Department of Clinical Neurosciences, University of Cambridge, UK.
Medical Research Council Cognition and Brain Sciences Unit, University of Cambridge, UK.
Brain. 2018 Aug 1;141(8):2486-2499. doi: 10.1093/brain/awy176.
The distribution of pathology in frontotemporal dementia is anatomically selective, to distinct cortical regions and with differential neurodegeneration across the cortical layers. The cytoarchitecture and connectivity of cortical laminae preferentially supports frequency-specific oscillations and hierarchical information transfer between brain regions. We therefore predicted that in frontotemporal dementia, core functional deficits such as disinhibition would be associated with differences in the frequency spectrum and altered cross-frequency coupling between frontal cortical regions. We examined this hypothesis using a 'Go-NoGo' response inhibition paradigm with 18 patients with behavioural variant frontotemporal dementia and 20 healthy aged-matched controls during magnetoencephalography. During Go and NoGo trials, beta desynchronization was severely attenuated in patients. Beta power was associated with increased impulsivity, as measured by the Cambridge Behavioural Inventory, a carer-based questionnaire of changes in everyday behaviour. To quantify the changes in cross-frequency coupling in the frontal lobe, we used dynamic causal modelling to test a family of hierarchical casual models, which included the inferior frontal gyrus, pre-supplementary motor area (preSMA) and primary motor cortex. This analysis revealed evidence for cross-frequency coupling in a fully connected network in both groups. However, in the patient group, we identified a significant loss of reciprocal connectivity of the inferior frontal gyrus, particularly for interactions in the gamma band and for theta to alpha coupling. Importantly, although prefrontal coupling was diminished, gamma connectivity between preSMA and motor cortex was enhanced in patients. We propose that the disruption of behavioural control arises from reduced frequency-specific connectivity of the prefrontal cortex, together with a hyper-synchronous reorganization of connectivity among preSMA and motor regions. These results are supported by preclinical evidence of the selectivity of frontotemporal lobar degeneration on oscillatory dynamics, and provide a clinically relevant yet precise neurophysiological signature of behavioural control as a potential pharmacological target for early phase experimental medicines studies.
额颞叶痴呆的病理学分布具有解剖选择性，涉及特定的皮质区域，并伴有皮质各层的不同神经退行性变。皮质层的细胞结构和连接优先支持特定频率的振荡和大脑区域之间的层次信息传递。因此，我们预测，在额颞叶痴呆中，核心功能缺陷（如抑制障碍）与额皮质区域之间的频谱差异和交叉频率耦合改变有关。我们使用 18 名行为变异型额颞叶痴呆患者和 20 名健康年龄匹配对照者在脑磁图（MEG）期间进行的“Go-NoGo”反应抑制范式来检验这一假设。在 Go 和 NoGo 试验中，患者的β去同步严重减弱。β功率与冲动性增加相关，冲动性是通过剑桥行为量表（一种基于照顾者的日常生活行为变化问卷）来衡量的。为了量化额叶交叉频率耦合的变化，我们使用动态因果建模来测试一个层次因果模型家族，该模型包括下额回、预备运动区（preSMA）和初级运动皮层。该分析在两组中均发现了完全连接网络中存在交叉频率耦合的证据。然而，在患者组中，我们发现下额回的往返连接明显丧失，特别是在γ波段和θ到α耦合的相互作用中。重要的是，尽管前额叶连接减弱，但患者的 preSMA 和运动皮层之间的γ连接增强。我们提出，行为控制的破坏源于前额叶皮层的频率特异性连接减少，以及 preSMA 和运动区域之间的连接过度同步重组。这些结果得到了额颞叶变性对振荡动力学的选择性的临床前证据的支持，并为行为控制提供了一个具有临床相关性但精确的神经生理学特征，作为早期阶段实验药物研究的潜在药理学靶点。
