Sustained deep-tissue voltage recording using a fast indicator evolved for two-photon microscopy.

Genetically encoded voltage indicators are emerging tools for monitoring voltage dynamics with cell-type specificity. However, current indicators enable a narrow range of applications due to poor performance under two-photon microscopy, a method of choice for deep-tissue recording. To improve indicators, we developed a multiparameter high-throughput platform to optimize voltage indicators for two-photon microscopy. Using this system, we identified JEDI-2P, an indicator that is faster, brighter, and more sensitive and photostable than its predecessors. We demonstrate that JEDI-2P can report light-evoked responses in axonal termini of Drosophila interneurons and the dendrites and somata of amacrine cells of isolated mouse retina. JEDI-2P can also optically record the voltage dynamics of individual cortical neurons in awake behaving mice for more than 30 min using both resonant-scanning and ULoVE random-access microscopy. Finally, ULoVE recording of JEDI-2P can robustly detect spikes at depths exceeding 400 µm and report voltage correlations in pairs of neurons.

Spatial Interactions in Interocular and Monocular "Blur Suppression".

SIGNIFICANCE: The suppression of blurred images in one eye by clear images in the other eye is thought to contribute to the success of monovision correction. We show that interocular suppression occurs also for low-contrast targets that are not blurred and, to a lesser extent, when clear and low-contrast targets are presented to the same eye. PURPOSE: A blurred target presented to one eye may be suppressed when a clear target is presented to the other eye. We sought to determine how this interocular suppression varies according to the separation between the blurred and clear targets and the magnitude of imposed blur. In addition, we examined whether a similar suppression occurs when the clear and blurred targets are imaged in the same eye. METHODS: Subjects (N = 4) viewed a clear 20/40 Sloan letter surrounded by four 2 × 10 min-arc flanking bars. In different blocks of trials, the gap between the letter and flanking bars varied from 0.5 to 4 bar widths. In addition, the flanking bars were either clear or spatially filtered to simulate 0.5 to 2 D of blur. The contrast required to detect the flanking bars was determined when the letter and flanking bars were presented either dichoptically or monoptically and compared with the thresholds for the bar targets presented alone. RESULTS: In both dichoptic and monoptic viewing conditions, detection thresholds for the blurred flanking bars are highest for the smallest spatial gap and decrease systematically as the gap increases. Thresholds are uniformly higher during dichoptic than monocular viewing, but the proportional change with the bar-to-letter separation is similar in both conditions. Surprisingly, the magnitude of imposed blur has very little influence on the magnitude of threshold elevation in either the dichoptic or monoptic viewing conditions. CONCLUSIONS: Because threshold elevation is nearly the same in the presence of 0 to 2 D of blur, we prefer to designate the phenomenon we studied as "contrast suppression." The similar spatial characteristics of suppression during dichoptic and monoptic viewing are consistent with contributions from a common neural mechanism.

Differential benefits of olanzapine on executive function in schizophrenia patients: Preliminary findings.

OBJECTIVE: Schizophrenia patients show executive function (EF) impairments in voluntary orienting as measured by eye-movements. We tested 14 inpatients to investigate the effects of the antipsychotic olanzapine on EF, as measured by antisaccade eye-movement performance. METHODS: Patients were tested at baseline (before olanzapine), 3-5 days post-medication, and 12-14 days post-medication. Patients were also assessed on the Positive and Negative Syndrome Scale (PANSS) to measure the severity of schizophrenia-related symptoms, and administered the Stroop task, a test of EF. Nine matched controls were also tested on the antisaccade and Stroop. RESULTS: Both groups showed improvement on Stroop and antisaccade; however, the schizophrenia group improved significantly more on antisaccade, indicating an additional benefit of olanzapine on EF performance. Patients with poorer baseline antisaccade performance (High-Deficit) showed significantly greater improvement on the antisaccade task than patients with better baseline performance (Low-Deficit), suggesting that baseline EF impairment predicts the magnitude of cognitive improvement with olanzapine. These subgroups showed significant and equivalent improvement on PANSS scores, indicating that improvement on the antisaccade task with olanzapine was not a result of differences in magnitude of clinical improvement. CONCLUSIONS: This preliminary study provides evidence that olanzapine may be most advantageous for patients with greater baseline EF deficits.

