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Purkinje cells (PCs) in the cerebellar flocculus carry rate-coded information that ultimately drives eye movement. Floccular PCs lying nearby each other exhibit partial synchrony of their simple spikes (SS). Elsewhere in the cerebellum, PC SS synchrony has been demonstrated to influence activity of the PCs' synaptic targets, and some suggest it constitutes another vector for information transfer. We investigated in the cerebellar flocculus the extent to which the rate code and PC synchrony interact. One motivation for the study was to explain the cerebellar deficits in ataxic mice like tottering; we speculated that PC synchrony has a positive effect on rate code transmission that is lost in the mutants. Working in transgenic mice whose PCs express channelrhodopsin, we exploited a property of optogenetics to control PC synchrony: pulsed photostimulation engenders stimulus-locked spiking, whereas continuous photostimulation engenders spiking whose timing is unconstrained. We photoactivated flocculus PCs using pulsed stimuli with sinusoidally varying timing vs. continuous stimuli with sinusoidally varying intensity. Recordings of PC pairs confirmed that pulsed stimuli engendered greater PC synchrony. We quantified the efficiency of transmission of the evoked PC firing rate modulation from the amplitudes of firing rate modulation and eye movement. Rate code transmission was slightly poorer in the conditions that generated greater PC synchrony, arguing against our motivating speculation regarding the origin of ataxia in tottering. Floccular optogenetic stimulation prominently augmented a 250–300 Hz local field potential oscillation, and we demonstrate relationships between the oscillation power and the evoked PC synchrony. [ABSTRACT FROM AUTHOR]

Background: Vaginal dilators (VD) are recommended following vaginal or pelvic radiotherapy for patients with endometrial carcinoma (EC) to prevent vaginal stenosis (VS). The time course of VS is not fully understood and the optimal duration of VD use is unknown.Methods: We reviewed 243 stage IA-II EC patients who received adjuvant brachytherapy (BT) at an academic tertiary referral center. Patients were instructed to use their VD three times per week for at least 1-year duration. The primary outcome was development of grade ≥ 1 VS using CTCAEv4 criteria during the follow-up period. The log-rank test and multivariable Cox proportional hazards modeling were used to evaluate the effect of VD use (noncompliance vs. standard compliance [up to 1 year] vs. extended compliance [over 1 year]) on VS.Results: The median follow-up was 15.2 months over the 5-year study period. At 15 months, the incidence of VS was 38.8% for noncompliant patients, 33.5% for those with standard compliance, and 21.4% for those with extended compliance (median time to grade ≥ 1 VS was 17.5 months, 26.7 months, and not yet reached for these groups, respectively). On multivariable Cox regression analysis, extended compliance remained a significant predictor of reduced VS risk when compared to both noncompliance (HR 0.38, 95% CI 0.18-0.80, p = 0.012) and standard compliance (HR 0.43, 95% CI 0.20-0.89, p = 0.023).Conclusions: The risk of VS persists beyond 1 year after BT. Extended VD compliance beyond 1 year may mitigate this risk. [ABSTRACT FROM AUTHOR]

The deaf-circling Ames waltzer (av) mouse harbors a mutation in the protocadherin 15 (Pcdh15) gene and is a model for inner ear defects associated with Usher syndrome type 1F. Earlier studies showed altered cochlear hair cell morphology in young av mice. In contrast, no structural abnormality consistent with significant vestibular dysfunction in young av mice was observed. Light and scanning electron microscopic studies showed that vestibular hair cells from presumptive null alleles Pcdh15(av-Tg) and Pcdh15(av-3J) are morphologically similar to vestibular sensory cells from control littermates, suggesting that the observed phenotype in these alleles might be a result of a central, rather than peripheral, defect. In the present study, a combination of physiologic and anatomic methods was used to more thoroughly investigate the source of vestibular dysfunction in Ames waltzer mice. Analysis of vestibular evoked potentials and angular vestibulo-ocular reflexes revealed a lack of physiologic response to linear and angular acceleratory stimuli in Pcdh15 mutant mice. Optokinetic reflex function was diminished but still present in the mutant animals, suggesting that the defect is primarily peripheral in nature. These findings indicate that the mutation in Pcdh15 results in either a functional abnormality in the vestibular receptor organs or that the defects are limited to the vestibular nerve. AM1-43 dye uptake has been shown to correlate with normal transduction function in hair cells. Dye uptake was found to be dramatically reduced in Pcdh15 mutants compared to control littermates, suggesting that the mutation affects hair cell function, although structural abnormalities consistent with significant vestibular dysfunction are not apparent by light and scanning electron microscopy in the vestibular neuroepithelia of young animals. [ABSTRACT FROM AUTHOR]

