Hypothetical membrane mechanisms in essential tremor.
BACKGROUND
Essential tremor (ET) is the most common movement disorder and its pathophysiology is unknown. We hypothesize that increased membrane excitability in motor circuits has a key role in the pathogenesis of ET. Specifically, we propose that neural circuits controlling ballistic movements are inherently unstable due to their underlying reciprocal innervation. Such instability is enhanced by increased neural membrane excitability and the circuit begins to oscillate. These oscillations manifest as tremor.


METHODS
Postural limb tremor was recorded in 22 ET patients and then the phenotype was simulated with a conductance-based neuromimetic model of ballistic movements. The model neuron was Hodgkin-Huxley type with added hyperpolarization activated cation current (Ih), low threshold calcium current (IT), and GABA and glycine mediated chloride currents. The neurons also featured the neurophysiological property of rebound excitation after release from sustained inhibition (post-inhibitory rebound). The model featured a reciprocally innervated circuit of neurons that project to agonist and antagonist muscle pairs.


RESULTS
Neural excitability was modulated by changing Ih and/or IT. Increasing Ih and/or IT further depolarized the membrane and thus increased excitability. The characteristics of the tremor from all ET patients were simulated when Ih was increased to approximately 10x the range of physiological values. In contrast, increasing other membrane conductances, while keeping Ih at a physiological value, did not simulate the tremor. Increases in Ih and IT determined the frequency and amplitude of the simulated oscillations.


CONCLUSIONS
These simulations support the hypothesis that increased membrane excitability in potentially unstable, reciprocally innervated circuits can produce oscillations that resemble ET. Neural excitability could be increased in a number of ways. In this study membrane excitability was increased by up-regulating Ih and IT. This approach suggests new experimental and clinical ways to understand and treat common tremor disorders.
Shaikh
Aasef G
AG
Department of Neurology, The Johns Hopkins University, Baltimore, MD, USA. ashaikh@dizzy.med.jhu.edu
Miura
Kenichiro
K
Optican
Lance M
LM
Ramat
Stefano
S
Tripp
Robert M
RM
Zee
David S
DS
D002462:Cell Membrane / Q000378:metabolism*; D003198:Computer Simulation; D020329:Essential Tremor / Q000209:etiology / Q000503:physiopathology*; D006801:Humans; D015640:Ion Channel Gating; D008564:Membrane Potentials / Q000502:physiology; D008959:Models, Neurological; D009046:Motor Neurons / Q000166:cytology / Q000502:physiology; D010641:Phenotype