Imaging of Neuropsychiatric Disorders with Developmental and Genetic Mechanisms

综合神经成像科继续朝着了解精神分裂症神经系统水平功能障碍的性质、分子基础、潜在的神经化学和临床相关性的目标取得进展。今年，我们在对一群独特的、不断增长的无药物治疗的精神分裂症患者进行多模式神经成像研究方面取得了实质性进展。特别是，不仅表征突触前多巴胺合成能力的新努力，而且在这一人群中D1和D2/3受体的可用性的新努力在今年已经成功，随着进一步的积累，将允许评估关于这种疾病中整合的突触前和突触后多巴胺功能的关键假说。结合在同一患者中收集的皮质认知激活数据，这些数据还将提供一个平台，以扩大该实验室在执行任务执行期间在前额叶激活过程中的特征精神分裂症相关损害和夸大的纹状体多巴胺合成。具体地说，这个正在进行的项目将使我们能够直接评估精神分裂症的神经病理生理变化反映在通过紊乱的皮质多巴胺能张力维持任务适当的网络活动失败，以及由于次优的D1至D2/3受体关系而导致的信噪比受损。 正如我们之前所描述的，精神分裂症中认知控制和助记神经回路的关键障碍不仅是受影响个体明显残疾的来源，而且还为检验与精神分裂症有关的基因如何可能导致风险的假说提供了一个有价值的表型。例如，通过测量N-back连续工作记忆任务期间的局部脑血流量，我们重新确认了即使在任务执行得相对较好的患者中也存在异常的前额叶激活模式，并进一步证明了前额叶和内侧颞叶区域深刻的异常连接，这显示出强大的区分健康和患病参与者的能力。后一项发现在另外两组数据中得到了前瞻性的验证，这表明前额叶-边缘功能轴的紊乱可能是疾病特征的标志。然后深入研究贡献分子机制，我们还报道了一种独特的基因-诊断相互作用，涉及编码儿茶酚-O-甲基转移酶的基因COMT，它包含共同的变异，与精神分裂症的风险弱但一致相关，在健康个体中，分别与执行和情感挑战期间的前额叶和边缘功能强烈相关。特别是，我们已经发现，即使在休息时，精神分裂症患者的前额叶背外侧皮质和内侧颞叶血流量之间也存在反向关系，这种关系是由COMT基因介导的。这是一种在健康研究参与者中未见的影响，表明在精神分裂症患者的基线前额叶-边缘神经网络活动中，遗传决定的皮质多巴胺能张力和基本偏差之间存在重要的交集。采用类似的策略，我们扩大了我们在这个队列中的工作，以确定基因诊断与其他风险基因的相互作用，这些基因在工作记忆表现和基础休息条件下都会影响神经功能。今年，我们已经证明，脑源性神经营养因子(BDNF)的遗传变异在多种认知条件下的海马区生理学中发挥着重要的、独立的预测作用，并且在精神分裂症停药患者中的作用大不相同(Eisenberg等人，2013年)。脑源性神经营养因子是调节海马体发育和功能的关键分子，也涉及精神分裂症的神经病理生理学方面。总之，这一系列实验阐明了以前在精神分裂症中发现的与特征静息状态和认知挑战相关的神经异常变化的机制解释。此外，我们最近扩大了对精神分裂症相关海马体功能障碍的研究，建立了助记编码期间的活动可能是这种疾病的遗传易感性的指标(Rasetti等人，2013年)。推进这些研究方向为其他中央生物标志物的研究提供了重要的补充(例如，Masdeu等人关于精神分裂症自身免疫筛查的报告(2013年))，并最终有望帮助发现治疗靶点。(Masdeu等人，2013) 同时，我们与行为神经内分泌科合作，采用了一种深入的激素操作、多模式神经成像方法，旨在了解经前焦虑症的神经基础(Baller等人，2013年)。在用促性腺激素释放激素激动剂抑制性激素的过程中，测量工作记忆的fMRI和PET指数，在健康和PMDD患者中，分别测量孕激素和雌激素加回给药，我们发现，无论何种方式或激素状况，PMDD患者对工作记忆挑战都表现出夸大的前额神经反应，这与临床症状测量有关，为解开这种常见且代价高昂的精神障碍的神经基础提供了亟需的立足点。 最后，与NHGRI的Sidransky博士合作，我们已经能够深入了解与Gba基因突变相关的帕金森病的病理生理学，Gba是一种在Gauchers病中被破坏的基因。使用我们的多示踪剂PET方法，我们表征了与特发性和GBA相关的帕金森病相关的多巴胺能和血流灌注异常(Goker-Alpanet等人，2012年)。

The Section on Integrative Neuroimaging continues to make advances toward its goals of understanding the nature, molecular underpinnings, underlying neurochemistry, and clinical correlates of neural systems-level dysfunction in schizophrenia. This year, we have made substantial progress in furthering our multimodal neuroimaging studies of a unique and growing cohort of medication-free patients with schizophrenia. In particular, new efforts to characterize not only presynaptic dopamine synthetic capacity, but also D1 and D2/3 receptor availability in this population have been successful in this years participants, and with further accrual, will allow evaluation of key hypotheses about integrated pre- and post-synaptic dopamine functioning in this disorder. In conjunction with cortical cognitive activation data collected in the same patients, these data will also provide a platform to expand work from this lab yolking characteristic schizophrenia-associated impairments in prefrontal activation during executive task performance and exaggerated striatal dopamine synthesis. Specifically, this ongoing project will allow us to directly evaluate theories that schizophrenic neuropathophysiological changes are reflected in failures of maintaining task appropriate network activity via disturbed cortical dopaminergic tone and impaired signal-to-noise ratios due to suboptimal D1 to D2/3 receptor relationships. As we have previously described, critical disturbances in cognitive control and mnemonic neural circuitry in schizophrenia not only serve as sources of marked disability in affected individuals, but also provide a valuable phenotype for testing hypotheses regarding how genes implicated in schizophrenia might contribute risk. For example, by measuring regional cerebral blood flow during the N-back continuous working memory task, we have re-confirmed an aberrant prefrontal activation pattern even in patients who perform relatively well on the task and further demonstrated profoundly aberrant connectivity in prefrontal and medial