Faster processing of moving compared with flashed bars in awake macaque V1 provides a neural correlate of the flash lag illusion.

When the brain has determined the position of a moving object, because of anatomical and processing delays the object will have already moved to a new location. Given the statistical regularities present in natural motion, the brain may have acquired compensatory mechanisms to minimize the mismatch between the perceived and real positions of moving objects. A well-known visual illusion-the flash lag effect-points toward such a possibility. Although many psychophysical models have been suggested to explain this illusion, their predictions have not been tested at the neural level, particularly in a species of animal known to perceive the illusion. To this end, we recorded neural responses to flashed and moving bars from primary visual cortex (V1) of awake, fixating macaque monkeys. We found that the response latency to moving bars of varying speed, motion direction, and luminance was shorter than that to flashes, in a manner that is consistent with psychophysical results. At the level of V1, our results support the differential latency model positing that flashed and moving bars have different latencies. As we found a neural correlate of the illusion in passively fixating monkeys, our results also suggest that judging the instantaneous position of the moving bar at the time of flash-as required by the postdiction/motion-biasing model-may not be necessary for observing a neural correlate of the illusion. Our results also suggest that the brain may have evolved mechanisms to process moving stimuli faster and closer to real time compared with briefly appearing stationary stimuli. NEW & NOTEWORTHY We report several observations in awake macaque V1 that provide support for the differential latency model of the flash lag illusion. We find that the equal latency of flash and moving stimuli as assumed by motion integration/postdiction models does not hold in V1. We show that in macaque V1, motion processing latency depends on stimulus luminance, speed and motion direction in a manner consistent with several psychophysical properties of the flash lag illusion.

Oculomotor executive function abnormalities with increased tic severity in Tourette syndrome.

BACKGROUND: Reports conflict as to whether Tourette syndrome (TS) confers deficits in executive function. This study's aim was to evaluate executive function in youths with TS using oculomotor tasks while controlling for confounds of tic severity, age, medication, and severity of comorbid disorders. METHOD: Four saccade tasks requiring the executive functions of response generation, response inhibition, and working memory (prosaccade, antisaccade, 0-back, and 1-back) were administered. Twenty youths with TS and low tic severity (TS-low), nineteen with TS and moderate tic severity (TS-moderate), and 29 typically developing control subjects (Controls) completed the oculomotor tasks. RESULTS: There were small differences across groups in the prosaccade task. Controlling for any small sensorimotor differences, TS-moderate subjects had significantly higher error rates than Controls and TS-low subjects in the 0-back and 1-back tasks. In the 1-back task, these patients also took longer to respond than Controls or TS-low subjects. CONCLUSIONS: In a highly controlled design, the findings demonstrate for the first time that increased tic severity in TS is associated with impaired response inhibition and impaired working memory and that these executive function deficits cannot be accounted for by differences in age, medication or comorbid symptom severity.

Playing three-dimensional video games boosts stereo vision.

Playing two-dimensional video games has been shown to result in improvements in a range of visual and cognitive tasks, and these improvements appear to generalize widely1,2,3,4,5,6. Here we report that young adults with healthy vision, surprisingly, showed a dramatic improvement in stereo vision after playing three-dimensional, but not two-dimensional, video games for a relatively short period of time. Intriguingly, neither group showed any significant improvement in binocular contrast sensitivity. This dissociation suggests that the visual enhancement was specific to genuine stereoscopic processing, not indirectly resulting from enhanced contrast processing, and required engaging in a disparity cue-rich three-dimensional environment.

Cellular composition and circuit organization of the locus coeruleus of adult mice.

