Age related prefrontal compensatory mechanisms for inhibitory control in the antisaccade task.

Cognitive decline during aging includes impairments in frontal executive functions like reduced inhibitory control. However, decline is not uniform across the population, suggesting individual brain response variability to the aging process. Here we tested the hypothesis, within the oculomotor system, that older adults compensate for age-related neural alterations by changing neural activation levels of the oculomotor areas, or even by recruiting additional areas to assist with cognitive performance. We established that the observed changes had to be related to better cognitive performance to be considered as compensatory. To probe this hypothesis we used the antisaccade paradigm and analyzed the effect of aging on brain activations during the inhibition of prepotent responses to visual stimuli. While undergoing a fMRI scan with concurrent eye tracking, 25 young adults (21.7 y/o ± 1.9 SDM) and 25 cognitively normal older adults (66.2 y/o ± 9.8 SDM) performed an interleaved pro/antisaccade task consisting of a preparatory stage and an execution stage. Compared to young adults, older participants showed a larger increase in antisaccade reaction times, while also generating more antisaccade direction errors. BOLD signal analyses during the preparatory stage, when response inhibition processes are established to prevent an automatic response, showed decreased activations in the anterior cingulate and the supplementary eye fields in the older group. Moreover, older adults also showed additional recruitment of the frontal pole not seen in the younger group, and larger activations in the dorsolateral prefrontal cortex during antisaccade preparation. Additional analyses to address the performance variability in the older group showed distinct behavioral-BOLD signal correlations. Larger activations in the saccade network, including the frontal pole, positively correlated with faster antisaccade reaction times, suggesting a functional recruitment of this area. However, only the activation in the dorsolateral prefrontal cortex during the antisaccade events showed a negative correlation with the number of errors across older adults. These findings support the presence of two dissociable age-related plastic mechanisms that result in different behavioral outcomes. One related to the additional recruitment of neural resources within anterior pole to facilitate modulation of cognitive responses like faster antisaccade reaction times, and another related to increased activation of the dorsolateral prefrontal cortex resulting in a better inhibitory control in aging.

Development and learning of saccadic eye movements in 7- to 42-month-old children.

From birth, infants move their eyes to explore their environment, interact with it, and progressively develop a multitude of motor and cognitive abilities. The characteristics and development of oculomotor control in early childhood remain poorly understood today. Here, we examined reaction time and amplitude of saccadic eye movements in 93 7- to 42-month-old children while they oriented toward visual animated cartoon characters appearing at unpredictable locations on a computer screen over 140 trials. Results revealed that saccade performance is immature in children compared to a group of adults: Saccade reaction times were longer, and saccade amplitude relative to target location (10° eccentricity) was shorter. Results also indicated that performance is flexible in children. Although saccade reaction time decreased as age increased, suggesting developmental improvements in saccade control, saccade amplitude gradually improved over trials. Moreover, similar to adults, children were able to modify saccade amplitude based on the visual error made in the previous trial. This second set of results suggests that short visual experience and/or rapid sensorimotor learning are functional in children and can also affect saccade performance.

Cognitive deterioration and functional compensation in ALS measured with fMRI using an inhibitory task.

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons, resulting in progressive weakness and muscle atrophy. Recent studies suggest that nondemented ALS patients can show selective cognitive impairments, predominantly executive dysfunction, but little is known about the neural basis of these impairments. Oculomotor studies in ALS have described deficits in antisaccade execution, which requires the implementation of a task set that includes inhibition of automatic responses followed by generation of a voluntary action. It has been suggested that the dorsolateral prefrontal cortex (DLPFC) contributes in this process. Thus, we investigated whether deterioration of executive functions in ALS patients, such as the ability to implement flexible behavior during the antisaccade task, is related to DLPFC dysfunction. While undergoing an fMRI scan, 12 ALS patients and 12 age-matched controls performed an antisaccade task with concurrent eye tracking. We hypothesized that DLPFC deficits would appear during the antisaccade preparation stage, when the task set is being established. ALS patients made more antisaccade direction errors and showed significant reductions in DLPFC activation. In contrast, regions, such as supplementary eye fields and frontal eye fields, showed increased activation that was anticorrelated with the number of errors. The ALS group also showed reduced saccadic latencies that correlated with increased activation across the oculomotor saccade system. These findings suggest that ALS results in deficits in the inhibition of automatic responses that are related to impaired DLPFC activation. However, they also suggest that ALS patients undergo functional changes that partially compensate the neurological impairment.

