Itsaso Olasagasti

Functional dissection of circuitry in a neural integrator

In neural integrators, transient inputs are accumulated into persistent firing rates that are a neural correlate of short-term memory. Integrators often contain two opposing cell populations that increase and decrease sustained firing as a stored parameter value rises. A leading hypothesis for the mechanism of persistence is positive feedback through mutual inhibition between these opposing populations. We tested predictions of this hypothesis in the goldfish oculomotor velocity-to-position integrator by measuring the eye position and firing rates of one population, while pharmacologically silencing the opposing one. In complementary experiments, we measured responses in a partially silenced single population. Contrary to predictions, induced drifts in neural firing were limited to half of the oculomotor range. We built network models with synaptic-input thresholds to demonstrate a new hypothesis suggested by these data: mutual inhibition between the populations does not provide positive feedback in support of integration, but rather coordinates persistent activity intrinsic to each population.

Gravity Dependence of Subjective Visual Vertical Variability

The brain integrates sensory input from the otolith organs, the semicircular canals, and the somatosensory and visual systems to determine self-orientation relative to gravity. Only the otoliths directly sense the gravito-inertial force vector and therefore provide the major input for perceiving static head-roll relative to gravity, as measured by the subjective visual vertical (SVV). Intraindividual SVV variability increases with head roll, which suggests that the effectiveness of the otolith signal is roll-angle dependent. We asked whether SVV variability reflects the spatial distribution of the otolithic sensors and the otolith-derived acceleration estimate. Subjects were placed in different roll orientations (0-360 degrees, 15 degrees steps) and asked to align an arrow with perceived vertical. Variability was minimal in upright, increased with head-roll peaking around 120-135 degrees, and decreased to intermediate values at 180 degrees. Otolith-dependent variability was modeled by taking into consideration the nonuniform distribution of the otolith afferents and their nonlinear firing rate. The otolith-derived estimate was combined with an internal bias shifting the estimated gravity-vector toward the body-longitudinal. Assuming an efficient otolith estimator at all roll angles, peak variability of the model matched our data; however, modeled variability in upside-down and upright positions was very similar, which is at odds with our findings. By decreasing the effectiveness of the otolith estimator with increasing roll, simulated variability matched our experimental findings better. We suggest that modulations of SVV precision in the roll plane are related to the properties of the otolith sensors and to central computational mechanisms that are not optimally tuned for roll-angles distant from upright.

A modeling framework for deriving the structural and functional architecture of a short-term memory microcircuit.

Although many studies have identified neural correlates of memory, relatively little is known about the circuit properties connecting single-neuron physiology to behavior. Here we developed a modeling framework to bridge this gap and identify circuit interactions capable of maintaining short-term memory. Unlike typical studies that construct a phenomenological model and test whether it reproduces select aspects of neuronal data, we directly fit the synaptic connectivity of an oculomotor memory circuit to a broad range of anatomical, electrophysiological, and behavioral data. Simultaneous fits to all data, combined with sensitivity analyses, revealed complementary roles of synaptic and neuronal recruitment thresholds in providing the nonlinear interactions required to generate the observed circuit behavior. This work provides a methodology for identifying the cellular and synaptic mechanisms underlying short-term memory and demonstrates how the anatomical structure of a circuit may belie its functional organization.

Egocentric and allocentric alignment tasks are affected by otolith input.