The locus coeruleus (LC) houses the vast majority of noradrenergic neurons in the brain and regulates many fundamental functions, including fight and flight response, attention control, and sleep/wake cycles. While efferent projections of the LC have been extensively investigated, little is known about its local circuit organization. Here, we performed large-scale multipatch recordings of noradrenergic neurons in adult mouse LC to profile their morpho-electric properties while simultaneously examining their interactions. LC noradrenergic neurons are diverse and could be classified into two major morpho-electric types. While fast excitatory synaptic transmission among LC noradrenergic neurons was not observed in our preparation, these mature LC neurons connected via gap junction at a rate similar to their early developmental stage and comparable to other brain regions. Most electrical connections form between dendrites and are restricted to narrowly spaced pairs or small clusters of neurons of the same type. In addition, more than two electrically coupled cell pairs were often identified across a cohort of neurons from individual multicell recording sets that followed a chain-like organizational pattern. The assembly of LC noradrenergic neurons thus follows a spatial and cell-type-specific wiring principle that may be imposed by a unique chain-like rule.

Spatial and temporal proximity of objects for maximal crowding.

Crowding refers to the deleterious visual interaction among nearby objects. Does maximal crowding occur when objects are closest to one another in space and time? We examined how crowding depends on the spatial and temporal proximity, retinally and perceptually, between a target and flankers. Our target was a briefly flashed T-stimulus presented at 10° right of fixation (3-o'clock position). It appeared at different target-onset-to-flanker asynchronies with respect to the instant when a pair of flanking Ts, revolving around the fixation target, reached the 3-o'clock position. Observers judged the orientation of the target-T (the crowding task), or its position relative to the revolving flankers (the flash-lag task). Performance was also measured in the absence of flanker motion: target and flankers were either presented simultaneously (closest retinal temporal proximity) with different angular spatial offsets, or were presented collinearly (closest retinal spatial proximity) with different temporal onset asynchronies. We found that neither retinal nor perceptual spatial or temporal proximity could account for when maximal crowding occurred. Simulations using a model based on feed-forward interactions between sustained and transient channels in static and motion pathways, taking into account the differential response latencies, can explain the crowding functions observed under various spatio-temporal conditions between the target and flankers.

Effects of adjunct valproic acid on clinical symptoms and saccadic eye movements in schizophrenia.

OBJECTIVE: Valproic acid (VPA) has been suggested as a potential adjunct therapy in schizophrenia for the treatment of clinical symptoms and cognitive deficits. Here, we investigate the effects of VPA on clinical symptoms and saccadic eye movements while controlling for multiple medication effects. METHODS: Remitted and first-episode schizophrenia patients taking haloperidol were given adjunct VPA for approximately 2 weeks and tested using a measure of clinical symptoms (Positive and Negative Syndrome Scale) and saccadic eye movement tasks over three testing periods. The effects of VPA were compared with schizophrenia patients medicated with equivalent doses of haloperidol alone (HAL group) and normal controls. RESULTS: Schizophrenia patients had higher error rates on the antisaccade task (AS task) compared with normal controls. Adjunct VPA did not affect AS task error rates but was associated with an increase in response times for both saccade and AS tasks, with a significantly greater and dose-dependent increase in response times for the AS task. There were no differences in clinical improvement between VPA and HAL schizophrenia patient groups when controlling for haloperidol medication state. CONCLUSIONS: These results suggest that adjuvant VPA therapy results in both sensorimotor and cognitive slowing but does not either help or further impair inhibitory control in schizophrenia, as measured by the elevated AS task errors.

Novel n-back spatial working memory task using eye movement response.

We created a novel eye movement version of the n-back task to measure spatial working memory (WM). Rather than one continuous trial, discrete trials were presented in order to develop a simpler WM task. In Experiment 1, we varied the visibility of the final stimulus to maximize the difference in performance between 0-back and 1-back tasks (WM effect). In Experiment 2, we administered the optimized task to children. In Experiment 3, we further simplified the task. Both adults and children easily completed our task, displaying significant WM effects. Further, similar WM effects were obtained in our original and simplified n-back spatial WM tasks, demonstrating flexibility. Because WM deficits are often an early feature of disease and a marker of disease progression, our saccadic measure of spatial WM may be particularly useful in hard-to-test populations, such as patients and children, and may have application in brain-imaging studies that require discrete trials.