Developmental improvements in voluntary control of behavior: effect of preparation in the fronto-parietal network?

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, 18-25years) 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.

Impaired executive function signals in motor brain regions in Parkinson's disease.

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.

Distractor-induced saccade trajectory curvature reveals visual contralateral bias with respect to the dominant eye.

The functional consequences of the visual system lateralization referred to as "eye dominance" remain poorly understood. We previously reported shorter hand reaction times for targets appearing in the contralateral visual hemifield with respect to the dominant eye (DE). Here, we further explore this contralateral bias by studying the influence of laterally placed visual distractors on vertical saccade trajectories, a sensitive method to assess visual processing. In binocular conditions, saccade trajectory curvature was larger toward a distractor placed in the contralateral hemifield with respect to the DE (e.g., in the left visual hemifield for a participant with a right dominant eye) than toward one presented in the ipsilateral hemifield (in the right visual hemifield in our example). When two distractors were present at the same time, the vertical saccade showed curvature toward the contralateral side. In monocular conditions, when one distractor was presented, a similar larger influence of the contralateral distractor was observed only when the viewing eye was the DE. When the non dominant eye (NDE) was viewing, curvature was symmetric for both distractor sides. Interestingly, this curvature was as large as the one obtained for the contralateral distractor when the DE was viewing, suggesting that eye dominance consequences rely on inhibition mechanisms present when the DE is viewing. Overall, these results demonstrate that DE influences visual integration occurring around saccade production and support a DE-based contralateral visual bias.

Dorsolateral prefrontal cortex hyperactivity during inhibitory control in children with ADHD in the antisaccade task.

Children with ADHD show significant deficits in response inhibition. A leading hypothesis suggests prefrontal hypoactivation as a possible cause, though, there is conflicting evidence. We tested the hypoactivation hypothesis by analyzing the response inhibition process within the oculomotor system. Twenty-two children diagnosed with ADHD and twenty control (CTRL) children performed the antisaccade task while undergoing an fMRI study with concurrent eye tracking. This task included a preparatory stage that cued a prosaccade (toward a stimuli) or an antisaccade (away from a stimuli) without an actual presentation of a peripheral target. This allowed testing inhibitory control without the confounding activation from an actual response. The ADHD group showed longer reaction times and more antisaccade direction errors. While both groups showed activations in saccade network areas, the ADHD showed significant hyperactivation in the dorsolateral prefrontal cortex during the preparatory stage. No other areas in the saccade network had significant activation differences between groups. Further ADHD group analysis OFF and ON stimulant medication did not show drug-related activation differences. However, they showed a significant correlation between the difference in OFF/ON preparatory activation in the precuneus, and a decrease in the number of antisaccade errors. These results do not support the hypoactivity hypothesis as an inhibitory control deficit general explanation, but instead suggest less efficiency during the inhibitory period of the antisaccade task in children. Our findings contrast with previous results in ADHD adults showing decreased preparatory antisaccade activity, suggesting a significant age-dependent maturation effect associated to the inhibitory response in the oculomotor system.

Spatial transfer of adaptation of scanning voluntary saccades in humans.

The properties and neural substrates of the adaptive mechanisms that maintain over time the accuracy of voluntary, internally triggered saccades are still poorly understood. Here, we used transfer tests to evaluate the spatial properties of adaptation of scanning voluntary saccades. We found that an adaptive reduction of the size of a horizontal rightward 7 degrees saccade transferred to other saccades of a wide range of amplitudes and directions. This transfer decreased as tested saccades increasingly differed in amplitude or direction from the trained saccade, being null for vertical and leftward saccades. Voluntary saccade adaptation thus presents bounded, but large adaptation fields, suggesting that at least part of the underlying neural substrate encodes saccades as vectors.

Oculomotor plasticity: are mechanisms of adaptation for reactive and voluntary saccades separate?

Saccadic eye movements are permanently controlled and their accuracy maintained by adaptive mechanisms that compensate for physiological or pathological perturbations. In contrast to the adaptation of reactive saccades (RS) which are automatically triggered by the sudden appearance of a single target, little is known about the adaptation of voluntary saccades which allow us to intentionally scan our environment in nearly all our daily activities. In this study, we addressed this issue in human subjects by determining the properties of adaptation of scanning voluntary saccades (SVS) and comparing these features to those of RS. We also tested the reciprocal transfers of adaptation between the two saccade types. Our results revealed that SVS and RS adaptations disclosed similar adaptation fields, time course and recovery levels, with only a slightly lower after-effect for SVS. Moreover, RS and SVS main sequences both remained unaffected after adaptation. Finally and quite unexpectedly, the pattern of adaptation transfers was asymmetrical, with a much stronger transfer from SVS to RS (79%) than in the reverse direction (22%). These data demonstrate that adaptations of RS and SVS share several behavioural properties but at the same time rely on partially distinct processes. Based on these findings, it is proposed that adaptations of RS and SVS may involve a neural network including both a common site and two separate sites specifically recruited for each saccade type.

