Dementia Research Centre, University College London, 8-11 Queen Square, London, WC1N 3AR, UK.
Huntington's Disease Centre, University College London, Russell Square House, London, WC1B 5EH, UK.
Brain. 2020 Dec 5;143(11):3435-3448. doi: 10.1093/brain/awaa270.
Visual hallucinations are common in Parkinson's disease and are associated with poorer prognosis. Imaging studies show white matter loss and functional connectivity changes with Parkinson's visual hallucinations, but the biological factors underlying selective vulnerability of affected parts of the brain network are unknown. Recent models for Parkinson's disease hallucinations suggest they arise due to a shift in the relative effects of different networks. Understanding how structural connectivity affects the interplay between networks will provide important mechanistic insights. To address this, we investigated the structural connectivity changes that accompany visual hallucinations in Parkinson's disease and the organizational and gene expression characteristics of the preferentially affected areas of the network. We performed diffusion-weighted imaging in 100 patients with Parkinson's disease (81 without hallucinations, 19 with visual hallucinations) and 34 healthy age-matched controls. We used network-based statistics to identify changes in structural connectivity in Parkinson's disease patients with hallucinations and performed an analysis of controllability, an emerging technique that allows quantification of the influence a brain region has across the rest of the network. Using these techniques, we identified a subnetwork of reduced connectivity in Parkinson's disease hallucinations. We then used the Allen Institute for Brain Sciences human transcriptome atlas to identify regional gene expression patterns associated with affected areas of the network. Within this network, Parkinson's disease patients with hallucinations showed reduced controllability (less influence over other brain regions), than Parkinson's disease patients without hallucinations and controls. This subnetwork appears to be critical for overall brain integration, as even in controls, nodes with high controllability were more likely to be within the subnetwork. Gene expression analysis of gene modules related to the affected subnetwork revealed that down-weighted genes were most significantly enriched in genes related to mRNA and chromosome metabolic processes (with enrichment in oligodendrocytes) and upweighted genes to protein localization (with enrichment in neuronal cells). Our findings provide insights into how hallucinations are generated, with breakdown of a key structural subnetwork that exerts control across distributed brain regions. Expression of genes related to mRNA metabolism and membrane localization may be implicated, providing potential therapeutic targets.
视觉幻觉在帕金森病中很常见，与预后较差有关。影像学研究表明，帕金森病视觉幻觉与白质损失和功能连接变化有关，但影响大脑网络特定部位的选择性脆弱性的生物学因素尚不清楚。最近的帕金森病幻觉模型表明，它们是由于不同网络的相对影响发生变化而产生的。了解结构连接如何影响网络之间的相互作用将提供重要的机制见解。为了解决这个问题，我们研究了帕金森病视觉幻觉伴有的结构连接变化，以及网络中优先受影响区域的组织和基因表达特征。我们对 100 名帕金森病患者（81 名无幻觉，19 名有视觉幻觉）和 34 名年龄匹配的健康对照进行了弥散加权成像。我们使用基于网络的统计学方法来识别帕金森病患者幻觉时的结构连接变化，并进行了可控性分析，这是一种新兴技术，可以量化大脑区域对网络其余部分的影响。使用这些技术，我们确定了帕金森病幻觉中连接减少的子网。然后，我们使用艾伦脑科学研究所的人类转录组图谱来识别与网络受影响区域相关的区域基因表达模式。在这个网络中，有幻觉的帕金森病患者的可控性（对其他大脑区域的影响较小）低于没有幻觉的帕金森病患者和对照组。这个子网似乎对整体大脑整合至关重要，因为即使在对照组中，可控性高的节点也更有可能在子网内。与受影响子网相关的基因模块的基因表达分析表明，下调的基因在与 mRNA 和染色体代谢过程（寡突胶质细胞中富集）相关的基因中最为显著富集，而上调的基因与蛋白质定位（神经元细胞中富集）相关。我们的研究结果提供了有关幻觉如何产生的见解，即关键结构子网的崩溃，该子网在分布于大脑区域中发挥控制作用。与 mRNA 代谢和膜定位相关的基因的表达可能与之相关，为潜在的治疗靶点提供了依据。
