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International audience; The ability to prepare for an action improves the speed and accuracy of its performance. While many studies indicate that behavior performance continues to improve throughout childhood and adolescence, it remains unclear whether or how preparatory processes change with development. Here, we used a rapid event-related fMRI design in three age groups (8-12, 13-17, 18-25 years) who were instructed to execute either a prosaccade (look toward peripheral target) or an antisaccade (look away from target) task. We compared brain activity within the core fronto-parietal network involved in saccade control at two epochs of saccade generation: saccade preparation related to task instruction versus saccade execution related to target appearance. The inclusion of catch trials containing only task instruction and no target or saccade response allowed us to isolate saccade preparation from saccade execution. Five regions of interest were selected: the frontal, supplementary, parietal eye fields which are consistently recruited during saccade generation, and two regions involved in top down executive control: the dorsolateral prefrontal and anterior cingulate cortices. Our results showed strong evidence that developmental improvements in saccade performance were related to better saccade preparation rather than saccade execution. These developmental differences were mostly attributable to children who showed reduced fronto-parietal activity during prosaccade and antisaccade preparation, along with longer saccade reaction times and more incorrect responses, compared to adolescents and adults. The dorsolateral prefrontal cortex was engaged similarly across age groups, suggesting a general role in maintaining task instructions through the whole experiment. Overall, these findings suggest that developmental improvements in behavioral control are supported by improvements in effectively presetting goal-appropriate brain systems.

Alzheimer’s disease (AD) is a disorder of progressive memory loss and executive dysfunction. Little is known about the progression from amnestic mild cognitive impairment (aMCI; isolated memory loss) to AD. Studies have found impairments in mild-stage AD and aMCI in specific tests of executive function. Here, we used objective saccade tasks to determine if they can effectively assess executive function deficits otherwise assessed by neuropsychological testing. To determine which executive function deficits the saccade tasks are most sensitive to, we also investigated the relationship between performance on saccade tasks and neuropsychological test scores. Twenty-two aMCI patients (63–90 years), 24 mild AD patients (61–87 years) and 76 healthy controls (60–85 years) performed a battery of neuropsychological tests, and two saccade tasks designed to probe sensory, motor and cognitive function. The prosaccade task requires a fast, automatic saccade toward an eccentric visual stimulus. The antisaccade task requires additional executive processing to inhibit the automatic prosaccade toward the stimulus, so that a voluntary saccade can be initiated to a location opposite the stimulus. Antisaccade performance was impaired similarly in aMCI and AD patients relative to controls; both groups were slower to initiate correct antisaccades and they made more direction errors (erroneous prosaccades), suggesting similar brain deficits. Scores on the Stroop task were inversely correlated with the percentage of short-latency direction errors in the antisaccade task for controls and aMCI patients, whereas other more global measures of executive function were not related to saccade measures in any subject group. Our results show that the antisaccade task is useful for detecting executive dysfunction in aMCI and AD, especially dysfunction in selective attention. Saccade tasks may therefore have potential to assess executive dysfunction when use of neuropsychological tests is not possible.

The superior colliculus (SC) is critical in localizing salient visual stimuli and making decisions on the location of the next saccade. Lateral interactions across the spatial map of the SC are hypothesized to help mediate these processes. Here, we investigate lateral interactions within the SC by applying whole-cell recordings in horizontal slices of mouse SC, which maintained the local structure of the superficial (SCs) visual layer, which is hypothesized to participate in localizing salient stimuli, and the intermediate (SCi) layer, which is supposed to participate in saccade decision-making. When effects of either electrical or chemical (uncaging of free glutamate) stimuli were applied to multiple sites with various distances from the recorded cell, a pattern of center excitation-surround inhibition was found to be prominent in SCs. When the interactions of synaptic effects induced by simultaneous stimulation of two sites were tested, non-linear facilitatory or inhibitory interactions were observed. In contrast, in the SCi, stimulation induced mainly excitation, which masked underlying inhibition. The excitatory synaptic effects of stimulation applied at remote sites were summed in a near linear manner. The result suggested that SCs lateral interactions appear suitable for localizing salient stimuli, while the lateral interactions within SCi are more suitable for faithfully accumulating subthreshold signals for saccadic decision-making. Implementation of this laminar-specific organization makes the SC a unique structure for serially processing signals for saliency localization and saccadic decision-making.

Tourette's syndrome is characterized by involuntary tics and, although the underlying pathogenesis and pathophysiology of Tourette's syndrome remains unclear, it is suspected that basal ganglia structures are involved. The basal ganglia also play an important role in the control of saccadic eye movements and we therefore hypothesize that Tourette's syndrome patients have abnormal control of saccadic eye movements. In this study, 10 subjects with Tourette's syndrome and 10 age- and sex-matched controls performed four different oculomotor paradigms requiring the execution and/or suppression of reflexive and/or voluntary saccades. In the immediate saccade tasks, subjects were required to look either toward (pro-saccade task) or away from (anti-saccade task) a peripheral target as soon as it appeared. In the delayed saccade tasks, subjects were instructed to wait for a central fixation point to disappear before initiating eye movements. Among Tourette's syndrome subjects, saccadic reaction times were longer in all tasks. Saccadic amplitudes were smaller in Tourette's syndrome subjects, and they made more saccades to reach the eccentric target. The occurrence of direction errors (i.e. reflexive pro-saccades on anti-saccade trials) was normal in the immediate anti-saccade task, suggesting that the ability to inhibit reflexive saccades towards novel stimuli was not impaired in Tourette's syndrome. Timing errors (i.e. eye movements made prior to disappearance of the central fixation point in delayed saccade tasks) were significantly greater among Tourette's syndrome subjects. Moreover, these errors were predominantly made towards the first target of the remembered sequence in a delayed memory-guided sequential saccade task. These results indicate that the ability to inhibit or delay planned motor programmes is significantly impaired in Tourette's syndrome. We hypothesize that altered cortical-basal ganglia circuitry leads to reduced cortical inhibition making it harder for Tourette's syndrome subjects to withhold the execution of planned motor programmes.

