Brain Advance Access originally published online on October 5, 2007
Brain 2007 130(11):3020-3031; doi:10.1093/brain/awm240
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A new familial disease of saccadic oscillations and limb tremor provides clues to mechanisms of common tremor disorders
Department of Neurology, Johns Hopkins University, Baltimore, MD, National Eye Institute, National Institutes of Health, Bethesda, MD, USA, University of Pavia, Pavia, Italy and Case Western Reserve University, Cleveland, OH, USA
Correspondence to: Aasef G. Shaikh, 600 North Wolfe Street, Path 2-210, Johns Hopkins University, Baltimore, MD 21287, USA. E-mail: ashaikh{at}dizzy.med.jhu.edu
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.
Key Words: ion channels; saccade; tremor; computational simulation; oscillations
Abbreviations: EBN, excitatory burst neurons; IBN, inhibitory burst neurons; IO, inferior olive; µSOLT, micro-saccadic oscillations and limb tremor; OPN, omni-directional pause neurons; PIR, post-inhibitory rebound; TC, thalamo-cortical; TR, thalamic reticular; VA, ventral anterior; VL, ventral lateral
Received July 9, 2007. Revised August 13, 2007. Accepted September 3, 2007.