Gravicentric visual alignments become less precise when the head is roll-tilted relative to gravity, which is most likely due to decreasing otolith sensitivity. To align a luminous line with the perceived gravity vector (gravicentric task) or the perceived body-longitudinal axis (egocentric task), the roll orientation of the line on the retina and the torsional position of the eyes relative to the head must be integrated to obtain the line orientation relative to the head. Whether otolith input contributes to egocentric tasks and whether the modulation of variability is restricted to vision-dependent paradigms is unknown. In nine subjects we compared precision and accuracy of gravicentric and egocentric alignments in various roll positions (upright, 45°, and 75° right-ear down) using a luminous line (visual paradigm) in darkness. Trial-to-trial variability doubled for both egocentric and gravicentric alignments when roll-tilted. Two mechanisms might explain the roll-angle-dependent modulation in egocentric tasks: 1) Modulating variability in estimated ocular torsion, which reflects the roll-dependent precision of otolith signals, affects the precision of estimating the line orientation relative to the head; this hypothesis predicts that variability modulation is restricted to vision-dependent alignments. 2) Estimated body-longitudinal reflects the roll-dependent variability of perceived earth-vertical. Gravicentric cues are thereby integrated regardless of the tasks reference frame. To test the two hypotheses the visual paradigm was repeated using a rod instead (haptic paradigm). As with the visual paradigm, precision significantly decreased with increasing head roll for both tasks. These findings propose that the CNS integrates input coded in a gravicentric frame to solve egocentric tasks. In analogy to gravicentric tasks, where trial-to-trial variability is mainly influenced by the properties of the otolith afferents, egocentric tasks may also integrate otolith input. Such a shared mechanism for both paradigms and frames of reference is supported by the significantly correlated trial-to-trial variabilities.

Velocity storage mechanism in zebrafish larvae

•  Five‐day‐old zebrafish larvae already exhibit a velocity storage mechanism (VSM). •  The VSM in zebrafish larvae emerges earlier than a functional horizontal angular vestibular reflex. •  The VSM may be critical to ocular motor control in larval zebrafish.

Positive or Negative Feedback of Optokinetic Signals: Degree of the Misrouted Optic Flow Determines System Dynamics of Human Ocular Motor Behavior

PURPOSE The optokinetic system in healthy humans is a negative-feedback system that stabilizes gaze: slow-phase eye movements (i.e., the output signal) minimize retinal slip (i.e., the error signal). A positive-feedback optokinetic system may exist due to the misrouting of optic fibers. Previous studies have shown that, in a zebrafish mutant with a high degree of the misrouting, the optokinetic response (OKR) is reversed. As a result, slow-phase eye movements amplify retinal slip, forming a positive-feedback optokinetic loop. The positive-feedback optokinetic system cannot stabilize gaze, thus leading to spontaneous eye oscillations (SEOs). Because the misrouting in human patients (e.g., with a condition of albinism or achiasmia) is partial, both positive- and negative-feedback loops co-exist. How this co-existence affects human ocular motor behavior remains unclear. METHODS We presented a visual environment consisting of two stimuli in different parts of the visual field to healthy subjects. One mimicked positive-feedback optokinetic signals and the other preserved negative-feedback optokinetic signals. By changing the ratio and position of the visual field of these visual stimuli, various optic nerve misrouting patterns were simulated. Eye-movement responses to stationary and moving stimuli were measured and compared with computer simulations. The SEOs were correlated with the magnitude of the virtual positive-feedback optokinetic effect. RESULTS We found a correlation among the simulated misrouting, the corresponding OKR, and the SEOs in humans. The proportion of the simulated misrouting needed to be greater than 50% to reverse the OKR and at least greater than or equal to 70% to evoke SEOs. Once the SEOs were evoked, the magnitude positively correlated to the strength of the positive-feedback OKR. CONCLUSIONS This study provides a mechanism of how the misrouting of optic fibers in humans could lead to SEOs, offering a possible explanation for a subtype of infantile nystagmus syndrome (INS).

Gaze direction affects linear self-motion heading discrimination in humans.