Cognitive and brain maturational changes continue throughout late childhood and adolescence. During this time, increasing cognitive control over behavior enhances the voluntary suppression of reflexive/impulsive response tendencies. Recently, with the advent of functional MRI, it has become possible to characterize changes in brain activity during cognitive development. In order to investigate the cognitive and brain maturation subserving the ability to voluntarily suppress context-inappropriate behavior, we tested 8–30 year olds in an oculomotor response–suppression task. Behavioral results indicated that adult-like ability to inhibit prepotent responses matured gradually through childhood and adolescence. Functional MRI results indicated that brain activation in frontal, parietal, striatal, and thalamic regions increased progressively from childhood to adulthood. Prefrontal cortex was more active in adolescents than in children or adults; adults demonstrated greater activation in the lateral cerebellum than younger subjects. These results suggest that efficient top-down modulation of reflexive acts may not be fully developed until adulthood and provide evidence that maturation of function across widely distributed brain regions lays the groundwork for enhanced voluntary control of behavior during cognitive development.

Significant advances in cognitive neuroscience can be achieved by combining techniques used to measure behavior and brain activity with neural modeling. Here we apply this approach to the initiation of rapid eye movements (saccades), which are used to redirect the visual axis to targets of interest. It is well known that the superior colliculus (SC) in the midbrain plays a major role in generating saccadic eye movements, and physiological studies have provided important knowledge of the activity pattern of neurons in this structure. Based on the observation that the SC receives localized sensory (exogenous) and voluntary (endogenous) inputs, our model assumes that this information is integrated by dynamic competition across local collicular interactions. The model accounts well for the effects upon saccadic reaction time (SRT) due to removal of fixation, the presence of distractors, execution of pro-versus antisaccades, and variation in target probability, and suggests a possible mechanism for the generation of express saccades. In each of these cases, the activity patterns of “neurons” within the model closely resemble actual cell behavior in the intermediate layer of the SC. The interaction structure we employ is instrumental for producing a physiologically faithful model and results in new insights and hypotheses regarding the neural mechanisms underlying saccade initiation.

The ability to inhibit reflexes in favor of goal-oriented behaviors is critical for optimal exploration and interaction with our environment. The antisaccade task can be used to investigate the ability of subjects to suppress a reflexive saccade (prosaccade) to a suddenly appearing visual stimulus and instead generate a voluntary saccade (antisaccade) to its mirror location. To understand the neural mechanisms required to perform this task, our lab has developed a non-human primate model. Two monkeys were trained on a task with randomly interleaved pro- and antisaccade trials, with the color of the central fixation point (FP) instructing the monkey to either make a prosaccade (red FP) or an antisaccade (green FP). In half of the trials, the FP disappeared 200 ms before stimulus presentation (gap condition) and in the remaining trials, the FP remained visible (overlap condition) during stimulus presentation. The effect of stimulus eccentricity and direction was examined by presenting the stimulus at one of eight different radial directions (0−360°) and five eccentricities (2, 4, 8, 10, and 16°). Antisaccades had longer saccadic reaction times (SRTs), more dysmetria, and lower peak velocities than prosaccades. Direction errors in the antisaccade task were more prevalent in the gap condition. The difference in mean SRT between correct pro- and antisaccades, the anti-effect, was greater in the overlap condition. The difference in mean SRT between the overlap and the gap condition, the gap effect, was larger for antisaccades than for prosaccades. The manipulation of stimulus eccentricity and direction influenced SRT and the proportion of direction errors. These results are comparable to human studies, supporting the use of this animal model for investigating the neural mechanisms subserving the generation of antisaccades.

This study examines two current ideas regarding the control of eye-head gaze shifts. The first idea stems from recent studies involving electrical stimulation in the primate superior colliculus that suggest that a residual feedback of gaze displacement persists for ∼100 ms after completion of a gaze shift. In light of this hypothesis, we examined the accuracy of gaze shifts generated very soon after the end of a preceding gaze shift. Human subjects were presented with a visual or auditory target along with an accompanying stimulus of the other modality. The accompanying stimulus appeared either at the same place as the target or at the diametrically opposite position, in which case it was termed a distractor. Subjects often made an incorrect gaze shift (IGS) in the direction of the distractor, followed by a recorrect gaze shift (RGS) in the direction of the target. We found that RGSs were accurately driven to the target, even when they followed IGSs by

This study was motivated by the observation of early head movements(EHMs) occasionally generated before gaze shifts. Human subjects were presented with a visual or auditory target, along with an accompanying stimulus of the other modality, that either appeared at the same location as the target (enhancer condition) or at the diametrically opposite location (distractor condition). Gaze shifts generated to the target in the distractor condition sometimes were preceded by EHMs directed either to the side of the target ( correct EHMs) or the side of the distractor ( incorrect EHMs). During EHMs, the eyes performed compensatory eye movements to keep gaze stable. Incorrect EHMs were usually between 1 and 5° in amplitude and reached peak velocities generally

