Shaikh Aasef G, Miura Kenichiro, Optican Lance M, Ramat Stefano, Leigh R John, Zee David S
Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA.
Brain. 2007 Nov;130(Pt 11):3020-31. doi: 10.1093/brain/awm240. Epub 2007 Oct 5.
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 (microSOLT)'--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 microSOLT 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 microSOLT 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 microSOLT. 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.
震颤障碍引发了关于疾病机制的基本问题，也给成功的神经治疗带来了挑战：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？在家族性震颤障碍中，遗传如何“决定”临床表型？在此，我们探讨这些问题。控制快速眼动（扫视）的神经回路与控制肢体运动的神经回路之间的类比，使我们能够将对扫视系统的解释应用到肢体运动系统。此外，相对为人熟知的眼动系统神经生理学为检验关于眼和肢体运动正常及异常运动控制的特定假设提供了独特机会。我们描述了一种新的家族性疾病——“微扫视振荡和肢体震颤（microSOLT）”——在一位母亲和女儿身上出现，她们有微小的眼扫视振荡和手部震颤。这种独特的振荡性运动障碍类似于其他常见的震颤障碍（如特发性震颤），这些障碍发生在中枢神经系统功能正常的患者身上。我们假设，microSOLT是由一种遗传性异常引起的，这种异常导致膜特性异常，从而减少了对运动前神经元的外部抑制，这些运动前神经元产生用于扫视和弹道式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microSOLT患者的手部震颤和眼动，特别是在去除对运动前扫视爆发神经元的抑制的自然情况下（如闭眼时）。然后，我们模拟了一个基于电导的运动前指令模型，该模型包括兴奋性和相互抑制性爆发神经元。这个生理现实模型的结构基于脑干（用于扫视）和丘脑（用于肢体运动）中已知的细胞类型和解剖连接。运动前爆发神经元中的抑制后反弹生理现象使回路本质上不稳定，容易振荡，除非受到外部抑制。事实上，随着模拟的外部抑制（在这种情况下是甘氨酸能抑制）的减少，扫视振荡和肢体震颤得以重现。我们的结果表明，单一的遗传缺陷可以改变膜特性，这会损害一个本质上不稳定的神经回路中的抑制，导致microSOLT中的眼和肢体振荡。这一概念对于理解异常振荡的机制和设计合理的药物治疗具有广泛的意义，可能适用于其他脑部无结构异常的常见疾病，如特发性震颤。