Asymmetry in visual information processing depends on the strength of eye dominance.

Unlike handedness, sighting eye dominance, defined as the eye unconsciously chosen when performing monocular tasks, is very rarely considered in studies investigating cerebral asymmetries. We previously showed that sighting eye dominance has an influence on visually triggered manual action with shorter reaction time (RT) when the stimulus appears in the contralateral visual hemifield with respect to the dominant eye (Chaumillon et al. 2014). We also suggested that eye dominance may be more or less pronounced depending on individuals and that this eye dominance strength could be evaluated through saccadic peak velocity analysis in binocular recordings (Vergilino-Perez et al. 2012). Based on these two previous studies, we further examine here whether the strength of the eye dominance can modulate the influence of this lateralization on manual reaction time. Results revealed that participants categorized as having a strong eye dominance, but not those categorized as having a weak eye dominance, exhibited the difference in RT between the two visual hemifields. This present study reinforces that the analysis of saccade peak velocity in binocular recordings provides an effective tool to better categorize the eye dominance. It also shows that the influence of eye dominance in visuo-motor tasks depends on its strength. Our study also highlights the importance of considering the strength of eye dominance in future studies dealing with brain lateralization.

Saccadic Adaptation in 10-41 Month-Old Children.

When saccade amplitude becomes systematically inaccurate, adaptation mechanisms gradually decrease or increase it until accurate saccade targeting is recovered. Adaptive shortening and adaptive lengthening of saccade amplitude rely on separate mechanisms in adults. When these adaptation mechanisms emerge during development is poorly known except that adaptive shortening processes are functional in children above 8 years of age. Yet, saccades in infants are consistently inaccurate (hypometric) as if adaptation mechanisms were not fully functional in early childhood. Here, we tested reactive saccade adaptation in 10-41 month-old children compared to a group of 20-30 year-old adults. A visual target representing a cartoon character appeared at successive and unpredictable locations 10° apart on a computer screen. During the eye movement toward the target, it systematically stepped in the direction opposite to the saccade to induce an adaptive shortening of saccade amplitude (Experiment 1). In Experiment 2, the target stepped in the same direction as the ongoing saccade to induce an adaptive lengthening of saccade amplitude. In both backward and forward adaptation experiments, saccade adaptation was compared to a control condition where there was no intrasaccadic target step. Analysis of baseline performance revealed both longer saccade reaction times and hypometric saccades in children compared to adults. In both experiments, children on average showed gradual changes in saccade amplitude consistent with the systematic intrasaccadic target steps. Moreover, the amount of amplitude change was similar between children and adults for both backward and forward adaptation. Finally, adaptation abilities in our child group were not related to age. Overall the results suggest that the neural mechanisms underlying reactive saccade adaptation are in place early during development.

Retention of saccadic adaptation in humans.

In the present study, we tested in human subjects the persistence of the oculomotor changes resulting from saccadic adaptation up to 19 days after exposure to the double step target protocol. The main results indicate that the reduction of saccade gain related to the adaptation session (mean gain change of 5 subjects = 22 +/- 4.7%) was partially but significantly retained after 1 day and 5 days (mean amount of retention = 36 +/- 17% and 19.7 +/- 13.3%, respectively) but was no longer significant at day 11 and 19. Unexpectedly, gain changes were larger for leftward than for rightward saccades. No change in saccade dynamics was observed. These data suggest that in humans, adaptive mechanisms induce long lasting changes in visually-guided saccade amplitude, probably reflecting plastic changes in the brain.

Eye position specificity of saccadic adaptation.

