Supplementary Material for: Literature Review on lesion-symptom mapping and Deep Brain Stimulation for poststroke spasticity: Restoring a dysfunctional network?

Objective
The present study aimed to define a structural network of stroke-induced and spasticity-related lesions and to relate this network to target sites and reported effects of Deep Brain Stimulation (DBS) to treat poststroke spasticity.

Methods
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [1] guidelines were followed. We performed two separate systematic literature reviews collecting data from previously published voxel-based lesion-symptom mapping (VLSM) studies for post-stroke spasticity patients searching the Medline database on Pubmed using the keywords “stroke”, “spasticity”, and “lesion mapping” as well as data from previously published cohorts undergoing DBS for poststroke spasticity using the keywords “brain stimulation” and “spasticity”. Data collected from each study included patient demographic characteristics, stroke diagnosis, movement disorder, DBS target, stimulation parameters, complications, and outcomes. Data from VLSM studies were used to calculate coordinate-based activation likelihood clusters, which were then used as seeds for enhanced fiber tracking to analyze affected networks.

Results
Data from five studies on voxel-based lesion-symptom mapping for stroke-induced spasticity were included in the analysis. Metaanalytical mapping of stroke-related lesions identified significant clusters located in the basal ganglia-thalamo-cortical network which were predominantly connected to the sensorimotor cortex. We identified eight studies (four retrospective case series, two prospective open-label non-randomized trials, two prospective double-blind trials) fulfilling our in- and exclusion criteria on DBS for spasticity reporting on 107 patients in total. Most studies reported on outcomes on patients with cerebral palsy (CP), a condition associated with both stroke-related spasticity and hypertonia-related dystonia, which are difficult to differentiate clinically. Target sites included different parts of the cerebellum and the motor thalamus with overall mixed results.

Conclusion
Because all reported effective DBS target sites are situated along the cerebello-thalamo-cortical network, we hypothesize, that the therapeutic effect of DBS on spasticity might be induced by resetting a functional imbalance between the basal ganglia-thalamo-cortical and the cerebello-thalamo-cortical networks in patients with a supraspinal etiology of spasticity. However, the results need to be interpreted cautiously due to the inevitable inclusion of stroke-related dystonia.

研究目的
本研究旨在明确卒中诱发及痉挛相关病灶的结构网络，并将该网络与治疗卒中后痉挛的深度脑刺激（Deep Brain Stimulation, DBS）靶点及已报道的治疗效果相关联。

研究方法
本研究遵循系统评价与Meta分析优先报告条目（Preferred Reporting Items for Systematic Reviews and Meta-Analyses, PRISMA）[1]指南。我们开展了两项独立的系统文献综述：其一，检索PubMed的Medline数据库，以"卒中""痉挛""病灶映射"为关键词，收集已发表的卒中后痉挛患者基于体素的病灶-症状映射（voxel-based lesion-symptom mapping, VLSM）研究数据；其二，以"脑刺激""痉挛"为关键词，收集已发表的接受DBS治疗卒中后痉挛的队列研究数据。每项研究收集的数据包括患者人口统计学特征、卒中诊断、运动障碍、DBS靶点、刺激参数、并发症及治疗结局。VLSM研究的数据被用于计算基于坐标的激活似然簇，随后将其作为种子点开展增强纤维追踪，以分析受累神经网络。

研究结果
本分析共纳入5项针对卒中诱发痉挛的基于体素的病灶-症状映射研究数据。卒中相关病灶的Meta分析映射显示，显著簇集区域位于基底节-丘脑-皮层网络，该网络主要与感觉运动皮层相连。我们共纳入8项符合卒中后痉挛DBS治疗纳入排除标准的研究，其中包括4项回顾性病例系列研究、2项前瞻性开放标签非随机试验、2项前瞻性双盲试验，共涉及107例患者。多数研究报道了脑瘫（cerebral palsy, CP）患者的治疗结局，脑瘫与卒中相关痉挛及肌张力增高相关性肌张力障碍均存在关联，而二者在临床上难以鉴别。DBS靶点包括小脑不同区域及运动丘脑，整体研究结果存在异质性。

研究结论
由于所有已报道的有效DBS靶点均位于小脑-丘脑-皮层网络沿线，我们提出假说：对于痉挛病因属于脊髓上起源的患者，DBS治疗痉挛的疗效可能通过重置基底节-丘脑-皮层与小脑-丘脑-皮层网络之间的功能失衡而实现。但由于研究不可避免地纳入了卒中相关肌张力障碍患者，因此对本研究结果需谨慎解读。