Humans may accomplish gaze shifts by eye-only saccades or combined eye–head saccades. The mechanisms that determine whether the head moves remain poorly understood. Many observations can be explained if phylogenetically ancient circuits generate eye–head saccades by default and frontal cerebral structures interrupt this synergy when eye-only saccades are preferable. Saccade-associated head movements have been reported to increase in the elderly. To test the hypothesis of frontal inhibition of head movements, we investigated whether the increase is associated with a decline in frontal cognitive function. We measured head movement tendencies and cognition in volunteers aged 61–80. Measures of head movement tendency included the customary range of eye eccentricity, customary range of head eccentricity, range of target eccentricities evoking predominantly eye-only saccades, and two measures of head amplitude variation as a function of target eccentricity. Cognitive measures encompassed verbal fluency, verbal memory, non-verbal memory, and executive function. There was no correlation between cognition and any measure of head movement tendency. We combined these elderly data with measurements of head movements in a group aged 21–67 and found mildly reduced, not increased, head movement tendencies with age. However, when confronted with a task that could be accomplished without moving the head, young subjects were more likely to cease all head movements. While inconclusive regarding the hypothesis of inhibition of saccade-associated head movements by cerebral structures, the results indicate the need to distinguish between mechanisms that define head movement tendencies and mechanisms that adapt head motion to the geometry of a specific task. [ABSTRACT FROM AUTHOR]

Humans exhibit considerable individuality in their propensity to make head movements during horizontal saccades. These variations originate in multiple quantifiable characteristics, including individuals’ preferred ranges of gaze, eye-in-head, and head-on-neck eccentricity. Such “eye–head tendencies” have been uniformly assessed in seated subjects. It is unknown whether they continue to influence behavior when subjects are in motion. Previous studies of eye–head coordination in subjects ambulating in laboratories would predict that wholly different eye–head tendencies become ascendant when subjects ambulate. We tested this prediction by recording eye and head positions in normal subjects in an outdoor environment as they spontaneously regarded their surroundings while seated, passively riding in a wheelchair, and ambulating. Individuals exhibited the usual subject-to-subject variations in the preferred ranges of eye, head, and gaze position, but their own behavior was similar across the different conditions. While ambulation did affect some of the measured eye–head tendencies, passively riding had similar effects, indicating that these effects relate more to motion through the environment than to the act of walking. In a surprising departure from studies of eye–head coordination in subjects ambulating in laboratory environments, neither head nor gaze was particularly strongly aligned with the direction of travel. Thus, the neural mechanisms of walking do not demand that specific gaze or head orientations be maintained continuously, at least not in the common situation of a non-challenging path that can be negotiated without much attention. In such situations eye and head control is flexible, and the eye–head tendencies manifesting when stationary can emerge. [ABSTRACT FROM AUTHOR]

The tendency to generate head movements during saccades varies from person to person. Head movement tendencies can be measured as subjects fixate sequences of illuminated targets, but the extent to which such measures reflect eye–head coupling during more natural behaviors is unknown. We quantified head movement tendencies in 20 normal subjects in a conventional laboratory experiment and in an outdoor setting in which the subjects directed their gaze spontaneously. In the laboratory, head movement tendencies during centrifugal saccades could be described by the eye-only range (EOR), customary ocular motor range (COMR), and the customary head orientation range (CHOR). An analogous EOR, COMR, and CHOR could be extracted from the centrifugal saccades executed in the outdoor setting. An additional six measures were introduced to describe the preferred ranges of eyes-in-head and head-on-torso manifest throughout the outdoor recording, i.e., not limited to the orientations following centrifugal saccades. These 12 measured variables could be distilled by factor analysis to one indoor and six outdoor factors. The factors reflect separable tendencies related to preferred ranges of visual search, head eccentricity, and eye eccentricity. Multiple correlations were found between the indoor and outdoor factors. The results demonstrate that there are multiple types of head movement tendencies, but some of these influence behavior across rather different experimental settings and tasks. Thus behavior in the two settings likely relies on common neural mechanisms, and the laboratory assays of head movement tendencies succeed in probing the mechanisms underlying eye–head coupling during more natural behaviors. [ABSTRACT FROM AUTHOR]