Influence of previous visual stimulus or saccade on saccadic reaction times in monkey. Saccadic reaction times (SRTs) to suddenly appearing targets are influenced by neural processes that occur before and after target presentation. The majority of previous studies have focused on how posttarget factors, such as target attributes or changes in task complexity, affect SRTs. Studies of pretarget factors have focused on how prior knowledge of the timing or location of the impending target, gathered through cueing or probabilistic information, affects SRTs. Our goal was to investigate additional pretarget factors to determine whether SRTs can also be influenced by the history of saccadic and visual activity even when these factors are spatially unpredictive as to the location of impending saccadic targets. Monkeys were trained on two paradigms. In the saccade-saccadeparadigm, monkeys were required to follow a saccadic target that stepped from a central location, to an eccentric location, back to center, and finally to a second eccentric location. The stimulus-saccade paradigm was similar, except the central fixation target remained illuminated during presentation of the first eccentric stimulus; the monkey was required to maintain central fixation and to make a saccade to the second eccentric stimulus only on disappearance of the fixation point. In both paradigms, the first eccentric stimulus was presented at the same, opposite, or orthogonal location with respect to the final target location in a given trial. We measured SRTs to the final target under conditions in which all parameters were identical except for the location of the first eccentric stimulus. In the saccade-saccade paradigm, we found that the SRT to the final target was slowest when it was presented opposite to the initial saccadic target, whereas in the stimulus-saccade paradigm the SRT to the final target was slowest when it was presented at the same location as the initial stimulus. In both paradigms, these increases in SRTs were greatest during the shortest intervals between presentation of successive eccentric stimuli, yet these effects remained present for the longest intervals employed in this study. SRTs became faster as the direction and eccentricity of the two successive stimuli became increasingly misaligned from that which produced the maximal SRT slowing in each paradigm. The results of the stimulus-saccade paradigm are similar to the phenomenon of inhibition of return (IOR) in which human subjects are slower to respond to stimuli that are presented at previously cued locations. We interpret these findings in terms of overlapping representations of visuospatial and oculomotor activity in the same neural structures.

Visual stimulus presentation activates the oculomotor network without requiring a gaze shift. Here, we demonstrate that primate neck muscles are recruited during such reflexive covert orienting in a manner that parallels activity recorded from the superior colliculus (SC). Our results indicate the presence of a brainstem circuit whereby reflexive covert orienting is prevented from shifting gaze, but recruits neck muscles, predicting that similarities between SC and neck muscle activity should extend to other cognitive processes that are known to influence SC activity.

One must be prudent when selecting potential saccadic targets because the eyes can only move to one location at a time, yet movements must occur quickly enough to permit interaction with a rapidly changing world. This process of efficiently acquiring relevant targets may be aided by advanced planning of a movement toward an upcoming target whose location is gathered via environmental cues or situational experience. We studied how saccadic reaction times (SRTs) and early pretarget neuronal activity covaried as a function of saccadic probability. Monkeys performed a saccadic task in which the probability of the required saccade being directed into the response field of a neuron varied systematically between blocks of trials. We recorded simultaneously the early pretarget activity of saccade-related neurons in the intermediate layers of the superior colliculus. We found that, as the likelihood of the saccade being generated into the response field of the neuron increased, the level of neuronal activity preceding target presentation also increased. Our data suggest that this early activity codes motor preparation because its activity was related to not only the metrics but also the timing of the saccade, with 94% (29/31) of the neurons tested having significant negative correlations between discharge rate and SRT. This view is supported by cases in which exceptionally high levels of pretarget activity were associated with anticipatory saccades into the response field of a neuron that occurred in advance of the target being presented. This study demonstrates how situational experience can expedite motor behavior via the advanced preparation of motor programs.

We measured saccadic eye movements in 168 normal human subjects, ranging in age from 5 to 79 years, to determine age-related changes in saccadic task performance. Subjects were instructed to look either toward (pro-saccade task) or away from (anti-saccade task) an eccentric target under different conditions of fixation. We quantified the percentage of direction errors, the time to onset of the eye movement (saccadic reaction time: SRT), and the metrics and dynamics of the movement itself (amplitude, peak velocity, duration) for subjects in different age groups. Young children (5-8 years of age) had slow SRTs, great intra-subject variance in SRT, and the most direction errors in the anti-saccade task. Young adults (20-30 years of age) typically had the fastest SRTs and lowest intra-subject variance in SRT. Elderly subjects (60-79 years of age) had slower SRTs and longer duration saccades than other subject groups. These results demonstrate very strong age-related effects in subject performance, which may reflect different stages of normal development and degeneration in the nervous system. We attribute the dramatic improvement in performance in the anti-saccade task that occurs between the ages of 5-15 years to delayed maturation of the frontal lobes.

Munoz, Douglas P. and Peter J. Istvan. Lateral inhibitory interactions in the intermediate layers of the monkey superior colliculus. J. Neurophysiol. 79: 1193–1209, 1998. The intermediate layers of the monkey superior colliculus (SC) contain neurons the discharges of which are modulated by visual fixation and saccadic eye movements. Fixation neurons, located in the rostral pole of the SC, discharge action potentials tonically during visual fixation and pause for most saccades. Saccade neurons, located throughout the remainder of the intermediate layers of the SC, discharge action potentials for saccades to a restricted region of the visual field. We defined the fixation zone as that region of the rostral SC containing fixation neurons and the saccade zone as the remainder of the SC. It recently has been hypothesized that a network of local inhibitory interneurons may help shape the reciprocal discharge pattern of fixation and saccade neurons. To test this hypothesis, we combined extracellular recording and microstimulation techniques in awake monkeys trained to perform oculomotor paradigms that enabled us to classify collicular fixation and saccade neurons. Microstimulation was used to electrically activate the fixation and saccade zones of the ipsilateral and contralateral SC to test for inhibitory and excitatory inputs onto fixation and saccade neurons. Saccade neurons were inhibited at short latencies following electrical stimulation of either the ipsilateral (1–5 ms) or contralateral (2–7 ms) fixation or saccade zones. Fixation neurons were inhibited 1–4 ms after electrical stimulation of the ipsilateral saccade zone. Stimulation of the contralateral saccade zone led to much weaker inhibition of fixation neurons. Stimulation of the contralateral fixation zone led to short-latency (1–2 ms) excitation of fixation neurons. Only a small percentage of saccade and fixation neurons were activated by the electrical stimulation (latency: 0.5–2.0 ms). These responses were confirmed as either orthodromic or antidromic responses using collision testing. The results suggest that a local network of inhibitory interneurons may help shape not only the reciprocal discharge pattern of fixation and saccade neurons but also permit lateral interactions between all regions of the ipsilateral and contralateral SC. These interactions therefore may be critical for maintaining stable visual fixation, suppressing unwanted saccades, and initiating saccadic eye movements to targets of interest.

