者、精神分裂症患者及其未受影响的兄弟姐妹的成像遗传学方面取得进展。使用fMRI，Callicott等人。(J Clin Invest，2013)扩展了先前和新颖的关于调节和改变海马体发育轨迹的遗传因素DISC1和NKCC1的翻译实验的发现。这些数据突显了上位性模型在理解基因与复杂大脑表型的关联以及复制的能力方面的重要性。复制也是Tost及其同事工作的关键(J Neurosci，2014)表明，NRG3的大胆功能磁共振和工作记忆效应与前额叶有关，以前与新的剪接形式表达有关。在另一项翻译研究中，Papaleo和他的同事(Mol Qichiatry，2014)在工作记忆中使用了BOLD功能磁共振成像，以探索两个经典的精神分裂症候选基因--DISC1和DTNBP1--在健康受试者工作记忆功能磁共振成像研究期间的基因-基因相互作用。从全基因组关联到一般智力，迪金森和他的同事(《美国医学会精神病学》，2014)还使用BOLD功能磁共振成像在精神分裂症患者和健康受试者中展示了SCN2A与前额皮质活动的关系。再次从死后表达转向体内功能，Morita和Callicott及其同事(J Neurosci，2014)表明，NKCC1内与转录表达相关的变化也与工作记忆、一般认知和fMRI激活有关。Magalona及其同事(CNS药物，2013)证明，在健康年轻人的事件相关心理灵活性任务(VAC任务)中，托卡彭(一种COMT抑制剂)调节了前扣带回的活动。在认知老化领域出现了一些有趣的发现。缪斯和他的同事研究了衰老过程中情景记忆(EM)的下降，并使用功能磁共振成像(FMRI)发现了与编码Kibra蛋白的WWC1基因的单核苷酸多态(Rs17070145)相关的下降速度，Kibra蛋白对长期增强和记忆巩固至关重要。最后，Rasetti和他的同事(《美国医学会精神病学》，2014)使用编码任务确定了一种与精神分裂症相关的潜在的新的中间或内表型。 去年，在几次国际会议上提交了摘要，相关手稿已进入后期准备阶段。我们有数据表明，与对照组相比，精神分裂症患者前扣带回皮质中的GABA水平略有下降，而未受影响的兄弟姐妹的水平有更明显的下降。与对照组相比，治疗和未治疗的精神分裂症患者以及未受影响的兄弟姐妹的谷氨酸水平似乎没有变化。我们还研究了停用抗精神病药对精神分裂症患者GABA水平的影响，发现没有明显的效果。对15名在精神药物暂停期间和积极的单一抗精神病药物治疗期间进行扫描的患者进行的初步发现表明，停药时的谷氨酸水平可能预测抗精神病药物的反应，而GABA水平不能。 利用DTI技术，我们发现了5-羟色胺转运体启动子区(5HTT-LPR)的多态对钩状束白质微结构的影响。这种多态与情绪障碍的原因有关，以前也与白质微结构的变化有关，尽管一些结果相互矛盾。我们实现了一种新的方法来定义钩状束，该方法允许自动描绘多个白质束并提取束指标。多条白质束的勾画和束指标的提取。 关于产科并发症是精神分裂症的环境风险因素的工作出版了(Jaffe等人。2014年，莫尔。心理。)这表明从头基因突变不太可能是已知的父亲年龄和精神分裂症之间联系的主要原因。产科并发症与精神分裂症的风险增加有关，特别是出生顺序较低的人，这与初次怀孕比后期怀孕更有可能出现问题这一事实相一致。有关产科并发症及其与遗传风险相互作用的进一步数据，目前正在与利伯脑发育研究所的温伯格博士合作进行分析。 还研究了城市教养(精神分裂症的危险因素)对工作记忆任务中大脑激活的影响，以及与儿茶酚氧位甲基转移酶(COMT Val158Met)基因变异的交互作用。城市教养导致激活效率降低，与COMT Val158Met多态存在显著交互作用，在农村环境中，具有Val/Val COMT基因的个体的激活效率最低，而在大城市长大的参与者中，Met携带者的效率最低。 最近的一项合作发现是基于松弛测量技术，并显示内侧颞叶和小脑白质中髓鞘水含量的增加。此外，通过我们在威廉姆斯综合征方面的合作，我们已经为在用于基因研究的个体的大型数据集中确定白质束体积奠定了基础。我们把重点放在额枕下束，因为初步工作表明，这可能是白质束，在威廉姆斯综合征染色体区域短缺失的参与者中体积特别小。

The group has continued to make strides in imaging genetics in healthy volunteers, patients with schizophrenia and their unaffected siblings. Using fMRI, Callicott et al. (J Clin Invest., 2013) extended findings from a previous and novel translational experiment regarding genetic factors that regulate and alter hippocampal developmental trajectory, DISC1 and NKCC1. These data highlight the importance of epistatic models in understanding genetic association with complex brain phenotypes and also the power of replication. Replication was also key to the work of Tost and colleagues (J Neurosci,2014) showed that BOLD fMRI and working memory effect of NRG3, previously associated with novel splice form expression, was associated with prefrontal. In another translational study, Papaleo and colleagues (Mol Psychiatry, 2014) used BOLD fMRI during working memory to explore the gene-gene interaction between two classic schizophrenia candidate genes -- DISC1 and DTNBP1-- in healthy subjects during working memory studied with fMRI. From genome-wide association to general intelligence, Dickinson and colleagues (JAMA Psychiatry, 2014) also showed a relationship of SCN2A to prefrontal cortex activity using BOLD fMRI in patients with schizophrenia and healthy subjects. Again moving from post-mortem expression to in vivo function, Morita, Callicott and colleagues (J Neurosci, 2014) showed that variation within NKCC1 related to transcript expression was also associated with working memory, general cognition and fMRI activation. Magalona and colleagues (CNS Drugs, 2013) demonstrated that tolcapone (a COMT inhibitor) modulated activity in the anterior cingulate during an event-related mental flexibility task (the VAC task) in healthy young people. Interesting findings have emerged in the field of cognitive aging. Muse and colleagues investigated episodic memory (EM) decline in aging and found the rate of decline associated with the single nucleotide polymorphism (rs17070145) in the WWC1 gene encoding the KIBRA protein critical for long-term potentiation and memory consolidation using functional magnetic resonance imaging (fMRI). Finally, Rasetti and colleagues (JAMA Psychiatry, 2014) identified a potential novel intermediate or endophenotype relevant to schizophrenia using an encoding task. In the last year, abstracts have been presented at several international meetings and the related manuscripts are in the late stages of preparation. We have data indicating that GABA levels in the anterior cingulate cortex are subtly decreased in patients with schizophrenia as compared to controls, while unaffected siblings have more marked reductions. Glutamate levels appear to be unchanged in treated and untreated patients with schizophrenia as compared to controls, as well as in unaffected siblings. We also studied the effects of suspension of neuroleptic medication on GABA levels in patients with schizophrenia, finding no apparent effect. A preliminary finding conducted on 15 patients who had been scanned during psychotropic suspension and during active single neuroleptic treatment indicates that the levels of glutamate while off medications may be predictive of neuroleptic response, while GABA levels are not. With DTI, we found an effect of a polymorphism in the serotonin transporter promoter region (5HTT-LPR) on the white matter microstructure of the uncinate fasciculus. This polymorphism has been implicated in the causation of mood disorders and has been previously associated with changes in white matter microstructure, though some results have been conflicting. We implemented a novel method to define the uncinate fasciculus that allows for automatic delineation of multiple white matter tracts and extraction of tract metrics. delineation of multiple white matter tracts and extraction of tract metrics. The work on obstetrical complications as an environmental risk factor for schizophrenia generated a publication (Jaffe et al. 2014, Mol. Psych.) showing that it is unlikely that de novo mutations are the main cause for the known association of paternal age and schizophrenia. Obstetrical complications were associated with increased risk for schizophrenia especially for lower birth order, consistent with the fact that initial pregnancies are more likely to be problematic than later ones. Further data on obstetrical complications and their interaction with genetic risk are currently being analyzed in collaboration with Dr. Weinberger at the Lieber Institute for Brain Development. Effects of urban upbringing (a risk factor for schizophrenia) on brain activation during a working memory task and interactions with genetic variation in catechol-O-methyltransferase (COMT Val158Met polymorphism) were also studied. Urban upbringing resulted in reduced efficiency of activation, and there was a significant interaction with the COMT Val158Met polymorphism, where the individuals reared in rural environments with a Val/Val COMT genotype were least efficient, while Met Carriers were least efficient among the participants raised in a large city. A recent finding in collaboration was based on relaxometry techniques and showed an increase in myelin water fraction in the medial temporal lobe and in the cerebellar white matter. Additionally, through our collaboration on Williams syndrome, we have laid the groundwork for determination of white matter tract volume in large datasets of individuals for genetic studies. We focused on the inferior fronto-occipital fasciculus because preliminary work indicated that this might be the white matter tract particularly reduced in volume in participants with short deletions of the Williams syndrome chromosome region.