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Biomedical subjects

John S Stahl

Publications and source records attributed to John S Stahl.

At least 19 recordsLinked to original sources
PubMed2005

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.

Aging↗
PubMed2005

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.

Adult↗
PubMed2005

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.

Accidents, Traffic↗
PubMed2005

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.

Adult↗
PubMed2005

Characterization of vestibular dysfunction in the mouse model for Usher syndrome 1F.

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.

Animals↗
PubMed2005

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.

Adenine Nucleotide Translocator 1↗
PubMed2005

Abnormal eye movements predict disability in MS: two-year follow-up.

We conducted a two-year follow-up study of 40 patients with MS in whom we had reported that abnormal eye movements (AEM) were associated with greater general disability. AEM patients (17/40) remained significantly (p < .001) more disabled (median EDSS of 7.0) than those with normal eye movements (median EDSS of 5.0). AEM and great disability were associated with abnormal MRI signals in brainstem or cerebellum, where disease may involve control circuits for eye movements as well as descending motor pathways.

Adult↗
PubMed2005

Internuclear ophthalmoparesis in episodic ataxia type 2.

Two patients sharing a novel mutation of the CACNA1A gene for P/Q calcium channels showed significant slowing of adducting saccades compared with normal subjects or patients with cerebellar disease. Internuclear ophthalmoparesis (INO) was clinically evident in one. While these findings might be specific to this mutation, INO in our patients with episodic ataxia type 2 suggested involvement outside the cerebellum, either in the brain-stem internuclear pathway or at the neuromuscular junction.

Adult↗
PubMed2005

Neural integrator function in murine CACNA1A mutants.

Time constants of gaze holding are shortened in rocker and tottering mice, two strains whose cerebellar dysfunction stems from genetic alterations of the P/Q calcium channel. The finding suggests that in mice as in primates, the cerebellum contributes to the function of the neural integrator. Studying CACNA1A mutants may elucidate how cerebellar signals support gaze holding.

Animals↗
PubMed2004

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

Mutations in the gene encoding the ion pore of the P/Q voltage-activated calcium channel (CACNA1A) are predicted to alter synaptic transmission and dendritic excitability within cerebellar granule and Purkinje cells. Determining the relationships between these alterations, neuronal activity, and behavior may yield insight into the relationship between neuronal intrinsic properties and signal processing within the ocular motor system. Toward this end, we compared ocular motor performance in the CACNA1A mutant rocker and C57BL/6 controls. Average vertical eye position was abnormally elevated in the mutants, a finding that may be analogous to downbeat nystagmus seen in human cerebellar disorders. Fast phases of vestibular nystagmus were slowed by approximately 18% of control values. The angular vestibuloocular reflex (VOR) in darkness and light (visual VOR, or VVOR), assessed at 0.1-1.6 Hz, exhibited subnormal gains at the highest stimulus frequencies and increased phase leads at the lowest stimulus frequencies. Horizontal optokinetic responses to constant velocity drum rotation of +/-2.5-40 degrees/s exhibited minimally reduced gains. Attempts to increase VOR gain by concomitant optokinetic and vestibular stimulation were confounded by the tendency of the mice to habituate to repetitive vestibular stimulation, but attempts to induce coupling of vertical eye movements to horizontal vestibular stimulation (cross-axis adaptation) generated rapid plastic changes in controls and little effect in mutants. With the notable exceptions of the vertical elevation and optokinetic gains, the ocular motor abnormalities were stable over a broad range of animal age, a result compatible with the abnormalities arising as direct consequences of the inborn alteration in calcium channel biophysics.

Adaptation, Physiological↗
PubMed2004

Functional and genomic changes in the mouse ocular motor system in response to light deprivation from birth.

Previous studies have suggested that abnormal visual experience early in life induces ocular motor abnormalities. The purpose of this study was to determine how visual deprivation alters the function and gene expression profile of the ocular motor system in mice. We measured the effect of dark rearing on eye movements, gene expression in the oculomotor nucleus, and contractility of isolated extraocular muscles. In vivo eye movement recordings showed decreased gains for optokinetic and vestibulo-ocular reflexes, confirming an effect of dark rearing on overall ocular motor function. Saccade peak velocities were preserved, however, arguing that the quantitative changes in these reflexes were not secondary to limitations in force generation. Using microarrays and quantitative PCR, we found that dark rearing shifted the oculomotor nucleus transcriptome to a state of delayed/arrested development. The expression of 132 genes was altered by dark rearing; these genes fit in various functional categories (signal transduction, transcription/translation control, metabolism, synaptic function, cytoskeleton), and some were known to be associated with neuronal development and plasticity. Extraocular muscle contractility was impaired by dark rearing to a greater extent than expected from the in vivo ocular motility studies: changes included decreased force and shortening speed and evidence of abnormal excitability. The results indicate that normal development of the mouse ocular motor system and its muscles requires visual experience. The transcriptional pattern of arrested development may indicate that vision is required to establish the adult pattern, but it also may represent the plastic response of oculomotor nuclei to abnormal extraocular muscles.