Although naming speed (NS) has been shown to predict reading into adulthood and differentiate between adult dyslexics and controls, the question remains why NS is related to reading. To address this question, eye movement methodology was combined with three letter NS tasks (the original letter NS task by Denckla & Rudel, Cortex 10:186–202, 1974, and two more developed by Compton, The Journal of Special Education 37:81–94, 2003, with increased phonological or visual similarity of the letters). Twenty undergraduate students with reading difficulties (RD) and 27 without (NRD) were tested on letter NS tasks (eye movements were recorded during the NS tasks), phonological processing, and reading fluency. The results indicated first that the RD group was slower than the NRD group on all NS tasks with no differences between the NS tasks. In addition, the NRD group had shorter fixation durations, longer saccades, and fewer saccades and fixations than the RD group. Fixation duration and fixation count were significant predictors of reading fluency even after controlling for phonological processing measures. Taken together, these findings suggest that the NS–reading relationship is due to two factors: less able readers require more time to acquire stimulus information during fixation and they make more saccades.

Human volitional actions are preceded by preparatory processes, a critical mental process of cognitive control for future behavior. Volitional action preparation is regulated by large-scale neural circuits including the cerebral cortex and the basal ganglia. Because volitional action preparation is a covert process, the network dynamics of such neural circuits have been examined by neuroimaging and recording event-related potentials. Here, we examined whether such covert processes can be measured by the overt responses of fixational saccades (including microsaccades), the largest miniature eye movements that occur during eye fixation. We analyzed fixational saccades while adult humans maintained fixation on a central visual stimulus as they prepared to generate a volitional saccade in response to peripheral stimulus appearance. We used the antisaccade paradigm, in which subjects generate a saccade toward the opposite direction of a peripheral stimulus. Appropriate antisaccade performance requires the following two aspects of volitional control: 1) facilitation of saccades away from the stimulus and 2) suppression of inappropriate saccades toward the stimulus. We found that fixational saccades that occurred before stimulus appearance reflected the dual preparatory states of saccade facilitation and suppression and correlated with behavioral outcome (i.e., whether subjects succeeded or failed to cancel inappropriate saccades toward the stimulus). Moreover, fixational saccades explained a large proportion of individual differences in behavioral performance (poor/excellent) across subjects. These results suggest that fixational saccades predict the outcome of future volitional actions and may be used as a potential biomarker to detect people with difficulties in volitional action preparation.

Saccadic eye movements are a major source of disruption to visual stability, yet we experience little of this disruption. We can keep track of the same object across multiple saccades. It is generally assumed that visual stability is due to the process of remapping, in which retinotopically organized maps are updated to compensate for the retinal shifts caused by eye movements. Recent behavioral and ERP evidence suggests that visual attention is also remapped, but that it may still leave a residual retinotopic trace immediately after a saccade. The current study was designed to further examine electrophysiological evidence for such a retinotopic trace by recording ERPs elicited by stimuli that were presented immediately after a saccade (80 msec SOA). Participants were required to maintain attention at a specific location (and to memorize this location) while making a saccadic eye movement. Immediately after the saccade, a visual stimulus was briefly presented at either the attended location (the same spatiotopic location), a location that matched the attended location retinotopically (the same retinotopic location), or one of two control locations. ERP data revealed an enhanced P1 amplitude for the stimulus presented at the retinotopically matched location, but a significant attenuation for probes presented at the original attended location. These results are consistent with the hypothesis that visuospatial attention lingers in retinotopic coordinates immediately following gaze shifts.

In an influential model of frontal eye field (FEF) and superior colliculus (SC) activity, saccade initiation occurs when the discharge rate of either single neurons or a population of neurons encoding a saccade motor plan reaches a threshold level of activity. Conflicting evidence exists for whether this threshold is fixed or can change under different conditions. We tested the fixed-threshold hypothesis at the single-neuron and population levels to help resolve the inconsistency between previous studies. Two rhesus monkeys performed a randomly interleaved pro- and antisaccade task in which they had to look either toward (pro) or 180° away (anti) from a peripheral visual stimulus. We isolated visuomotor (VM) and motor (M) neurons in the FEF and SC and tested three specific predictions of a fixed-threshold hypothesis. We found little support for fixed thresholds. First, correlations were never totally absent between presaccadic discharge rate and saccadic reaction time when examining a larger (plausible) temporal period. Second, presaccadic discharge rates varied markedly between saccade tasks. Third, visual responses exceeded presaccadic motor discharges for FEF and SC VM neurons. We calculated that only a remarkably strong bias for M neurons in downstream projections could render the fixed-threshold hypothesis plausible at the population level. Also, comparisons of gap vs. overlap conditions indicate that increased inhibitory tone may be associated with stability of thresholds. We propose that fixed thresholds are the exception rather than the rule in FEF and SC, and that stabilization of an otherwise variable threshold depends on task-related, inhibitory modulation.

Background: The traditional view of Parkinson’s disease (PD) as a motor disorder only treated by dopaminergic medications is now shifting to include non-pharmacologic interventions. We have noticed that patients with PD obtain an immediate, short-lasting benefit to mobility by the end of a dance class, suggesting some mechanism by which dancing reduces bradykinetic symptoms. We have also found that patients with PD are unimpaired at initiating highly automatic eye-movements to visual stimuli (pro-saccades) but are impaired at generating willful eye movements away from visual stimuli (anti-saccades). We hypothesized that the mechanisms by which a dance class improves movement initiation may generalize to the brain networks impacted in PD (frontal lobe and basal ganglia), and thus could be assessed objectively by measuring eye movements, which rely on the same neural circuitry. Methods: Participants with PD performed pro- and anti-saccades before, and after, a dance class. ‘Before’ and ‘after’ saccade performance measurements were compared. These measurements were then contrasted with a control condition (observing a dance class in a video), and with older and younger adult populations, who rested for an hour between measurements. Results: We found an improvement in anti-saccade performance following the observation of dance (but not following dancing), but we found a detriment in pro-saccade performance following dancing. Conclusions: We suggest that observation of dance induced plastic changes in frontal-basal ganglia networks that are important for executive control. Dancing, in contrast, increased voluntary movement signals that benefited mobility, but interfered with the automaticity of efficient pro-saccade execution.