Orthopaedic and brain injuries over last 10 seasons in the National Football League (NFL): number and effect on missed playing time.

OBJECTIVE: To examine trends in number and seriousness of major injuries in the National Football League (NFL) over seasons 2010-2019 and the effect of rule changes to injuries to the leg, back, arm and head. METHODS: We calculated, from publicly available weekly injury reports, the number of players that were injured and playing time missed, that is, the number of weeks on average that an injured player had to sit out, as a function of injury to a specific body part. Using classical time series analysis techniques, we fitted injury data with linear and non-linear functions. RESULTS: The number of major injuries to the leg, back, arm and head has not declined over the last 10 years. During this time period, time missed because of injuries to the head has shown a significantly increasing trend. Rule changes designed specifically to protect arm or head have, respectively, succeeded in shortening the time that the injured player misses, but the impact lasts only over a single season. CONCLUSIONS: Overall, our data support the argument that new, well-intentioned rules adopted every season by the NFL have been proven to be too weak to make the NFL game safer. Broad-based management of brain and orthopaedic injuries and adoption of preventative measures to reduce the number of players injured and the seriousness of their injuries are required in the modern NFL.

Heading-Related Slowing by Twenty-Four Hours in Youth Athletes.

Research suggests cumulative effects of repetitive head impacts (RHIs) on brain structure, especially with younger age of first exposure. Further, recent evidence suggests no immediate cognitive changes with increased RHIs but impairments across a sports season. The aim was to examine more closely the short-term time course of behavioral effects of exposure to RHI. Across 2 years, 18 female adolescent soccer players were tested on ProPoint (sensorimotor) and AntiPoint (cognitive) tasks with reaction time (RT) being the main outcome measure. The athletes were tested before and after workout with ball heading (immediate effect), as well as 24 h after workout (24 h effect) throughout two consecutive seasons. The number of headers performed 24 h before workout, during workout, and season average per workout were recorded. The athletes showed a decrease in ProPoint and AntiPoint RTs immediately after a workout, with no change or decrease in RTs with increasing RHIs. However, increasing RHIs during workout increased RTs in both tasks when tested 24 h later. The athletes also showed an increase in AntiPoint RTs with increasing season average RHIs. Our findings show a complex time course of effects of RHIs on sensorimotor and cognitive performance in adolescent athletes, with exposure to RHIs associated with no change or immediate benefits and then deficits by 24 h. Pathophysiological changes associated with exercise and traumatic brain injury can account for the sensorimotor and cognitive performance changes occurring within 24 h after RHIs.

The temporal impulse response function in infantile nystagmus.

Despite rapid to-and-fro motion of the retinal image that results from their incessant involuntary eye movements, persons with infantile nystagmus (IN) rarely report the perception of motion smear. We performed two experiments to determine if the reduction of perceived motion smear in persons with IN is associated with an increase in the speed of the temporal impulse response. In Experiment 1, increment thresholds were determined for pairs of successively presented flashes of a long horizontal line, presented on a 65-cd/m2 background field. The stimulus-onset asynchrony (SOA) between the first and second flash varied from 5.9 to 234 ms. In experiment 2, temporal contrast sensitivity functions were determined for a 3-cpd horizontal square-wave grating that underwent counterphase flicker at temporal frequencies between 1 and 40 Hz. Data were obtained for 2 subjects with predominantly pendular IN and 8 normal observers in Experiment 1 and for 3 subjects with IN and 4 normal observers in Experiment 2. Temporal impulse response functions (TIRFs) were estimated as the impulse response of a linear second-order system that provided the best fit to the increment threshold data in Experiment 1 and to the temporal contrast sensitivity functions in Experiment 2. Estimated TIRFs of the subjects with pendular IN have natural temporal frequencies that are significantly faster than those of normal observers (ca. 13 vs. 9 Hz), indicating an accelerated temporal response to visual stimuli. This increase in response speed is too small to account by itself for the virtual absence of perceived motion smear in subjects with IN, and additional neural mechanisms are considered.

