Spontaneous Nystagmus Violating the Alexander’s Law: Neural Substrates and Mechanisms

Abstract

Alexander's law states that spontaneous nystagmus increases when looking in the direction of fast-phase and decreases during gaze in slow-phase direction. Disobedience to Alexander’s law is occasionally observed in central nystagmus, but the underlying neural circuit mechanisms are poorly understood. We found a violation of Alexander’s law in one or both directions of lateral gaze in lesions of unilateral lateral medulla affecting the vestibular nucleus. When Alexander’s law is violated, the time constant (Tc) was larger than that in the controls (median [interquartile range, IQR]: 14.4 s [6.4–38.9] vs 9.0 s [IQR 5.5–12.6], p = 0.036) while the Tc did not differ between the groups when Alexander’ law is obeyed (9.6 s [3.6–16.1] vs 9.0 s [5.5–12.6], p = 0.924). To test the study hypothesis that an unstable neural integrator may generate nystagmus violating Alexander's law, we primarily utilized the gaze-holding neural integrator computational model, incorporating lesion-induced changes. With normal integrator function, the false rotational cue generates nystagmus following Alexander’s law. The first lesion, which changes the brainstem neural integrator, and the second lesion, which causes the Purkinje synapse to exert excitatory input, both lead to nystagmus that violates Alexander’s law. We propose that when the neural integrator is unstable with lesions in the brainstem neural integrator itself or the neural synapse between Purkinje cells and the brainstem vestibular nucleus, nystagmus violates Alexander’s law.