The ability to dissociate eye movements from head movements is essential to animals with foveas and fovea-like retinal specializations, as these species shift the eyes constantly, and moving the head with each gaze shift would be impractical and energetically wasteful. The processes by which the dissociation is effected remain unclear. We hypothesized that the dissociation is accomplished by means of a neural gate, which prevents a common gaze-shift command from reaching the neck circuitry when eye-only saccades are desired. We further hypothesized that such a gate would require a finite period to reset following opening to allow a combined eye–head saccade, and thus the probability of generating a head movement during a saccade would be augmented when a new visual target (the ‘test’ target) appeared during, or soon after, a combined eye–head saccade made to an earlier, ‘conditioning’ target. We tested human subjects using three different combinations of targets—a horizontal conditioning target followed by a horizontal test target (H/H condition), horizontal conditioning followed by vertical test (H/V), and vertical conditioning followed by horizontal test (V/H). We varied the delay between the onset of the conditioning head movement and the presentation of the test target, and determined the probability of generating a head movement to the test target as a function of target delay. As predicted, head movement probability was elevated significantly at the shortest target delays and declined thereafter. The half-life of the increase in probability averaged 740, 490, and 320 ms for the H/H, H/V, and V/H conditions, respectively. For the H/H condition, the augmentation appeared to outlast the duration of the conditioning head movement. Because the augmentation could outlast the conditioning head movement and did not depend on the head movements to the conditioning and test targets lying in the same directions, we could largely exclude the possibility that the augmentation arises from mechanical effects. These results support the existence of the hypothetical eye–head gate, and suggest ways that its constituent neurons might be identified using neurophysiological methods. [ABSTRACT FROM AUTHOR]

Mammals with foveas (or analogous retinal specializations) frequently shift gaze without moving the head, and their behavior contrasts sharply with “afoveate” mammals, in which eye and head movements are strongly coupled. The ability to move the eyes without moving the head could reflect a gating mechanism that blocks a default eye-head synergy when an attempted head movement would be energetically wasteful. Based upon such considerations of efficiency, we predicted that for saccades to targets lying within the ocular motor range, the tendency to generate a head movement would depend upon a subject’s expectations regarding future directions of gaze. We tested this hypothesis in two experiments with normal human subjects instructed to fixate sequences of lighted targets on a semicircular array. In the target direction experiment, we determined whether subjects were more likely to move the head during a small gaze shift if they expected that they would be momentarily required to make a second, larger shift in the same direction. Adding the onward-directed target increased significantly the distribution of final head positions (customary head orientation range, CHOR) observed during fixation of the primary target from 16.6±4.9° to 25.2±7.8°. The difference reflected an increase in the probability, and possibly the amplitude, of head movements. In the target duration experiment, we determined whether head movements were potentiated when subjects expected that gaze would be held in the vicinity of the target for a longer period of time. Prolonging fixation increased CHOR significantly from 53.7±18.8° to 63.2±15.9°. Larger head movements were evoked for any given target eccentricity, due to a narrowing in the gap between the x-intercepts of the head amplitude:target eccentricity relationship. The results are consistent with the idea that foveate mammals use knowledge of future gaze direction to influence the coupling of saccadic commands to premotor circuitry of the head. While the circuits ultimately mediating the coupling may lie within the brainstem, our results suggest that the cerebrum plays a supervisory role, since it is a likely seat of expectation regarding target behavior. Eye-head coupling may reflect separate gating and scaling mechanisms, and changes in head movement tendencies may reflect parametric modulation of either mechanism. [ABSTRACT FROM AUTHOR]

Advances in understanding the organization of the ocular motor system, including its anatomy and pharmacology, have provided new insights into the pathogenesis of various forms of nystagmus. The discoveries of fibromuscular pulleys that govern the pulling directions of the extraocular muscles has provided a new conceptual framework to account for the different axes of rotation of vestibular and other types of movements that may contribute to nystagmus. Theoretical and experimental evidence has suggested that acquired pendular nystagmus, which is commonly due to multiple sclerosis, arises from the neural network that normally guarantees steady gaze by integrating premotor signals. Pharmacologic inactivation studies have implicated both g-aminobutyric acid (GABA) and glutamate as important transmitters in the neural integrator and suggested new drug therapies. New electro-optic devices may eventually prove to be effective treatment for the visual symptoms cause by acquired nystagmus. The demonstration of proprioceptive mechanisms in the distal extraocular muscles has provided a rationale for new operative treatments for congenital nystagmus. [ABSTRACT FROM AUTHOR]

