Impact of Purkinje Cell Simple Spike Synchrony on Signal Transmission from Flocculus.

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.

Mouse Extraocular Muscles and the Musculotopic Organization of Their Innervation.

The organization of extraocular muscles (EOMs) and their motor nuclei was investigated in the mouse due to the increased importance of this model for oculomotor research. Mice showed a standard EOM organization pattern, although their eyes are set at the side of the head. They do have more prominent oblique muscles, whose insertion points differ from those of frontal-eyed species. Retrograde tracers revealed that the motoneuron layout aligns with the general vertebrate plan with respect to nuclei and laterality. The mouse departed in some significant respects from previously studied species. First, more overlap between the distributions of muscle-specific motoneuronal pools was present in the oculomotor nucleus (III). Furthermore, motoneuron dendrites for each pool filled the entire III and extended beyond the edge of the abducens nucleus (VI). This suggests mouse extraocular motoneuron afferents must target specific pools based on features other than dendritic distribution and nuclear borders. Second, abducens internuclear neurons are located outside the VI. We concluded this because no unlabeled abducens internuclear neurons were observed following lateral rectus muscle injections and because retrograde tracer injections into the III labeled cells immediately ventral and ventrolateral to the VI, not within it. This may provide an anatomical substrate for differential input to motoneurons and internuclear neurons that allows rodents to move their eyes more independently. Finally, while soma size measurements suggested motoneuron subpopulations supplying multiply and singly innervated muscle fibers are present, markers for neurofilaments and perineuronal nets indicated overlap in the size distributions of the two populations. Anat Rec, 302:1865-1885, 2019. © 2019 American Association for Anatomy.

Mechanics of mouse ocular motor plant quantified by optogenetic techniques.

Rigorous descriptions of ocular motor mechanics are often needed for models of ocular motor circuits. The mouse has become an important tool for ocular motor studies, yet most mechanical data come from larger species. Recordings of mouse abducens neurons indicate the mouse mechanics share basic viscoelastic properties with larger species but have considerably longer time constants. Time constants can also be extracted from the rate at which the eye re-centers when released from an eccentric position. The displacement can be accomplished by electrically stimulating ocular motor nuclei, but electrical stimulation may also activate nearby ocular motor circuitry. We achieved specific activation of abducens motoneurons through photostimulation in transgenic mice expressing channelrhodopsin in cholinergic neurons. Histology confirmed strong channelrhodopsin expression in the abducens nucleus with relatively little expression in nearby ocular motor structures. Stimulation was delivered as 20- to 1,000-ms pulses and 40-Hz trains. Relaxations were modeled best by a two-element viscoelastic system. Time constants were sensitive to stimulus duration. Analysis of isometric relaxation of isolated mouse extraocular muscles suggest the dependence is attributable to noninstantaneous decay of active forces in non-twitch fibers following stimulus offset. Time constants were several times longer than those obtained in primates, confirming that the mouse ocular motor mechanics are relatively sluggish. Finally, we explored the effects of 0.1- to 20-Hz sinusoidal photostimuli and demonstrated their potential usefulness in characterizing ocular motor mechanics, although this application will require further data on the temporal relationship between photostimulation and neuronal firing in extraocular motoneurons.

Flocculus Purkinje cell signals in mouse Cacna1a calcium channel mutants of escalating severity: an investigation of the role of firing irregularity in ataxia.

Mutation of the Cacna1a gene for the P/Q (CaV2.1) calcium channel invariably leads to cerebellar dysfunction. The dysfunction has been attributed to disrupted rhythmicity of cerebellar Purkinje cells, but the hypothesis remains unproven. If irregular firing rates cause cerebellar dysfunction, then the irregularity and behavioral deficits should covary in a series of mutant strains of escalating severity. We compared firing irregularity in floccular and anterior vermis Purkinje cells in the mildly affected rocker and moderately affected tottering Cacna1a mutants and normal C57BL/6 mice. We also measured the amplitude and timing of modulations of floccular Purkinje cell firing rate during the horizontal vestibuloocular reflex (VOR, 0.25-1 Hz) and the horizontal and vertical optokinetic reflex (OKR, 0.125-1 Hz). We recorded Purkinje cells selective for rotational stimulation about the vertical axis (VAPCs) and a horizontal axis (HAPCs). Irregularity scaled with behavioral deficit severity in the flocculus but failed to do so in the vermis, challenging the irregularity hypothesis. Mutant VAPCs exhibited unusually strong modulation during VOR and OKR, the response augmentation scaling with phenotypic severity. HAPCs exhibited increased OKR modulation but in tottering only. The data contradict prior claims that modulation amplitude is unaffected in tottering but support the idea that attenuated compensatory eye movements in Cacna1a mutants arise from defective transfer of Purkinje cell signals to downstream circuitry, rather than attenuated synaptic transmission within the cerebellar cortex. Shifts in the relative sizes of the VAPC and HAPC populations raise the possibility that Cacna1a mutations influence the development of floccular zone architecture.