We investigated the effect of eye‐in‐head and head‐on‐trunk direction on heading discrimination. Participants were passively translated in darkness along linear trajectories in the horizontal plane deviating 2° or 5° to the right or left of straight‐ahead as defined by the subjects trunk. Participants had to report whether the experienced translation was to the right or left of the trunk straight‐ahead. In a first set of experiments, the head was centered on the trunk and fixation lights directed the eyes 16° either left or right. Although eye position was not correlated with the direction of translation, rightward reports were more frequent when looking right than when looking left, a shift of the point of subjective equivalence in the direction opposite to eye direction (two of the 38 participants showed the opposite effect). In a second experiment, subjects had to judge the same trunk‐referenced trajectories with head‐on‐trunk deviated 16° left. Comparison with the performance in the head‐centered paradigms showed an effect of the head in the same direction as the effect of eye eccentricity. These results can be qualitatively described by biases reflecting statistical regularities present in human behaviors such as the alignment of gaze and path. Given the known effects of gaze on auditory localization and perception of straight‐ahead, we also expect contributions from a general influence of gaze on the head‐to‐trunk reference frame transformations needed to bring motion‐related information from the head‐centered otoliths into a trunk‐referenced representation.

Dynamic Cyclovergence during Vertical Translation in Humans

When humans are accelerated along the body vertical, the right and left eyes show oppositely directed torsional modulation (cyclovergence). The origin of this paradoxical response is unknown. We studied cyclovergence during linear sinusoidal vertical motion in healthy humans. A small head-fixed visual target minimized horizontal and vertical motion of the eyes and therefore isolated the torsional component. For stimuli between 1 and 2 Hz (near the natural range of head motion), the phase of cyclovergence with respect to inertial acceleration was 8.7 ± 2.4° (mean ± 95% CI) and the sensitivity (in degrees per second per g) showed a small but statistically significant increase with frequency. These characteristics contrast with those of cycloversion (conjugate torsion) during horizontal (interaural) inertial stimuli at similar frequencies. From these and previous results, we propose that cyclovergence during vertical translation has two sources, one, like cycloversion, from the low-frequency component of linear acceleration, and another, which we term dynamic cyclovergence, with high-pass characteristics. Furthermore, we suggest that this cyclovergence response in humans is a vestige of the response of lateral-eyed animals to vertical linear acceleration of the head.

Modulation of Saccade Curvature by Ocular Counterroll

PURPOSE On close inspection, it can be seen that most saccadic trajectories are not straight but curve slightly; in other words, they are not single-axis ocular rotations. The authors asked whether saccade curvatures are systematically influenced by static ocular counterroll (OCR). METHODS OCR was elicited by static whole-body roll position. Eight healthy human subjects performed horizontal and vertical saccades (10 degrees amplitude; 0 degrees and 10 degrees eccentricity; head-fixed coordinate system) in upright and ear-down whole-body roll positions (45 degrees right, 45 degrees left). Three-dimensional eye movements were recorded with modified dual-search coils at 1000 Hz. RESULTS Saccade curvature was systematically modulated by OCR depending on saccade direction. In the horizontal-vertical plane, primarily vertical saccades were modulated with downward saccades curving toward the upper ear and upward saccades curving toward the lower ear. Modulation of saccade curvature in the torsional direction correlated significantly with OCR only in abducting saccades. CONCLUSIONS No universal mechanism, such as visual-motor coordinate transformation or kinematic characteristics of the saccadic burst generator, alone could explain the complex modulation pattern of saccade curvature. OCR-induced changes of the ocular motor plant, including transient force imbalances between agonist eye muscles (vertical rectus and oblique muscles) and shifting eye muscle pulleys, are suitable to explain the found direction-dependent modulation pattern.

Cyclovergence evoked by up-down acceleration along longitudinal axis in humans.

We present results of a study of torsional eye movements evoked by earth-vertical accelerations along the subjects longitudinal axis. The earth-vertical stimulus leads to a gravito-inertial acceleration vector that changes magnitude but not direction. It can therefore be viewed as a dynamic change of the gravity level. Up-down oscillations induced relatively symmetric cyclovergence (0.6-2.2 degrees peak-to-peak). Eyes intorted/extorted for higher/lower effective gravity. The phase of this modulation was small relative to chair acceleration. We contrast this behaviour to the dynamics of cycloversion in response to interaural acceleration, which shows a considerably larger phase lag. This strikingly different dynamics suggest a different processing of otolith signals during interaural and longitudinal stimulation.