temporal lobe regions, which showed strong ability to discriminate between healthy and ill participants. This latter finding was prospectively validated in two additional data sets, suggesting that disturbances in the prefrontal-limbic functional axis may be an illness trait marker. Delving then into contributing molecular mechanisms, we have also reported on a unique gene-diagnosis interaction operating on regional cerebral blood flow involving the gene coding for catechol-O-methyltransferase, COMT, which harbors common variation that is weakly but consistently associated with schizophrenia risk and strongly implicated in both prefrontal and limbic functioning during executive and affective challenge, respectively, in healthy individuals. In particular, we have identified that even at rest there exists in patients with schizophrenia an inverse relationship between dorsolateral prefrontal cortical and medial temporal lobe blood flow, which is mediated by COMT genotype. This is an effect not seen in healthy study participants and suggests an important intersection between genetically determined cortical dopaminergic tone and fundamental biases in baseline prefrontal-limbic neural network activity in patients suffering with schizophrenia. Adopting a similar strategy, we have broadened our work in this cohort to identify gene-diagnosis interactions with other risk genes that impact neural functioning during both working-memory performance and basal resting conditions. This year, we have shown that genetic variation in brain-derived neurotrophic factor (BDNF), a key molecule regulating hippocampal development and function, which has also been implicated in aspects of schizophrenic neuropathophysiology, plays an important, independent predictive role in hippocampal physiology under multiple cognitive conditions and does so much differently in medication-withdrawn patients with schizophrenia (Eisenberg et al., 2013). Together, this series of experiments elucidates a mechanistic explanation for variation in characteristic resting-state and cognitive challenge-related neural abnormalities previously identified in schizophrenia. In addition, we have very recently extended our study of schizophrenia-associated hippocampal dysfunction by establishing that activity during mnemonic encoding is a likely indicator of genetic liability for this illness (Rasetti et al, 2013). Advancing these lines of research provides an important complement to studies of other central biomarkers (e.g., Masdeu et als report screening for autoimmunity in schizophrenia (2013)) and ultimately promises to aid treatment target discovery. (Masdeu et al., 2013) In parallel, in collaboration with the Behavioral Neuroendocrinology Section we have employed an incisive hormone manipulation, multimodal neuroimaging approach aimed at understanding the neural substrate of premenstrual dysphoric disorder (Baller et al., 2013). Measuring both fMRI and PET indices of working-memory during sex steroid hormone suppression with a GnRH agonist and individually, progesterone and estrogen add-back administration, in both healthy and PMDD patients, we found that regardless of the modality or hormone condition, PMDD patients showed exaggerated prefrontal neural response to working memory challenge, which was related to clinical symptom measurements, providing a much-needed foothold towards unraveling the neural underpinnings of this common and costly mental disorder. Finally, in collaboration with Dr. Sidransky in NHGRI, we have been able to advance insight into the pathophysiology of parkinsonism associated with genetic mutations in GBA, a gene disrupted in Gauchers disease. With our multitracer PET approach, we have characterized both dopaminergic and perfusion abnormalities related to idiopathic and GBA-linked parkinsonism (Goker-Alpan et al., 2012).