Investigating the neuroanatomical substrate of pathological laughing and crying in amyotrophic lateral sclerosis with multimodal neuroimaging techniques

Objective: Pathological laughing and crying (PLC) is common in several neurological and psychiatric diseases and is associated with a distributed network involving the frontal cortex, the brainstem and cortico-pontine-cerebellar circuits. By applying multimodal neuroimaging approach, we examined the neuroanatomical substrate of PLC in a sample of patients with amyotrophic lateral sclerosis (ALS). Methods: We studied 56 non-demented ALS patients and 25 healthy controls (HC). PLC was measured in ALS using the Center of Neurologic Study Lability Scale (CNS-LS; cutoff score: 13). All participants underwent 3D-T1-weighted and 30-directional diffusion-weighted imaging at 3T. Voxel-based morphometry and tract-based spatial-statistics analysis was used to examine gray matter (GM) and white matter (WM) differences between ALS patients with and without PLC (ALS-PLC and ALS-nonPLC, respectively). Comparisons were restricted to regions with detected differences between ALS and HC, controlling for age, gender, total intracranial volume and depressive symptoms. Results: In regions with significant differences between ALS and HC, ALS-PLC patients showed decreased GM volume in left orbitofrontal cortex, frontal operculum, and putamen and bilateral frontal poles, compared to ALS-nonPLC. They also had decreased fractional anisotropy in left cingulum bundle and posterior corona radiata. WM abnormalities were additionally detected in WM associative and ponto-cerebellar tracts (using a more liberal threshold). Conclusions: PLC in ALS is driven by both GM and WM abnormalities which highlight the role of circuits rather than isolated centers in the emergence of this condition. ALS is suggested as a useful natural experimental model to study PLC.研究目的：病理性哭笑（Pathological laughing and crying, PLC）在多种神经及精神疾病中较为常见，其发生与包含额叶皮层、脑干以及皮质-脑桥-小脑环路的分布式神经网络密切相关。本研究采用多模态神经成像技术，对肌萎缩侧索硬化症（amyotrophic lateral sclerosis, ALS）患者群体中PLC的神经解剖学基础进行了探究。研究方法：本研究纳入56例无痴呆的ALS患者与25例健康对照（healthy controls, HC）。采用神经研究中心情绪不稳量表（Center of Neurologic Study Lability Scale, CNS-LS；截断值：13）对ALS患者的PLC症状进行评估。所有受试者均接受3特斯拉（3T）磁共振下的三维T1加权成像与30方向扩散加权成像。采用基于体素的形态测量学与基于纤维束的空间统计分析，对比伴PLC的ALS患者（ALS-PLC）与不伴PLC的ALS患者（ALS-nonPLC）的灰质（gray matter, GM）与白质（white matter, WM）差异。本研究的组间比较限定于ALS患者与健康对照存在显著差异的脑区，并对年龄、性别、颅内总体积及抑郁症状进行协变量控制。研究结果：在ALS患者与健康对照存在显著差异的脑区内，与ALS-nonPLC患者相比，ALS-PLC患者的左侧眶额叶皮层、额叶岛盖、壳核以及双侧额极的灰质体积显著降低。同时，ALS-PLC患者的左侧扣带束与后辐射冠的各向异性分数（fractional anisotropy, FA）也出现下降。此外，采用更宽松的阈值时，还可在联合纤维束与脑桥小脑束中观察到白质异常。研究结论：ALS患者的PLC症状由灰质与白质的异常共同介导，这一结果凸显了神经网络而非孤立脑区在该症状发生中的作用。本研究提示，ALS可作为研究PLC的理想自然实验模型。