Nguyen Megan X, Brown Amanda M, Lin Tao, Sillitoe Roy V, Gill Jason S
Department of Pediatrics, Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA.
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.
bioRxiv. 2024 May 21:2024.05.21.595095. doi: 10.1101/2024.05.21.595095.
Dystonia is the third most common movement disorder and an incapacitating co-morbidity in a variety of neurologic conditions. Dystonia can be caused by genetic, degenerative, idiopathic, and acquired etiologies, which are hypothesized to converge on a "dystonia network" consisting of the basal ganglia, thalamus, cerebellum, and cerebral cortex. In acquired dystonia, focal lesions to subcortical areas in the network - the basal ganglia, thalamus, and cerebellum - lead to a dystonia that can be difficult to manage with canonical treatments, including deep brain stimulation (DBS). While studies in animal models have begun to parse the contribution of individual nodes in the dystonia network, how acquired injury to the cerebellar outflow tracts instigates dystonia; and how network modulation interacts with symptom latency remain as unexplored questions. Here, we present an electrolytic lesioning paradigm that bilaterally targets the cerebellar outflow tracts. We found that lesioning these tracts, at the junction of the superior cerebellar peduncles and the medial and intermediate cerebellar nuclei, resulted in acute, severe dystonia. We observed that dystonia is reduced with one hour of DBS of the centrolateral thalamic nucleus, a first order node in the network downstream of the cerebellar nuclei. In contrast, one hour of stimulation at a second order node in the short latency, disynaptic projection from the cerebellar nuclei, the striatum, did not modulate the dystonia in the short-term. Our study introduces a robust paradigm for inducing acute, severe dystonia, and demonstrates that targeted modulation based on network principles powerfully rescues motor behavior. These data inspire the identification of therapeutic targets for difficult to manage acquired dystonia.
肌张力障碍是第三常见的运动障碍，也是多种神经系统疾病中使人丧失能力的合并症。肌张力障碍可由遗传、退行性、特发性和后天性病因引起，据推测这些病因会汇聚在一个由基底神经节、丘脑、小脑和大脑皮层组成的“肌张力障碍网络”上。在后天性肌张力障碍中，该网络中皮质下区域——基底神经节、丘脑和小脑——的局灶性病变会导致一种肌张力障碍，这种肌张力障碍很难用包括深部脑刺激（DBS）在内的传统治疗方法进行管理。虽然动物模型研究已开始剖析肌张力障碍网络中各个节点的作用，但小脑传出束的后天性损伤如何引发肌张力障碍，以及网络调节如何与症状潜伏期相互作用，仍是未探索的问题。在此，我们提出一种双侧靶向小脑传出束的电解损伤范式。我们发现，在小脑上脚与内侧和中间小脑核的交界处损伤这些束，会导致急性、严重的肌张力障碍。我们观察到，对中央外侧丘脑核进行1小时的DBS可减轻肌张力障碍，中央外侧丘脑核是小脑核下游网络中的一级节点。相比之下，对小脑核的短潜伏期、双突触投射的二级节点——纹状体——进行1小时的刺激，在短期内并未调节肌张力障碍。我们的研究引入了一种诱导急性、严重肌张力障碍的强大范式，并证明基于网络原理的靶向调节能有力地挽救运动行为。这些数据激发了对难以治疗的后天性肌张力障碍治疗靶点的识别。
