Modelling drug modulation of nystagmus.
A better understanding of the neural and functional mechanisms underlying drug-induced changes in pathological nystagmus is likely to improve medical treatment. A treatment option for downbeat nystagmus (DBN), a common form of acquired fixation nystagmus that often occurs with cerebellar degeneration, is low doses of the potassium channel blocker 4-aminopyridine (4-AP). The upward ocular drift in DBN has a spontaneous and a vertical gaze-evoked component. Detailed analysis of the effect of 4-AP in patients showed that the drug consistently improved the gaze-evoked component, but had less effect in reducing the spontaneous drift. We show by a combination of computational modelling at the systems level and at the neuronal level how this differential effect can be investigated. We have previously postulated that DBN is caused by damage to the floccular lobe (FL). 4-AP, which has been shown to increase the excitability of Purkinje cells (PCs) in slice experiments, may thus suppress DBN by partly restoring floccular function. We simulated the effect of low concentrations of 4-AP on the cellular level using a multicompartment model of a PC, in which we changed ion channel properties to simulate damage. The transition from the cellular level to the systems level was achieved by constructing a population response. Systems level modelling predicted that the effect of 4-AP on the PCs should reduce DBN, but the predicted effect on the gaze-dependent component was less than is observed in patients. Our results suggest that the beneficial effect of 4-AP on DBN cannot be solely explained by its effect at the neuronal level of PCs, and suggests added effects at the level of the population of neurons.
Glasauer
Stefan
S
Department of Neurology, Ludwig-Maximilian University, Munich, Germany. sglasauer@nefo.med.uni-muenchen.de
Rössert
Christian
C
D015761:4-Aminopyridine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D005133:Eye Movements / Q000187:drug effects; D005246:Feedback / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009759:Nystagmus, Pathologic / Q000188:drug therapy* / Q000503:physiopathology; D026902:Potassium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*
D026902:Potassium Channel Blockers; D015761:4-Aminopyridine