4-aminopyridine does not enhance flocculus function in tottering, a mouse model of vestibulocerebellar dysfunction and ataxia.

The potassium channel antagonist 4-aminopyridine (4-AP) improves a variety of motor abnormalities associated with disorders of the cerebellum. The most rigorous quantitative data relate to 4-AP's ability to improve eye movement deficits in humans referable to dysfunction of the cerebellar flocculus. Largely based on work in the ataxic mouse mutant tottering (which carries a mutation of the Cacna1a gene of the P/Q voltage-activated calcium channel), 4-AP is hypothesized to function by enhancing excitability or rhythmicity of floccular Purkinje cells. We tested this hypothesis by determining whether systemic or intrafloccular administration of 4-AP would ameliorate the eye movement deficits in tottering that are attributable to flocculus dysfunction, including the reductions in amplitude of the yaw-axis vestibulo-ocular reflex (VOR) and vision-enhanced vestibulo-ocular reflex (VVOR), and the optokinetic reflex (OKR) about yaw and roll axes. Because tottering's deficits increase with age, both young and elderly mutants were tested to detect any age-dependent 4-AP effects. 4-AP failed to improve VOR, VVOR, and OKR gains during sinusoidal stimuli, although it may have reduced the tendency of the mutants' responses to VOR and VVOR to decline over the course of a one-hour recording session. For constant-velocity optokinetic stimuli, 4-AP generated some enhancement of yaw OKR and upward-directed roll OKR, but the effects were also seen in normal C57BL/6 controls, and thus do not represent a specific reversal of the electrophysiological consequences of the tottering mutation. Data support a possible extra-floccular locus for the effects of 4-AP on habituation and roll OKR. Unilateral intrafloccular 4-AP injections did not affect ocular motility, except to generate mild eye elevations, consistent with reduced floccular output. Because 4-AP did not produce the effects expected if it normalized outputs of floccular Purkinje cells, there is a need for further studies to elucidate the drug's mechanism of action on cerebellar motor dysfunction.

Handheld cellular phones restrict head movements and range of visual regard.

Numerous studies have reported the ability of mobile phones to distract users and thereby degrade performance of concurrent tasks. Less is known about whether the phone-holding posture can itself influence concurrent motor activities. Horizontal eye movements are often coordinated with head movements, particularly when the amplitude of the gaze shift is large. Holding a phone to one ear has been shown to restrict the range of spontaneously generated head movements. In order to determine whether the phone-holding posture also influences gaze, we recorded eye and head movements as volunteers looked about themselves spontaneously. Holding the phone to the ear narrowed the range of gaze, principally in subjects who exhibit a strong propensity to move the head with the eyes. We argue that visual exploration may be influenced by the balance between costs and benefits of turning the head, with the phone-holding posture increasing the costs. The effects on gaze would be seen most clearly in subjects who have a higher predilection for coupling eye and head movements. Conversely, this effect would be minimal if tested in tasks that rarely elicit head movements in the specific subjects being tested. The results emphasize the close coordination between eye and head movements, and have implications for the design of ergonomic studies comparing the effects of handheld vs. hands-free mobile phones on performance of specific tasks, such as driving.

Dynamics of abducens nucleus neurons in the awake mouse.