Although eye movement onset typically precedes hand movement onset when reaching to targets presented in peripheral vision, arm motor commands appear to be issued at around the same time, and possibly in advance, of eye motor commands. A fundamental question, therefore, is whether eye movement initiation is linked or yoked to hand movement. We addressed this issue by having participants reach to targets after adapting to a visuomotor reversal (or 180° rotation) between the position of the unseen hand and the position of a cursor controlled by the hand. We asked whether this reversal, which we expected to increase hand reaction time (HRT), would also increase saccadic reaction time (SRT). As predicted, when moving the cursor to targets under the reversal, HRT increased in all participants. SRT also increased in all but one participant, even though the task for the eyes – shifting gaze to the target – was unaltered by the reversal of hand position feedback. Moreover, the effects of the reversal on SRT and HRT were positively correlated across participants; those who exhibited the greatest increases in HRT also showed the greatest increases in SRT. These results indicate that the mechanisms underlying the initiation of eye and hand movements are linked. In particular, the results suggest that the initiation of an eye movement to a manual target depends, at least in part, on the specification of hand movement.

Computational models of visual attention have attracted strong interest by accurately predicting how humans deploy attention. However, little research has utilized these models to detect clinical populations whose attention control has been affected by neurological disorders. We designed a framework to decypher disorders from the joint analysis of video and patients' natural eye movement behaviors watch television for 5 minutes. We employ convolutional deep neural networks to extract visual features in real-time at the point of gaze, followed by SVM and Adaboost to classify typically developing children vs. children with fetal alcohol spectrum disorder FASD, who exhibit impaired attentional control. The classifier achieved 74.1% accuracy ROC: 0.82. Our results demonstrate that there is substantial information about attentional control in even very short recordings of natural viewing behavior. Our new method could lead to high-throughput, low-cost screening tools for identifying individuals with deficits in attentional control.

We studied the influences of competing visual and auditory stimuli on horizontal gaze shifts in humans. Gaze shifts were made to visual or auditory targets in the presence of either an irrelevant visual or auditory cue. Within an experiment, the target and irrelevant cue were either aligned (enhancer condition) or misaligned (distractor condition) in space. The times of presentation of the target and irrelevant cue were varied so that the target could have been presented before the irrelevant cue, or the irrelevant cue before the target. We compared subject performance in the enhancer and distractor conditions, measuring reaction latencies and the frequency of incorrect gaze shifts. Performance differed the most when the irrelevant cue was presented before the target and differed the least when the target was presented before the irrelevant cue. Our results reveal that, in addition to the spatial and temporal register of the stimuli, the experimental context in which the stimuli are presented also influences multisensory integration: an irrelevant auditory cue influenced gaze shifts to visual targets differently than an irrelevant visual cue influenced gaze shifts to auditory targets. Furthermore, we observed patterns of influence unique to either visual or auditory irrelevant cues that occurred regardless of the modality of the target. We believe that subjects adopted a state of motor readiness that reflected the unique demands of target selection in each experiment and that this state modulated the influences of the irrelevant cue on the target.

1. The introduction of a period of darkness between the disappearance of an initial fixation target and the appearance of a peripheral saccade target produces a general reduction in saccadic reaction time (SRT)-known as the gap effect- and often very short latency express saccades. To account for these phenomena, premotor processes may be facilitated by release of visual fixation and advanced preparation of saccadic programs. The experiments described in this paper were designed to test the relevance of the ocular fixation disengagement and oculomotor preparation hypotheses by identifying the influence of different factors on SRTs and the occurrence of express saccades in the monkey. 2. The SRTs of two monkeys were measured in two behavioral paradigms. A peripheral saccade target appeared at the time of disappearance of a central fixation target in the no-gap task, whereas a 200-ms period of no stimuli was interposed between the fixation target disappearance and the saccade target appearance in the gap task. The distribution of SRTs in these tasks was generally bimodal; the first and second mode was composed of express and regular saccades, respectively. We measured the mean SRT, mean regular saccade latency, mean express saccade latency, and percentage of express saccades in both tasks. We also estimated the gap effect, i.e., the difference between the SRTs in no-gap trial and the SRTs in gap trials. 3. Once the animals were trained to make saccades to a single target location and produce express saccades, SRTs in both no-gap and gap trials displayed a broad tuning with respect to the spatial location of the trained target when the target location was varied randomly in a block of trials. Express saccades were made only to a restricted region of the visual field surrounding the trained target location. A gap effect was present for nearly all target locations tested, irrespective of express saccade occurrence. Finally, the probability of generating an express saccade at the trained target location decreased with the introduction of uncertainty about target location. 4. The occurrence of express saccades increased with the duration of the visual and nonvisual (gap) fixation that the animal was required to maintain before the onset of a saccade target. The gap duration was effective in reducing the mean SRT for gaps < or = 300 ms, and it was more influential than comparable variation in the visual fixation duration. 5. The occurrence of express saccades made to targets of identical eccentricity increased when the initial eye fixation position was shifted eccentric in a direction opposite to the saccade direction. Concomitantly, mean SRT decreased by approximately 2 ms for each 1-deg change in initial eye fixation position. 6. The occurrence of express saccades depended upon contextual factors, i.e., on both the behavioral task (no-gap or gap) and the latency of the saccade that the monkey executed to the same target in the preceding trial. The highest percentage of express saccades was observed after an express saccade in a no-gap trial, whereas the lowest percentage was obtained after a regular saccade in a gap trial. 7. These findings indicate that training-dependent express saccades are restricted to a specific spatial location dictated by the training target, and their incidence is facilitated by high predictability of target presentation, long-duration foreperiod, absence of visual fixation, eccentric initial eye position opposite to the saccade direction, and express saccade occurrence in the previous trial. The release of fixation afforded by the gap accounts for the general gap effect, but has only a modulatory influence on express saccade generation. We conclude that advanced motor preparation of saccadic programs generally reduces SRT and is primarily responsible for the occurrence of express saccades, which therefore may be caused mainly by neuronal changes restricted to a specific locus-coding for the trained movemen