Animals↗
PubMed2004

Using eye movements to assess brain function in mice.

Examining eye movements is an important part of the neurological evaluation of humans; the distribution of the neural circuits that control these movements is such that they are disrupted--often in highly characteristic fashions--by many disease processes. Technical advances have made it possible to measure accurately the eye movements of mice, so it is now possible to use the detective power of eye movement recording to characterize neurological dysfunction in genetically altered strains. Here we introduce analytical tools used in ocular motor research and demonstrate their ability to reveal disorders of the visual pathways, inner ear, and cerebellum.

Animals↗
PubMed2004

Application of adaptive filters to visual testing and treatment in acquired pendular nystagmus.

Acquired pendular nystagmus (APN) complicates multiple sclerosis and other neurological disorders, causes visual impairment, and frequently resists treatment. Vision could be improved by a visual aid that gates or shifts the seen world in lockstep with the APN. Since the pathological oscillations are embedded in normal eye movements, such a device must track the nystagmus selectively. We evaluated the ability of an adaptive filter to perform this tracking and improve acuity when coupled to either of two devices--a shutter that permitted brief glimpses of the world synchronized with the nystagmus, or simulated image-shifting optics. In 10 normal subjects whose decimal acuity averaged 1.46 +/- 0.20, acuity fell to 0.36 +/- 0.08 under viewing conditions simulating APN. The synchronized shutter restored acuity to 0.60 +/- 0.12, while image-stabilization raised it to 1.17 +/- 0.13. Adaptive filters provide a practical means by which to track nystagmus. The most effective visual aid would couple such filters to image-stabilizing optics.

Adaptation, Physiological↗
PubMed2004

Image-shifting optics for a nystagmus treatment device.

Acquired pendular nystagmus (APN) complicates multiple sclerosis and other neurological disorders, causes visual impairment, and is often refractory to available treatments. Vision could be improved by an optical aid that shifts the seen world in lockstep with the APN. An essential component of such a device is the image-shifting mechanism, which must be light, accurate, suitable for battery operation, and capable of image shifting at the frequencies and amplitudes seen in APN. We determined that a three-lens image-shifting mechanism used in commercial image-stabilizing lenses has the potential to satisfy all these requirements. In combination with software designed to track nystagmus, the optical mechanism proved capable of improving visual acuity in 12 normal subjects experiencing simulated two-dimensional nystagmus. Acuity was restored to within an average of 0.12 logMAR (range 0.0-0.22) of the subjects' values without the simulated nystagmus. These results support the feasibility of an assistive device for patients with APN.

Adaptation, Physiological↗
PubMed2003

The influence of future gaze orientation upon eye-head coupling during saccades.

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 degrees to 25.2+/-7.8 degrees. 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 degrees to 63.2+/-15.9 degrees. 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.

Adult↗
PubMed2002

Calcium channelopathy mutants and their role in ocular motor research.

Thanks to technical advances in eye movement recording, the mouse is destined to become increasingly important in ocular motor research. An advantage of this species is the wide range of existing mutant strains and techniques to generate new mutations affecting specific cell types. Mutations of ion channels may be used to modulate the intrinsic properties of neurons, and this approach may generate insight into the degree to which neuronal computations depend upon those intrinsic properties as opposed to the properties of circuits of neurons. Dendritic calcium currents carried by P-type voltage-activated calcium channels have been widely postulated to perform important computational functions in cerebellar Purkinje cells. Mutations of this channel lead to human diseases, and several ataxic strains of mice are now known to harbor mutations of this calcium channel. Murine P-channel mutants such as rocker are ataxic, but have normal or near-normal numbers of cerebellar Purkinje cells and thus offer the opportunity to study the effects of biophysical perturbations as opposed to outright cell destruction or inactivation. Initial studies of rocker mice reveal an array of ocular motor abnormalities, including static hyperdeviation of the eyes and an attenuation of vestibulo-ocular reflex gains at high stimulus frequencies. The pattern of gain and phase abnormalities is entirely different in lurcher, an ataxic mutant in which Purkinje cells degenerate. The ocular motor abnormalities of rocker progress with animal age, underscoring the importance of careful attention to animal age when performing ocular motor studies in this short-lived species.

Animals↗