The mechanics of the eyeball and orbital tissues (the "ocular motor plant") are a fundamental determinant of ocular motor signal processing. The mouse is used increasingly in ocular motor physiology, but little is known about its plant mechanics. One way to characterize the mechanics is to determine relationships between extraocular motoneuron firing and eye movement. We recorded abducens nucleus neurons in mice executing compensatory eye movements during 0.1- to 1.6-Hz oscillation in the light. We analyzed firing rates to extract eye position and eye velocity sensitivities, from which we determined time constants of a viscoelastic model of the plant. The majority of abducens neurons were already active with the eye in its central rest position, with only 6% recruited at more abducted positions. Firing rates exhibited largely linear relationships to eye movement, although there was a nonlinearity consisting of increasing modulation in proportion to eye movement as eye amplitudes became small (due to reduced stimulus amplitude or reduced alertness). Eye position and velocity sensitivities changed with stimulus frequency as expected for an ocular motor plant dominated by cascaded viscoelasticities. Transfer function poles lay at approximately 0.1 and 0.9 s. Compared with previously studied animal species, the mouse plant is stiffer than the rabbit but laxer than cat and rhesus. Differences between mouse and rabbit can be explained by scaling for eye size (allometry). Differences between the mouse and cat or rhesus can be explained by differing ocular motor repertoires of animals with and without a fovea or area centralis.

The ataxic mouse as a model for studying downbeat nystagmus.

Downbeat nystagmus (DBN) is a common eye movement complication of cerebellar disease. Use of mice to study pathophysiology of vestibulocerebellar disease is increasing, but it is unclear if mice can be used to study DBN; it has not been reported in this species. We determined whether DBN occurs in the ataxic mutant tottering, which carries a mutation in the Cacna1a gene for P/Q calcium channels. Spontaneous DBN occurred only rarely, and its magnitude did not exhibit the relationship to head tilt seen in human patients. DBN during yaw rotation was more common and shares some properties with the tilt-independent, gaze-independent component of human DBN, but differs in its dependence on vision. Hyperactivity of otolith circuits responding to pitch tilts is hypothesized to contribute to the gaze-independent component of human DBN. Mutants exhibited hyperactivity of the tilt maculo-ocular reflex (tiltMOR) in pitch. The hyperactivity may serve as a surrogate for DBN in mouse studies. TiltMOR hyperactivity correlates with hyperdeviation of the eyes and upward deviation of the head during ambulation; these may be alternative surrogates. Muscimol inactivation of the cerebellar flocculus suggests a floccular role in the tiltMOR hyperactivity and provides insight into the rarity of frank DBN in ataxic mice.

Crossover trial of gabapentin and memantine as treatment for acquired nystagmus.

We conducted a masked, crossover, therapeutic trial of gabapentin (1,200mg/day) versus memantine (40 mg/day) for acquired nystagmus in 10 patients (aged 28-61 years; 7 female; 3 multiple sclerosis [MS]; 6 post-stroke; 1 post-traumatic). Nystagmus was pendular in 6 patients (4 oculopalatal tremor; 2 MS) and jerk upbeat, hemi-seesaw, torsional, or upbeat-diagonal in each of the others. For the group, both drugs reduced median eye speed (p < 0.001), gabapentin by 32.8% and memantine by 27.8%, and improved visual acuity (p < 0.05). Each patient improved with 1 or both drugs. Side effects included unsteadiness with gabapentin and lethargy with memantine. Both drugs should be considered as treatment for acquired forms of nystagmus.

Probing the mechanism of saccade-associated head movements through observations of head movement propensity and cognition in the elderly.

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.

An altered phenotype in a conditional knockout of Pitx2 in extraocular muscle.

PURPOSE: To determine the temporal and spatial expression of Pitx2, a bicoid-like homeobox transcription factor, during postnatal development of mouse extraocular muscle and to evaluate its role in the growth and phenotypic maintenance of postnatal extraocular muscle. METHODS: Mouse extraocular muscles of different ages were examined for the expression of Pitx2 by RT-PCR, q-PCR, and immunostaining. A conditional mutant mouse strain, in which Pitx2 function is inactivated at postnatal day (P)0, was generated with a Cre-loxP strategy. Histology, immunostaining, real-time PCR, in vitro muscle contractility, and in vivo ocular motility were used to study the effect of Pitx2 depletion on extraocular muscle. RESULTS: All three Pitx2 isoforms were expressed by extraocular muscle and at higher levels than in other striated muscles. Immunostaining demonstrated the presence of Pitx2 mainly in extraocular muscle myonuclei. However, no obvious expression patterns were observed in terms of anatomic region (orbital versus global layer), innervation zone, or muscle fiber types. The mutant extraocular muscle had no obvious pathology but had altered muscle fiber sizes. Expression levels of myosin isoforms Myh1, Myh6, Myh7, and Myh13 were reduced, whereas Myh2, Myh3, Myh4, and Myh8 were not affected by postnatal loss of Pitx2. In vitro, Pitx2 loss made the extraocular muscles stronger, faster, and more fatigable. Eye movement recordings found saccades to have a lower peak velocity. CONCLUSIONS: Pitx2 is important in maintaining the mature extraocular muscle phenotype and regulating the expression of critical contractile proteins. Modulation of Pitx2 expression can influence extraocular muscle function with long-term therapeutic implications.