The capture of covert spatial attention by salient visual events influences subsequent gaze behavior. A task irrelevant stimulus (cue) can reduce (Attention capture) or prolong (Inhi-bition of return) saccade reaction time to a subsequent target stimulus depending on the cue-target delay. Here we investigated the mechanisms that underlie the sensory-based account of AC/IOR by manipulating the visual processing stage where the cue and target interact. In Experiment 1, liquid crystal shutter goggles were used to test whether AC/IOR occur at a monocular versus binocular processing stage (before versus after signals from both eyes converge). In Experiment 2, we tested whether visual orientation selective mechanisms are critical for AC/IOR by using oriented “Gabor” stimuli. We found that the magnitude of AC and IOR was not different between monocular and interocular viewing conditions, or between iso- and ortho-oriented cue-target interactions. The results suggest that the visual mechanisms that contribute to AC/IOR arise at an orientation-independent binocular processing stage.

1. The reduction in saccadic reaction time associated with the introduction of a period of darkness between the disappearance of an initial fixation point and the appearance of a new peripheral saccade target is known as the gap effect. Fixation cells in the rostral pole of the monkey superior colliculus have been implicated in the control of active visual fixation and suppressing saccadic eye movements. To determine whether specific variations of fixation cell discharge was correlated to the gap effect, we recorded the activity of fixation cells while a monkey generated visually guided saccades with various temporal gaps between the disappearance of the initial fixation point and the appearance of a peripheral saccade target. 2. The saccadic reaction times of the monkey were shortest with gap durations of 200-300 ms and increased with shorter or longer gap durations. The activity of fixation cells followed a similar time course, having a minimum discharge rate 200-300 ms into the gap, and increased activity at the time of target appearance with smaller or larger gap durations. 3. We propose that the activity of fixation cells in the monkey superior colliculus provide a neural correlate of the gap effect. The decrease in activity of fixation cells 200-300 ms into the gap weakens the powerful state of inhibition which they normally exert upon the saccade generating system, allowing targets to be acquired at shorter reaction times.

Here we examined the influence of the visual response in the superior colliculus (SC) (an oculomotor control structure integrating sensory, motor and cognitive signals) on the development of the motor command that drives saccadic eye movements in monkeys. We varied stimulus luminance to alter the timing and magnitude of visual responses in the SC and examined how these changes correlated with resulting saccade behavior. Increasing target luminance resulted in multiple modulations of the visual response, including increased magnitude and decreased response onset latency. These signal modulations correlated strongly with changes in saccade latency and metrics, indicating that these signal properties carry through to the neural computations that determine when, where and how fast the eyes will move. Thus, components of the earliest part of the visual response in the SC provide important building blocks for the neural basis of the sensory-motor transformation, highlighting a critical link between the properties of the visual response and saccade behavior.

Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.

The orienting reflex is initiated by a salient stimulus and facilitates quick, appropriate action. It involves a rapid shift of the eyes, head, and attention and other physiological responses such as changes in heart rate and transient pupil dilation. The SC is a critical structure in the midbrain that selects incoming stimuli based on saliency and relevance to coordinate orienting behaviors, particularly gaze shifts, but its causal role in pupil dilation remains poorly understood in mammals. Here, we examined the role of the primate SC in the control of pupil dynamics. While requiring monkeys to keep their gaze fixed, we delivered weak electrical microstimulation to the SC, so that saccadic eye movements were not evoked. Pupil size increased transiently after microstimulation of the intermediate SC layers (SCi) and the size of evoked pupil dilation was larger on a dim versus bright background. In contrast, microstimulation of the superficial SC layers did not cause pupil dilation. Thus, the SCi is directly involved not only in shifts of gaze and attention, but also in pupil dilation as part of the orienting reflex, and the function of pupil dilation may be related to increasing visual sensitivity. The shared neural mechanisms suggest that pupil dilation may be associated with covert attention.

International audience; Recent evidence has shown that patients with Parkinson's disease (PD) often display deficits in executive functions, such as planning for future behavior, and these deficits may stem from pathologies in prefrontal cortex and basal ganglia circuits that are critical to executive control. Using the antisaccade task (look away from a visual stimulus), we show that when the preparatory 'readiness' to perform a given action is dissociated from the actual execution of that action, PD patients off and on dopamine medication display behavioral impairments and reduced cortical brain activation that cannot be explained by a pathology related to dysfunction in movement execution. Rather, they show that the appropriate task set signals were not in place in motor regions prior to execution, resulting in impairments in the control of subsequent voluntary movement. This is the first fMRI study of antisaccade deficits in Parkinson's disease, and importantly, the findings point to a critical role of the basal ganglia in translating signals related to rule representation (executive) into those governing voluntary motor behavior.

