The long-term goal of this research is to better understand diseases of the ocular motor system in humans and to assess potential treatments. The focus of interest is on the three-dimensional (horizontal, vertical, torsional) kinematical properties of ocular rotations. For the next grant period, our research will concentrate on two themes, in which three-dimensional (3D) eye movements play an eminent role: (A) The influence of visual, vestibular, and pharmacological stimuli on the dynamics and kinematics of infantile nystagmus syndrome (INS) in humans and of its behavioral model in zebrafish and (B) the electro-myo-oculographic (EMG) characterization of angular and linear vestibulo-ocular reflexes (VOR) in healthy human subjects and patients with vestibular disorders. AIMSWe will examine how spontaneous nystagmus in achiasmatic zebrafish bel mutant and patients with INS can be reduced by varying the properties of visual input (e.g. frequency, contrast, luminance) and how it is influenced by vestibular stimulation (e.g. changing the direction of gravity) and drugs (e.g. gabapentin, memantine). Experimental findings will lead to the construction of detailed computer models of INS and therapeutic measures to reduce INS. - We will also characterize the short-latency VOR evoked by controlled, impulsive head angular and linear acceleration in multiple planes in healthy human subjects and in patients with unilateral peripheral-vestibular deficits. We will develop analytical methods to distinguish between semicircular canal and otolith driven ocular EMG responses based on latency. This analysis, in turn, will elucidate the mechanisms of interaction between the angular and linear VOR in the intact system and how this system compensates for unilateral semicircular canal or otolith deficits.IMPORTANCE AND IMPACTOur research will elucidate the pathomechanism of INS and lead to visual and pharmacological strategies to dampen this nystagmus, which will improve vision in INS patients. In addition, we will establish an EMG-based separation of angular and linear VOR signals in humans and demonstrate how semicircular canal or otolith deficits are centrally compensated by the signals from the intact sensors.