Age-Dependent Performance on Pro-point and Anti-point Tasks.

Changes in prefrontal cortex are thought to be responsible for many of the characteristic behavioral changes that are seen during adolescence and late adulthood. Disruption of prefrontal cortex is an early sign for many developmental, neurological, and psychiatric disorders. Goal directed eye movements, such as Anti-saccades, have been shown to have high sensitivity as a gross assessment of prefrontal lobe function. Previous studies on the developmental changes of saccades across age have shown that stimulus-driven and goal-directed eye movements follow a U-shaped trend with peaks in performance occuring during adolescence. Using novel tablet-based pointing tasks, modeled on eye movement tests, this study aims to provide a preliminary understanding of how age affects manual pointing performance, in order to more easily track behavioral changes of the prefrontal cortex. In this study, 82 participants between the ages of 10 and 63 were recruited to participate. Results show that similarly to saccades, manual pointing responses are age dependent with fastest response times found during late adolescence to early adulthood (U-shaped curves). Importantly, we also demonstrated significant differences in the effect of age in stimulus-driven (Pro-point) and goal-directed (Anti-point) pointing tasks. The effect of age on response time (RT) is greater on Anti-point compared to Pro-point task (with a 79 ms greater mean decrease during early development and a 148 ms greater mean increase during later aging). Further, for Pro-point task, the U-shaped curve flattens at about 45 years whereas for Anti-point task the U-shaped curve continues up to the maximum age tested (about 60 years). This dissociation between age-related changes in sensorimotor and cognitive performance suggests independent development of associated brain circuity. Thus, changes of performance in disease that are specific for age and task may be able to help identify brain circuitry involved. Finally, given that these tablet-based pointing tasks show similar age-related patterns reported previously with eye-tracking technology, our findings suggest that such tablet-based tasks may provide an inexpensive, quick, and more practical way of detecting neurological deficits or tracking cognitive changes.

Correction: Evidence of Cognitive Dysfunction after Soccer Playing with Ball Heading Using a Novel Tablet-Based Approach.

[This corrects the article DOI: 10.1371/journal.pone.0057364.].

Mechanisms of perceptual learning of depth discrimination in random dot stereograms.

Perceptual learning is a training induced improvement in performance. Mechanisms underlying the perceptual learning of depth discrimination in dynamic random dot stereograms were examined by assessing stereothresholds as a function of decorrelation. The inflection point of the decorrelation function was defined as the level of decorrelation corresponding to 1.4 times the threshold when decorrelation is 0%. In general, stereothresholds increased with increasing decorrelation. Following training, stereothresholds and standard errors of measurement decreased systematically for all tested decorrelation values. Post training decorrelation functions were reduced by a multiplicative constant (approximately 5), exhibiting changes in stereothresholds without changes in the inflection points. Disparity energy model simulations indicate that a post-training reduction in neuronal noise can sufficiently account for the perceptual learning effects. In two subjects, learning effects were retained over a period of six months, which may have application for training stereo deficient subjects.

Attraction of flashes to moving dots.

Motion is known to distort visual space, producing illusory mislocalizations for flashed objects. Previously, it has been shown that when a stationary bar is flashed in the proximity of a moving stimulus, the position of the flashed bar appears to be shifted in the direction of nearby motion. A model consisting of predictive projections from the sub-system that processes motion information onto the sub-system that processes position information can explain this illusory position shift of a stationary flashed bar in the direction of motion. Based on this model of motion-position interactions, we predict that the perceived position of a flashed stimulus should also be attracted towards a nearby moving stimulus. In the first experiment, observers judged the perceived vertical position of a flash with respect to two horizontally moving dots of unequal contrast. The results of this experiment were in agreement with our prediction of attraction towards the high contrast dot. We obtained similar findings when the moving dots were replaced by drifting gratings of unequal contrast. In control experiments, we found that neither attention nor eye movements can account for this illusion. We propose that the visual system uses predictive influences from the motion processing sub-system on the position processing sub-system to overcome the temporal limitations of the position processing system.

