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1.  The effects of ion channel blockers validate the conductance-based model of saccadic oscillations 
Conductance-based models of reciprocally inhibiting burst neurons suggest that intrinsic membrane properties and postinhibitory rebound (PIR) determine the amplitude and frequency of saccadic oscillations. Reduction of the low-threshold calcium currents (IT) in the model decreased the amplitude but increased the frequency of the simulated oscillations. Combined reduction of hyperpolarization-activated cation current (Ih) and IT in the model abolished the simulated oscillations. We measured the effects of a selective blocker of IT (ethosuximide) in healthy subjects on the amplitude and frequency of saccadic oscillations evoked by eye closure and of a nonselective blocker of Ih and IT (propronolol) in a patient with microsaccadic oscillation and limb tremor syndrome (mSOLT). Ethosuximide significantly reduced the amplitude but increased the frequency of the saccadic oscillations during eye closure in healthy subjects. Propranolol abolished saccadic oscillations in the mSOLT patient. These results support the hypothetical role of postinhibitory rebound, Ih, and IT, in generation of saccadic oscillations and determining their kinematic properties.
PMCID: PMC3431800  PMID: 21950976
burst neurons; hyperpolarization-activated cation current; low-threshold calcium current; reciprocal innervations
2.  Sustained eye closure slows saccades 
Vision research  2010;50(17):1665-1675.
Saccadic eye movements rapidly orient the line of sight towards the object of interest. Pre-motor burst neurons (BNs) controlling saccades receive excitation from superior colliculus and cerebellum, but inhibition by omnipause neurons (OPNs) prevents saccades. When the OPNs pause, BNs begin to fire. It has been presumed that part of the BN burst comes from post-inhibitory rebound (PIR). We hypothesized that in the absence of prior inhibition from OPNs there would be no PIR, and thus the increase in initial firing rate of BNs would be reduced. Consequently, saccade acceleration would be reduced. We measured eye movements and showed that sustained eye closure, which inhibits the activity of OPNs and thus hypothetically should weaken PIR, reduced the peak velocity, acceleration, and deceleration of saccades in healthy human subjects. Saccades under closed eyelids also had irregular trajectories; the frequency of the oscillations underlying this irregularity was similar to that of high-frequency ocular flutter (back-to-back saccades) often seen in normal subjects during attempted fixation at straight ahead while eyes are closed. Saccades and quick phases of nystagmus are generated by the same pre-motor neurons, and we found that the quick-phase velocity of nystagmus was also reduced by lid closure. These changes were not due to a mechanical hindrance to the eyes, because lid closure did not affect the peak velocities or accelerations of the eyes in the “slow-phase” response to rapid head movements of comparable speeds to those of saccades. These results indicate a role for OPNs in generating the abrupt onset and high velocities of saccades. We hypothesize that the mechanism involved is PIR in pre-motor burst neurons.
PMCID: PMC2929924  PMID: 20573593
Omnipause neurons; Burst neurons; Oscillations; Ballistic movement; Post-inhibitory rebound
3.  Saccadic Burst Cell Membrane Dysfunction Is Responsible for Saccadic Oscillations 
Saccadic oscillations threaten clear vision by causing image motion on the retina. They are either purely horizontal (ocular flutter) or multidimensional (opsoclonus). We propose that ion channel dysfunction in the burst cell membrane is the underlying abnormality. We have tested this hypothesis by simulating a neuromimetic computational model of the burst neurons. This biologically realistic model mimics the physiologic properties and anatomic connections in the brainstem saccade generator. A rebound firing after sustained inhibition, called post-inhibitory rebound (PIR), and reciprocal inhibition between premotor saccadic burst neurons are the key features of this conceptual scheme. PIR and reciprocal inhibition make the circuits that generate the saccadic burst inherently unstable and can lead to oscillations unless stabilized by external inhibition. Our simulations suggest that alterations in membrane properties that lead to an increase in PIR, a reduction in external glycinergic inhibition, or both can cause saccadic oscillations.
PMCID: PMC2752370  PMID: 19145136
4.  Hypothetical membrane mechanisms in essential tremor 
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.
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.
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 ~10× 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.
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.
PMCID: PMC2613385  PMID: 18990221
5.  The visual motion detectors underlying ocular following responses in monkeys 
Vision research  2005;46(6-7):869-878.
Psychophysical evidence indicates that visual motion can be sensed by low-level (energy-based) and high-level (feature-based) mechanisms. The present experiments were undertaken to determine which of these mechanisms mediates the initial ocular following response (OFR) that can be elicited at ultra-short latencies by sudden motion of large-field images. We used the methodology of Sheliga, Chen, FitzGibbon and Miles (Initial ocular following in humans: a response to first-order motion energy. Vision Research, In press), who studied the initial OFRs of humans, to study the initial OFRs of monkeys. Accordingly, we applied horizontal motion to 1) vertical square-wave gratings lacking the fundamental (“missing fundamental stimulus”), and 2) vertical grating patterns consisting of the sum of two sinusoids of frequency 3f and 4f, which created a repeating pattern with beat frequency, f. Both visual stimuli share a critical property: when subject to ¼-wavelength steps, their overall pattern (feature) shifts in the direction of the steps, whereas their major Fourier component shifts in the reverse direction (because of spatial aliasing). We found that the initial OFRs of monkeys to these stimuli, like those of humans, were always in the opposite direction to the ¼-wavelength shifts, i.e., in the direction of the major Fourier component, consistent with detection by (low-level) oriented spatio-temporal filters as in the well-known energy model of motion analysis. Our data indicate that the motion detectors mediating the initial OFR have quantitatively similar properties in monkeys and humans, suggesting that monkeys provide a good animal model for the human OFR.
PMCID: PMC2426752  PMID: 16356529
Missing fundamental; Spatio-temporal filtering; Energy-based mechanisms; Eye movements

Results 1-5 (5)