The brain's ability to ignore repeating, often redundant, information while enhancing novel information processing is paramount to survival. When stimuli are repeatedly presented, the response of visually sensitive neurons decreases in magnitude, that is, neurons adapt or habituate, although the mechanism is not yet known. We monitored the activity of visual neurons in the superior colliculus (SC) of rhesus monkeys who actively fixated while repeated visual events were presented. We dissociated adaptation from habituation as mechanisms of the response decrement by using a Bayesian model of adaptation, and by employing a paradigm including rare trials that included an oddball stimulus that was either brighter or dimmer. If the mechanism is adaptation, response recovery should be seen only for the brighter stimulus; if the mechanism is habituation, response recovery ('dishabituation') should be seen for both the brighter and dimmer stimuli. We observed a reduction in the magnitude of the initial transient response and an increase in response onset latency with stimulus repetition for all visually responsive neurons in the SC. Response decrement was successfully captured by the adaptation model, which also predicted the effects of presentation rate and rare luminance changes. However, in a subset of neurons with sustained activity in response to visual stimuli, a novelty signal akin to dishabituation was observed late in the visual response profile for both brighter and dimmer stimuli, and was not captured by the model. This suggests that SC neurons integrate both rapidly discounted information about repeating stimuli and novelty information about oddball events, to support efficient selection in a cluttered dynamic world.

The primary function of the superior colliculus (SC) is to orient the visual system toward behaviorally relevant stimuli defined by features such as color. However, a longstanding view has held that visual activity in the SC arises exclusively from achromatic pathways. Recently, we reported evidence that the primate SC is highly sensitive to signals originating from chromatic pathways, but these signals are delayed relative to luminance signals ([White et al., 2009][1]). Here, we describe a functional consequence of this difference in visual arrival time on the processes leading to target selection and saccade initiation. Two rhesus monkeys performed a simple color-singleton selection task in which stimuli carried a chromatic component only (target and distractors were isoluminant with the background, but differed in chromaticity) or a combined chromatic–achromatic component (36% luminance contrast added equally to all stimuli). Although visual responses were delayed in the chromatic-only relative to the combined chromatic–achromatic condition, SC neurons discriminated the target from distractors at approximately the same time provided stimulus chromaticity was held constant. However, saccades were triggered sooner, and with more errors, with the chromatic–achromatic condition, suggesting that luminance signals associated with these stimuli increased the probability of triggering a saccade before the target color was adequately discriminated. These results suggest that separate mechanisms may independently influence the saccadic command in the SC, one linked to the arrival time of pertinent visual signals, and another linked to the output of the visual selection process. [1]: #ref-49

1. We studied the role of the superior colliculus (SC) in the control of visual fixation by recording from cells in the rostral pole of the SC in awake monkeys that were trained to perform fixation and saccade tasks. 2. We identified a subset of neurons in three monkeys that we refer to as fixation cells. These cells increased their tonic discharge rate when the monkey actively fixated a visible target spot to obtain a reward. This sustained activity persisted when the visual stimulation of the target spot was momentarily removed but the monkey was required to continue fixation. 3. The fixation cells were in the rostral pole of the SC. As the electrode descended through the SC, we encountered visual cells with foveal and parafoveal receptive fields most superficially, saccade-related burst cells with parafoveal movement fields below these visual cells, and fixation cells below the burst cells. From this sequence in depth, the fixation cells appeared to be centered in the deeper reaches of the intermediate layers, and this was confirmed by small marking lesions identified histologically. 4. During saccades, the tonically active fixation cells showed a pause in their rate of discharge. The duration of this pause was correlated to the duration of the saccade. Many cells did not decrease their discharge rate for small-amplitude contraversive saccades. 5. The saccade-related pause in fixation cell discharge always began before the onset of the saccade. The mean time from pause onset to saccade onset for contraversive saccades and ipsiversive saccades was 36.2 and 33.0 ms, respectively. Most fixation cells were reactivated before the end of contraversive saccades. The mean time from saccade terminatioN to pause end was -2.6 ms for contraversive saccades and 9.9 ms for ipsiversive saccades. The end of the saccade-related pause in fixation cell discharge was more tightly correlated to saccade termination, than pause onset was to saccade onset. 6. After the saccade-related pause in discharge, many fixation cells showed an increased discharge rate exceeding that before the pause. This increased postsaccadic discharge rate persisted for several hundred milliseconds. 7. The discharge rate of fixation cells was not consistently altered when the monkey actively fixated targets requiring different orbital positions. 8. Fixation cells discharged during smooth pursuit eye movements as they did during fixation. They maintained a steady tonic discharge during pursuit at different speeds and in different directions, provided the monkey looked at the moving target.(ABSTRACT TRUNCATED AT 400 WORDS)

A dominant basal ganglia (BG) model consists of two functionally opposite pathways: one facilitates motor output and the other suppresses it. Although this idea was originally proposed to account for motor deficits, it has been extended recently also to explain cognitive deficits. Here, we employed the antisaccade paradigm (look away from a stimulus) to address the role of the caudate nucleus, the main BG input stage where the two pathways diverge, in conflict resolution. Using single neuron recordings in awake monkeys, we identified the following three groups of neurons. The first group of neurons showed activity consistent with sensory-driven (automatic) saccades toward a contralateral visual stimulus. The second group of neurons showed activity consistent with internally driven (volitional) saccades toward the contralateral side regardless of stimulus locations. The third group of neurons showed similar firing characteristics with the second group of neurons, except that their preferred saccade direction was ipsilateral. The activity of the three groups of neurons was correlated with behavioral outcome. Based on these findings, we suggest the following hypothesis: the first and second groups of neurons encoding automatic and volitional saccades, respectively, might give rise to the facilitation (direct) pathway and promote saccades toward the opposite directions, which creates a response conflict. This conflict could be resolved by the third group of caudate neurons, which might give rise to the suppression (indirect) pathway and attenuate inappropriate saccade commands toward the stimulus.