Eye-head coupling tendencies in stationary and moving subjects.

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.

Idiosyncratic variations in eye-head coupling observed in the laboratory also manifest during spontaneous behavior in a natural setting.

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.

Eye hyperdeviation in mouse cerebellar mutants is comparable to the gravity-dependent component of human downbeat nystagmus.

Humans with cerebellar degeneration commonly exhibit downbeat nystagmus (DBN). DBN has gravity-independent and -dependent components, and the latter has been proposed to reflect hyperactive tilt maculo-ocular reflexes (tilt-MOR). Mice with genetically determined cerebellar ataxia do not exhibit DBN, but they do exhibit tonic hyperdeviation of the eyes, which we have proposed to be the DBN equivalent. As such, the tilt-MOR might be predicted to be hyperactive in these mutant mice. We measured the tilt-MOR in 10 normal C57BL/6 mice and in 6 tottering, a mutant exhibiting ataxia and ocular motor abnormalities due to mutation of the P/Q calcium channel. Awake mice were placed in body orientations spanning 360 degrees about the pitch axis. The absolute, equilibrium vertical angular deviations of one eye were measured using infrared videooculography. In both strains, eye elevation varied quasi-sinusoidally with tilt angle in the range of 90 degrees nose-up to 90 degrees nose-down. Beyond this range the eye returned to a neutral position. Deviation over +/-30 degrees of tilt was an approximately linear function of the projection of the gravity vector into the animal's horizontal plane, and can thus be summarized by its slope (sensitivity). Sensitivity measured 14.9 degrees/g for C57BL/6 and 20.3 degrees/g for tottering, a statistically significant difference. Thus the pitch otolithic reflex of the ataxic mutants is hyperactive relative to controls and could explain tonic hyperdeviation of the eyes, consistent with the idea that the tonic hyperdeviation is analogous to DBN.

Eye orientation during static tilts and its relationship to spontaneous head pitch in the laboratory mouse.

Both eye position and head orientation are influenced by the macular (otolith) organs, via the tilt maculo-ocular reflex (tiltMOR) and the vestibulo-collic reflexes, respectively. The mechanisms that control head position also influence the rest position of the eye because head orientation influences eye position through the tiltMOR. Despite the increasing popularity of mice for studies of vestibular and ocular motor functions, relatively little is known in this species about tiltMOR, spontaneous orientation of the head, and their interrelationship. We used 2D video oculography to determine in C57BL/6 mice the absolute horizontal and vertical positions of the eyes over body orientations spanning 360 degrees about the pitch and roll axes. We also determined head pitch during ambulation in the same animals. Eye elevation varied approximately sinusoidally as functions of pitch or roll angle. Over the central +/-30 degrees of pitch, sensitivity and gain in the light were 31.7 degrees/g and 0.53, respectively. The corresponding values for roll were 31.5 degrees/g and 0.52. Absolute positions adopted in light and darkness differed only slightly. During ambulation, mice carried the lambda-bregma plane at a downward pitch of 29 degrees , corresponding to a horizontal eye position of 64 degrees and a vertical eye position of 22 degrees . The vertical position is near the center of the range of eye movements produced by the pitch tiltMOR. The results indicate that the tiltMOR is robust in this species and favor standardizing pitch orientation across laboratories. The robust tiltMOR also has significant methodological implications for the practice of pupil-tracking video oculography in this species.

Eye movements of the murine P/Q calcium channel mutant tottering, and the impact of aging.