Individual humans exhibit differing propensity to move the head in association with saccadic shifts in gaze. We assessed whether this tendency can be modified in normal subjects by either reducing neck mobility with a cervical collar or restricting the field of view using aperture spectacles. We quantified head movement propensity in terms of the range of orbital eccentricity within which the eyes are customarily maintained (customary ocular motor range), and the range of final eye-in-head eccentricity for which a planned saccade is likely to be executed without a concomitant head movement (eye-only range). Three subjects wore rigid collars during waking hours for periods of up to 9 days. We measured customary and eye-only ranges with the collar removed, at various times during the adaptation and recovery periods. Collar adaptation reduced head movement propensity in all three subjects, increasing the average customary ocular range from 27.6±8.9° (mean ± SD) to 66.1±4.5° and the eye-only range from 24.6±17.0° to 67.6±7.4°. In two subjects the modifications persisted for weeks following final collar removal. In parallel with the reduction in head movement propensity, all subjects improved in their ability to maintain eccentric gaze, suggesting that neck restriction led to effects at the level of the brainstem. Three subjects were adapted to spectacles, masked to restrict the field of view to approximately 20°. The aperture spectacles were worn for periods of up to 9 days. When tested without the apertures, one subject exhibited a definite increase in head movement propensity; in the other two, the data were equivocal, indicating either a small increase in head movement propensity or no effect. Averaged across subjects, customary ocular motor range decreased from 35.1±12.8° to 25.4±13.4° and eye-only range decreased from 35.1±7.5° to 23.0±4.0°. The marked difference in the magnitudes of collar- and spectacle-induced changes suggests that the responses to the two restrictive appliances are mediated by different mechanisms. Collar adaptation may involve parametric modulation of circuits mediating reflex recruitment of head movements, while aperture adaptation may primarily reflect substitution of an alternative mode of head control triggered by the presence of the restricted field of view, with only minor parametric modulation of the underlying head recruitment circuit. The enduring effects of restricting neck mobility upon head movement tendencies may relate to the common clinical association between neck injury and persistent dysequilibrium. [ABSTRACT FROM AUTHOR]

Different humans vary widely in the tendency to move the head during saccadic shifts in gaze. The reasons for this variation are unknown. Because combined eye-head movements are associated with a recentering of the eyes in the orbits, humans who are "head movers" tend to maintain the eyes within a narrower range than do non-head movers. We explored the possibility that variations in the ability to control eye movements at eccentric positions lead to variations in customary ocular motor range and, by extension, explain the variations in head-movement tendencies. We studied ten normal adults. In each, we measured the full-scale ocular motor range and customary ocular motor range (the eccentricity range within which the eye was found at the conclusion of eye- or eye-head saccades). We also determined the eye-only range, the orbital range within which the probability of a head movement accompanying a gaze shift was low. Customary, eye-only, and full-scale ranges spanned (mean ±SD) 41.1±16.9°, 30.2±18.8°, and 92.8±9.1°, respectively. We then assessed variations in kinematics of several ocular motor behaviors as functions of eye eccentricity. The stable fixation range, defined by the range over which drift velocities were below 1°/s, spanned 81.1±11.2° in the light and 69.5±21.5° in the dark. The range over which the gains of the vestibulo-ocular reflex in the light and smooth pursuit approached their values at zero eccentricity spanned 66.3±7.1° and 69.0±10.0°, respectively. Small centrifugal saccades (5–10°) tended to become either slowed or hypometric with increasing eccentricity. Sensitive to both slowing and hypometria, the ratio of peak gaze velocity to target shift amplitude was flat over a range spanning 65.7±14.9°. Finally, the ranges over which the initial saccade placed the fovea upon the target averaged 35.5±10.7° for eye-only saccades and 36.6±15.0° for eye-head saccades. With the exception of the range of stable fixation in the light, the kinematic ranges were either unrelated or inconsistently related to full-scale range, indicating that the deterioration of eye movements with increasing ocular eccentricity is not a simple consequence of the eyes encountering the limits of their excursion. None of the kinematic ranges correlated positively with customary or eye-only range. Thus, while head movements may be orchestrated so as to maintain the eyes within a desired range, that range (and thus head movement tendencies) is not predicated upon the range of ocular eccentricity over which eye movements are accurately controlled. [ABSTRACT FROM AUTHOR]