PURPOSE: The accuracy of saccadic eye movements is maintained throughout life by adaptive mechanisms. With the double-step target paradigm, eight human subjects were investigated to determine whether saccadic adaptation depends only on the eye-displacement vector, or also on eye position as a context cue when two saccades of identical vector are adapted simultaneously. METHODS: First, bidirectional adaptations (BDAs) of horizontal saccades of the same vector were induced in a single training phase. Each direction of adaptation in BDAs (backward and forward) was linked to one vertical eye position (e.g., forward adaptation performed with the eyes directed 12.5 degrees upward and backward adaptation with the eyes 25 degrees downward) and alternated from trial to trial. Second, unidirectional adaptations (UDAs) were tested in two control conditions in which training trials of a single direction (backward or forward) were presented at both 12.5 degrees and -25 degrees eye elevations. RESULTS: Opposite changes in saccade amplitude could develop simultaneously in BDA, indicating that saccadic adaptation depends on orbital eye position. Comparing these data with the control conditions further indicated that eye position specificity was complete for backward, but not for forward, adaptation. CONCLUSIONS: The results indicate that saccadic adaptation mechanisms use vectorial eye displacement signals, but can also take eye position signals into account as a contextual cue when the training involves conflicting saccade amplitude changes.

Adaptation of saccadic eye movements: transfer and specificity.

The present study was designed to test whether the adaptation of saccadic eye movements depends only on the eye displacement vector of the trained saccade or also on eye position information. Using the double-step target paradigm in eight human subjects, we first induced in a single session two "opposite directions adaptations" (ODA) of horizontal saccades of the same vector. Each ODA (backward or forward) was linked to one vertical eye position (12.5 degrees up or 25 degrees down) and alternated from trial to trial. The results showed that opposite changes of saccade amplitude can develop simultaneously, indicating that saccadic adaptation depends on orbital eye position. This finding has important functional implications because in everyday life our eyes saccade from constantly changing orbital positions. A comparison of these data to two control conditions in which training trials of a single type (backward or forward) were presented at both 12.5 degrees and -25 degrees eye elevations further indicated that eye position specificity is complete for backward, but not for forward, adaptation. Finally, the control conditions also indicated that the adaptation of a single saccade fully transferred to untrained saccades of the same vector, but initiated from different vertical eye positions. In conclusion, our study indicates that saccadic adaptation mechanisms use vectorial eye displacement signals, but can also take eye position signals into account as a contextual cue when the training involves conflicting saccade amplitude changes.

Preparatory neural networks are impaired in adults with attention-deficit/hyperactivity disorder during the antisaccade task.

Adults with attention-deficit/hyperactivity disorder (ADHD) often display executive function impairments, particularly in inhibitory control. The antisaccade task, which measures inhibitory control, requires one to suppress an automatic prosaccade toward a salient visual stimulus and voluntarily make an antisaccade in the opposite direction. ADHD patients not only have longer saccadic reaction times, but also make more direction errors (i.e., a prosaccade was executed toward the stimulus) during antisaccade trials. These deficits may stem from pathology in several brain areas that are important for executive control. Using functional MRI with a rapid event-related design, adults with combined subtype of ADHD (coexistence of attention and hyperactivity problems), who abstained from taking stimulant medication 20 h prior to experiment onset, and age-match controls performed pro- and antisaccade trials that were interleaved with pro- and anti-catch trials (i.e., instruction was presented but no target appeared, requiring no response). This method allowed us to examine brain activation patterns when participants either prepared (during instruction) or executed (after target appearance) correct pro or antisaccades. Behaviorally, ADHD adults displayed several antisaccade deficits, including longer and more variable reaction times and more direction errors, but saccade metrics (i.e., duration, velocity, and amplitude) were normal. When preparing to execute an antisaccade, ADHD adults showed less activation in frontal, supplementary, and parietal eye fields, compared to controls. However, activation in these areas was normal in the ADHD group during the execution of a correct antisaccade. Interestingly, unlike controls, adults with ADHD produced greater activation than controls in dorsolateral prefrontal cortex during antisaccade execution, perhaps as part of compensatory mechanisms to optimize antisaccade production. Overall, these data suggest that the saccade deficits observed in adults with ADHD do not result from an inability to execute a correct antisaccade but rather the failure to properly prepare (i.e., form the appropriate task set) for the antisaccade trial. The data support the view that the executive impairments, including inhibitory control, in ADHD adults are related to poor response preparation.

Adaptation of voluntary saccades, but not of reactive saccades, transfers to hand pointing movements.