Spatial and temporal properties of the illusory motion-induced position shift for drifting stimuli.

The perceived position of a stationary Gaussian window of a Gabor target shifts in the direction of motion of the Gabor's carrier stimulus, implying the presence of interactions between the specialized visual areas that encode form, position, and motion. The purpose of this study was to examine the temporal and spatial properties of this illusory motion-induced position shift (MIPS). We measured the magnitude of the MIPS for a pair of horizontally separated (2 or 8deg) truncated-Gabor stimuli (carrier=1 or 4cpd sinusoidal grating, Gaussian envelope SD=18arc min, 50% contrast) or a pair of Gaussian-windowed random-texture patterns that drifted vertically in opposite directions. The magnitude of the MIPS was measured for drift speeds up to 16deg/s and for stimulus durations up to 453ms. The temporal properties of the MIPS depended on the drift speed. At low velocities, the magnitude of the MIPS increased monotonically with the stimulus duration. At higher velocities, the magnitude of the MIPS increased with duration initially, then decreased between approximately 45 and 75ms before rising to reach a steady-state value at longer durations. In general, the magnitude of the MIPS was larger when the truncated-Gabor or random-texture stimuli were more spatially separated, but was similar for the different types of carrier stimuli. Our results are consistent with a framework that suggests that perceived form is modulated dynamically during stimulus motion.

Slowed Prosaccades and Increased Antisaccade Errors As a Potential Behavioral Biomarker of Multiple System Atrophy.

Current clinical diagnostic tools are limited in their ability to accurately differentiate idiopathic Parkinson's disease (PD) from multiple system atrophy (MSA) and other parkinsonian disorders early in the disease course, but eye movements may stand as objective and sensitive markers of disease differentiation and progression. To assess the use of eye movement performance for uniquely characterizing PD and MSA, subjects diagnosed with PD (N = 21), MSA (N = 11), and age-matched controls (C, N = 20) were tested on the prosaccade and antisaccade tasks using an infrared eye tracker. Twenty of these subjects were retested ~7 months later. Saccade latencies, error rates, and longitudinal changes in saccade latencies were measured. Both PD and MSA patients had greater antisaccade error rates than C subjects, but MSA patients exhibited longer prosaccade latencies than both PD and C patients. With repeated testing, antisaccade latencies improved over time, with benefits in C and PD but not MSA patients. In the prosaccade task, the normal latencies of the PD group show that basic sensorimotor oculomotor function remain intact in mid-stage PD, whereas the impaired latencies of the MSA group suggest additional degeneration earlier in the disease course. Changes in antisaccade latency appeared most sensitive to differences between MSA and PD across short time intervals. Therefore, in these mid-stage patients, increased antisaccade errors combined with slowed prosaccade latencies might serve as a useful marker for early differentiation between PD and MSA, and, antisaccade performance, a measure of MSA progression. Together, our findings suggest that eye movements are promising biomarkers for early differentiation and progression of parkinsonian disorders.

The attenuation of perceived motion smear during combined eye and head movements.

The extent of perceived motion smear was compared for targets that underwent similar velocities of retinal image motion during the vestibulo-ocular reflex (VOR) in the dark, the visually enhanced VOR (VVOR), VOR suppression, and fixation. Compared to the extent of perceived motion smear during fixation, observers reported significantly less smear when the target moved either in the same direction or against the direction of the head movement during the VVOR and VOR. We also confirmed a previous finding that perceived smear is attenuated asymmetrically during VOR suppression, with attenuation occurring primarily for targets that move against the direction of the observer's head motion. The results support the hypothesis that the visual system employs extra-retinal signals that accompany eye and head movements to reduce the perception of motion smear for targets that move physically in the opposite direction of eye and/or head movements.