It is still debated to what degree top–down and bottom–up driven attentional control processes are subserved by shared or by separate mechanisms. Interactions between these attentional control forms were investigated using a rapid event-related fMRI design, using an attentional search task. Following a prestimulus mask, target stimuli (consisting of a letter C or a mirror image of the C, enclosed in a diamond outline) were presented either at one unique location among three nontarget items (consisting of a random letter, enclosed in a circle outline; 50% probability), or at all four possible target locations (also 50% probability). On half the trials, irrelevant color singletons were presented, consisting of a color change of one of the four prestimulus masks, just prior to target appearance. Participants were required to search for a target letter inside the diamond and report its orientation. Results indicate that, in addition to a common network of parietal areas, medial frontal cortex is uniquely involved in top–down orienting, whereas bottom–up control is mainly subserved by a network of occipital and parietal areas. Additionally, we found that participants who were better able to suppress orienting to the color singleton showed middle frontal gyrus activation, and that the degree of top–down control correlated with insular activity. We conclude that, in addition to a common set of parietal areas, separate brain areas are involved in top–down and bottom–up driven attentional control, and that frontal areas play a role in the suppression of attentional capture by an irrelevant color singleton.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent neuropsychiatric disorder in both children and adults, characterized by symptoms of inattention, hyperactivity, and impulsiveness. Diagnosis is currently made using a battery of examinations, rating scales, and interviews. Many of these sources are subjective and not always correlated. The questionable reliability of these sources highlights the need for more objective tests of ADHD. In this chapter, we address this need with the design, development and testing of an efficient computational system for differentiation based on altered control of saccadic eye movements in ADHD subjects and a control group. Our hypothesis is that there is sufficient predictive information contained in existing eye movement data to allow for the development of a knowledge-based system that could be used to identify meaningful groups of ADHD subjects. Specifically, a case-based reasoning (CBR) system was implemented to retrieve and apply previous ADHD diagnostic cases to novel problems based on saccade performance data. An iterative refinement methodology was used to incrementally improve the CBR system, resulting in a tool that could distinguish ADHD from normal control subjects with an accuracy of over 70 subjects incorrectly classified by the CBR system were shown to represent a meaningful subgroup within the ADHD case base. The incorrectly classified ADHD subjects demonstrated a significantly decreased benefit from medication, as measured by improvements in saccade performance, when compared to correctly classified subjects. The ability of the CBR system to identify meaningful ADHD subgroups supports its potential use as a diagnostic tool by contributing to a multi-source diagnostic battery when coupled with other objective tests.

Systematic modulations of microsaccades have been observed in humans during covert orienting. We show here that monkeys are a suitable model for studying the neurophysiology governing these modulations of microsaccades. Using various cue-target saccade tasks, we observed the effects of visual and auditory cues on microsaccades in monkeys. As in human studies, following visual cues there was an early bias in cue-congruent microsaccades followed by a later bias in cue-incongruent microsaccades. Following auditory cues there was a cue-incongruent bias in left cues only. In a separate experiment, we observed that brainstem omnipause neurons, which gate all saccades, also paused during microsaccade generation. Thus, we provide evidence that at least part of the same neurocircuitry governs both large saccades and microsaccades.

Patients with Parkinson's disease (PD) show slowed movement initiation and can have deficits in executive function, leading to impairments in controlling involuntary behavior. This results in difficulties performing an antisaccade, which requires one to suppress an automatic eye movement (a prosaccade) to a visual stimulus, and execute a voluntary eye movement in the opposite direction. Antisaccade deficits are similar to those seen in task switching, whereby one is required to change a response after performing a different behavior. Both antisaccade (Hood et al., 2007) and task switching (Cools, Barker, Sahakian, & Robbins, 2001) deficits in PD have been attributed to fronto-basal ganglia (BG) dysfunction. Previously, we demonstrated with functional magnetic resonance imaging that BG circuitry is important to both task switching and voluntary saccade generation, as greater caudate activation was seen when healthy young adults first prepared a prosaccade, but then switched to an antisaccade (Cameron, Coe, et al., 2009). Therefore, we hypothesized that PD patients would have difficulty switching from one saccade response to the other, with particular impairment in switching from a pro to an antisaccade. Here, we not only confirmed this prediction, but also showed that PD patients performed better than controls in switching from an anti to a prosaccade. This suggests that task switching deficits in PD are particularly pronounced when more automatic behavior needs to be overridden with alternative behavior. We suggest that this occurs primarily at the level of establishing the appropriate task set, which is an internalized rule that governs how to respond.

Color is important for segmenting objects from backgrounds, which can in turn facilitate visual search in complex scenes. However, brain areas involved in orienting the eyes toward colored stimuli in our environment are not believed to have access to color information. Here, we show that neurons in the intermediate layers of the monkey superior colliculus (SC), a critical structure for the production of saccadic eye movements, can respond to isoluminant color stimuli with the same magnitude as a maximum contrast luminance stimulus. In contrast, neurons from the superficial SC layers showed little color-related activity. Crucially, visual onset latencies were 30–35 ms longer for color, implying that luminance and chrominance information reach the SC through distinct pathways and that the observed color-related activity is not the result of residual luminance signals. Furthermore, these differences in visual onset latency translated directly into differences in saccadic reaction time. The results demonstrate that the saccadic system can signal the presence of chromatic stimuli only one stage from the brainstem premotor circuitry that drives the eyes.

Contains fulltext : 75710.pdf (Publisher’s version ) (Closed access) In a previous study we quantified the effect of multisensory integration on the latency and accuracy of saccadic eye movements toward spatially aligned audiovisual (AV) stimuli within a rich AV-background (Corneil et al. in J Neurophysiol 88:438-454, 2002). In those experiments both stimulus modalities belonged to the same object, and subjects were instructed to foveate that source, irrespective of modality. Under natural conditions, however, subjects have no prior knowledge as to whether visual and auditory events originated from the same, or from different objects in space and time. In the present experiments we included these possibilities by introducing various spatial and temporal disparities between the visual and auditory events within the AV-background. Subjects had to orient fast and accurately to the visual target, thereby ignoring the auditory distractor. We show that this task belies a dichotomy, as it was quite difficult to produce fast responses (