A new familial disease of saccadic oscillations and limb tremor provides clues to mechanisms of common tremor disorders.
A new familial disease of saccadic oscillations and limb tremor provides clues to mechanisms of common tremor disorders.
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一种新的家族性疾病——扫视振荡和肢体震颤为常见震颤疾病的机制提供了线索。
DOI：
10.1093/brain/awm240
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Zee,DavidS
中科院分区：
文献类型：
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作者：
Shaikh,AasefG;Miura,Kenichiro;Optican,LanceM;Ramat,Stefano;Leigh,RJohn;Zee,DavidS
震颤性疾病提出了关于疾病机制的基本问题，并对成功的神经治疗提出了挑战：在中枢神经系统看似正常的疾病中，是什么导致运动回路振荡？遗传如何“决定”家族性震颤障碍的临床表型？在这里，我们解决这些问题。控制快速眼球运动（扫视）的神经回路和控制肢体运动的神经回路之间的类比使我们能够将扫视系统的解释转化为肢体运动系统。此外，眼运动系统的神经生理学的相对较好的理解提供了一个独特的机会，以测试特定的假设正常和异常的运动控制的眼睛和肢体运动。我们描述了一个新的家族性疾病-'微扫视振荡和肢体震颤（μSOLT震颤）'-在母亲和女儿谁有微小的扫视振荡的眼睛和震颤的手。这种独特的振荡运动障碍类似于其他常见的震颤障碍（如原发性震颤），发生在中枢神经系统功能正常的患者中。我们假设μSOLT是由遗传性异常引起的，这种异常导致膜特性异常，导致运动前神经元的外部抑制减少，这些神经元产生用于扫视和弹道肢体运动的高频放电（爆发）。为了验证这一假设，我们记录了两名μSOLT患者的手震颤和眼球运动，特别是在自然情况下，当运动前扫视爆发神经元的抑制被去除时（例如闭眼）。然后，我们模拟了一个基于电导的模型的前运动命令，其中包括兴奋性和抑制性爆发神经元。这个生理上真实的模型的结构是基于已知的细胞类型和脑干（用于扫视）和丘脑（用于肢体运动）中的解剖学连接。前运动爆发神经元中的抑制后反弹的生理现象使得回路固有地不稳定并且倾向于振荡，除非通过外部抑制来阻止。事实上，与模拟减少外部抑制（在这种情况下甘氨酸），扫视振荡和肢体震颤再现。我们的研究结果表明，一个单一的遗传缺陷可以改变膜的特性，这损害了抑制在一个固有的不稳定的神经回路，导致眼睛和肢体振荡μSOLT。这一概念具有广泛的意义，了解机制和设计合理的药物治疗异常振荡，并可能适用于其他常见的疾病，其中没有结构异常的大脑，如特发性震颤。
Tremor disorders pose fundamental questions about disease mechanisms, and challenges to successful neurotherapeutics: What causes motor circuits to oscillate in disorders in which the central nervous system otherwise seems normal? How does inheritance ‘determine’ the clinical phenotype in familial tremor disorders? Here, we address these questions. Analogies between the neural circuits controlling rapid eye movements (saccades) and those controlling limb movements allow us to translate the interpretations from the saccadic systems to the limb movement system. Moreover, the relatively well understood neurophysiology of the ocular motor system offers a unique opportunity to test specific hypotheses about normal and abnormal motor control of both eye and limb movements. We describe a new familial disorder—‘micro-saccadic oscillations and limb tremor (μSOLT)’—in a mother and daughter who had tiny saccadic oscillations of the eyes and tremor of the hands. This unique oscillatory movement disorder resembles other common tremor disorders (such as essential tremor) that occur in patients who have an otherwise normally functioning central nervous system. We hypothesize that μSOLT is caused by an inherited abnormality that results in abnormal membrane properties causing reduced external inhibition in the premotor neurons that generate the high-frequency discharge (burst) for saccades and for ballistic limb movements. To test this hypothesis, we recorded hand tremor and eye movements in two patients with μSOLT and particularly during natural circumstances when inhibition of the premotor saccadic burst neurons is removed (e.g. eye closure). We then simulated a conductance-based model for the premotor commands which included excitatory and reciprocally inhibitory burst neurons. The structure of this physiologically realistic model was based upon known cell types and anatomical connections in the brainstem (for saccades) and the thalamus (for limb movements). The physiological phenomenon of post-inhibitory rebound in premotor burst neurons makes the circuit inherently unstable and prone to oscillate unless prevented by external inhibition. Indeed, with simulated reduction of external inhibition (in this case glycinergic), saccadic oscillations and limb tremor were reproduced. Our results suggest that a single-inherited deficit can alter membrane properties, which impairs inhibition in an inherently unstable neural circuit causing the eye and limb oscillations in μSOLT. This concept has broad implications for understanding the mechanism and designing rationale pharmacotherapy for abnormal oscillations and may be applicable to other common disorders in which there are no structural abnormalities in the brain such as essential tremor.