Studying the transfer of visuomotor adaptation from a given effector (e.g., the eye) to another (e.g., the hand) allows us to question whether sensorimotor processes influenced by adaptation are common to both effector control systems and thus to address the level where adaptation takes place. Previous studies have shown only very weak transfer of the amplitude adaptation of reactive saccades--i.e., produced automatically in response to the sudden appearance of visual targets--to hand pointing movements. Here we compared the amplitude of hand pointing movements recorded before and after adaptation of either reactive or voluntary saccades, produced either in a saccade sequence task or in a single saccade task. No transfer to hand pointing movements was found after adaptation of reactive saccades. In contrast, a substantial transfer to the hand was obtained following adaptation of voluntary saccades produced in sequence. Large amounts of transfer between the two saccade types were also found. These results demonstrate that the visuomotor processes influenced by saccadic adaptation depend on the type of saccades and that, in the case of voluntary saccades, they are shared by hand pointing movements. Implications for the neurophysiological substrates of the adaptation of reactive and voluntary saccades are discussed.

Long-lasting modifications of saccadic eye movements following adaptation induced in the double-step target paradigm.

The adaptation of saccadic eye movements to environmental changes occurring throughout life is a good model of motor learning and motor memory. Numerous studies have analyzed the behavioral properties and neural substrate of oculomotor learning in short-term saccadic adaptation protocols, but to our knowledge, none have tested the persistence of the oculomotor memory. In the present study, the double-step target protocol was used in five human subjects to adaptively decrease the amplitude of reactive saccades triggered by a horizontally-stepping visual target. We tested the amplitude of visually guided saccades just before and at different times (up to 19 days) after the adaptation session. The results revealed that immediately after the adaptation session, saccade amplitude was significantly reduced by 22% on average. Although progressively recovering over days, this change in saccade gain was still statistically significant on days 1 and 5, with an average retention rate of 36% and 19%, respectively. On day 11, saccade amplitude no longer differed from the pre-adaptation value. Adaptation was more effective and more resistant to recovery for leftward saccades than for rightward ones. Lastly, modifications of saccade gain related to adaptation were accompanied by a decrease of both saccade duration and peak velocity. A control experiment indicated that all these findings were specifically related to the adaptation protocol, and further revealed that no change in the main sequence relationships could be specifically related to adaptation. We conclude that in humans, the modifications of saccade amplitude that quickly develop during a double-step target adaptation protocol can remain in memory for a much longer period of time, reflecting enduring plastic changes in the brain.

Self-generated saccades do not modify the gain of adapted reactive saccades.

The gain of reactive saccades was manipulated in 17 subjects using a target-jump paradigm. Following adaptation three sub-groups were formed: (1) rest 15 min in the dark, eyes closed; (2) perform self-generated saccades for 15 min; (3) perform reactive saccades for 15 min. The series of saccades were the same in groups 2 and 3 (amplitude, sequence), except that group 3 performed fewer saccades (same number as the lowest number of saccades performed by one subject in group 2). Neither the rest period nor the series of self-generated saccades affected the adapted gain. The series of reactive saccades generated, by contrast, quick de-adaptation. These results support the conclusion that the gain of self-generated and reactive saccades is independently controlled.

Transfer of adaptation from visually guided saccades to averaging saccades elicited by double visual targets.

The adaptive mechanisms that control the amplitude of visually guided saccades (VGS) are only partially elucidated. In this study, we investigated, in six human subjects, the transfer of VGS adaptation to averaging saccades elicited by the simultaneous presentation of two visual targets. The generation of averaging saccades requires the transformation of two representations encoding the desired eye displacement toward each of the two targets into a single representation encoding the averaging saccade (averaging programming site). We aimed to evaluate whether VGS adaptation acts upstream (hypothesis 1) or at/below (hypothesis 2) the level of averaging saccades programming. Using the double-step target paradigm, we simultaneously induced a backward adaptation of 17.5 degrees horizontal VGS and a forward adaptation of 17.5 degrees oblique VGS performed along the +/- 40 degrees directions relative to the azimuth. We measured the effects of this dual adaptation protocol on averaging saccades triggered by two simultaneous targets located at 17.5 degrees along the +/- 40 degrees directions. To increase the yield of averaging saccades, we instructed the subjects to move their eyes as fast as possible to an intermediate position between the two targets. We found that the amplitude of averaging saccades was smaller after VGS adaptation than before and differed significantly from that predicted by hypothesis 1, but not by hypothesis 2, with an adaptation transfer of 50%. These findings indicate that VGS adaptation largely occurs at/below the averaging saccade programming site. Based on current knowledge of the neural substrate of averaging saccades, we suggest that VGS adaptation mainly acts at the level of the superior colliculus or downstream.