Mice carrying mutations of the gene encoding the ion pore of the P/Q calcium channel (Cacna1a) are an instance in which cerebellar dysfunction may be attributable to altered electrophysiology and thus provide an opportunity to study how neuronal intrinsic properties dictate signal processing in the ocular motor system. P/Q channel mutations can engender multiple effects at the single neuron, circuit, and behavioral levels; correlating physiological and behavioral abnormalities in multiple allelic strains will ultimately facilitate determining which alterations of physiology are responsible for specific behavioral aberrations. We used videooculography to quantify ocular motor behavior in tottering mutants aged 3 mo to 2 yr and compared their performance to data previously obtained in the allelic mutant rocker and C57BL/6 controls. Tottering mutants shared numerous abnormalities with rocker, including upward deviation of the eyes at rest, increased vestibuloocular reflex (VOR) phase lead at low stimulus frequencies, reduced VOR gain at high stimulus frequencies, reduced gain of the horizontal and vertical optokinetic reflex, reduced time constants of the neural integrator, and reduced plasticity of the VOR as assessed in a cross-axis training paradigm. Unlike rocker, young tottering mutants exhibited normal peak velocities of nystagmus fast phases, arguing against a role for neuromuscular transmission defects in the attenuation of compensatory eye movements. Tottering also differed by exhibiting directional asymmetries of the gains of optokinetic reflexes. The data suggest at least four pathophysiological mechanisms (two congenital and two acquired) are required to explain the ocular motor deficits in the two Cacna1a mutant strains.

Amplitudes of head movements during putative eye-only saccades.

The mechanisms allowing humans and other primates to dissociate head and eye movements during saccades are poorly understood. A more precise knowledge of head movement behavior during apparent eye-only saccades may provide insight into those mechanisms. We studied the distributions of head amplitude in normal humans. In half of the subjects, these distributions indicated the presence of a population of minor ("residual") head movements during eye-only saccades, distinct from the continuum of head movements generated during frank eye-head saccades. Like full-sized head movements, the residual movements grew in proportion to target eccentricity, indicating their drive is derived from the premotor command for the saccade. Furthermore, their amplitudes related most strongly to the head amplitudes obtained when subjects produced full-sized head movements and were reduced when subjects were instructed to perform exclusively eye-only saccades. Both observations suggest that the drive for residual head movements originates downstream of the point in which the head movement command diverges from the generalized gaze shift command. The results are consistent with a model of head control in which a neural gate prevents the common gaze shift command from reaching the head premotor circuitry whenever an eye-only saccade is desired. However, the gate is either imperfect or the multiple pathways that relay gaze shift signals to the head motor circuitry allow for the gate to be circumvented. The results underscore the need for physiological studies to probe neuronal activity related to neck activation during eye-only saccades.

Eliminating the Ant1 isoform produces a mouse with CPEO pathology but normal ocular motility.

PURPOSE: The adenine nucleotide transporter 1 gene (ANT1) encodes an inner mitochondrial membrane protein that transports ATP into the cell. Mutations within ANT1 produce a syndrome of chronic progressive external ophthalmoplegia (CPEO) in humans. Ant1 knockout (Ant1-/-) mice develop cardiomyopathy and mitochondrial myopathy of limb muscles. Because the extraocular muscles (EOM) are preferentially affected in human CPEO, the objective of this study was to determine whether Ant1-/- mice also exhibit an EOM mitochondrial myopathy. METHODS: ANT isoform expression of isolated EOMs, EOM morphology and mitochondrial content, mitochondrial structure and function, ocular motility in intact mice, and contractile performance in isolated muscle preparations were examined. RESULTS: Ant1-/- EOMs had the typical appearance of mitochondrial myopathy, including increase in mitochondrial size, number, and oxidative phosphorylation (OXPHOS) staining. However, there were no measurable ocular motor abnormalities in intact Ant1-/- mice, and their isolated EOMs did not show evidence of increased fatigability. EOMs of wild-type mice exhibited higher levels of Ant2 mRNA compared with hindlimb muscle, which may compensate for the Ant1 loss in mutant mouse EOMs and account for the normal EOM function. CONCLUSIONS: The Ant1-/- mice provide a model in which to study CPEO pathology and compensatory mechanisms.

Inhibited head movements: a risk of combining phoning with other activities?

Studies of cellular phone use while driving have attributed impaired performance to the distractions of conversation. We determined that holding an inactive phone to the ear reduces the probability of eccentric head positions, potentially indicating reduced ability to monitor the visual surround. This effect may constitute a risk of cellular phone use independent of conversation and peculiar to handheld models.

Overlapping gaze shifts reveal timing of an eye-head gate.

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.