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We combined fMRI with eye tracking and speech recording to examine the neural and cognitive mechanisms that underlie reading. To simplify the study of the complex processes involved during reading, we used naming speed (NS) tasks (also known as rapid automatized naming or RAN) as a focus for this study, in which average reading right-handed adults named sets of stimuli (letters or objects) as quickly and accurately as possible. Due to the possibility of spoken output during fMRI studies creating motion artifacts, we employed both an overt session and a covert session. When comparing the two sessions, there were no significant differences in behavioral performance, sensorimotor activation (except for regions involved in the motor aspects of speech production) or activation in regions within the left-hemisphere-dominant neural reading network. This established that differences found between the tasks within the reading network were not attributed to speech production motion artifacts or sensorimotor processes. Both behavioral and neuroimaging measures showed that letter naming was a more automatic and efficient task than object naming. Furthermore, specific manipulations to the NS tasks to make the stimuli more visually and/or phonologically similar differentially activated the reading network in the left hemisphere associated with phonological, orthographic and orthographic-to-phonological processing, but not articulatory/motor processing related to speech production. These findings further our understanding of the underlying neural processes that support reading by examining how activation within the reading network differs with both task performance and task characteristics.

The removal of a fixation point (FP) prior to the appearance of a saccade target (gap effect) influences pre-motor circuits and reduces saccadic reaction time (SRT). Saccade preparation signals underlying the gap effect have been observed within the intermediate layers of the superior colliculus (SCi). Neurons in the caudal SCi, coding a target location, increase their activity during the gap, while neurons in the rostral SCi, with tonic activity related to visual fixation, decrease activity. However, the gap effect confounds two factors: (1) a goal-driven temporal warning component (upcoming saccade target appearance) and (2) a stimulus-driven sensory component (FP disappearance). These factors combine to reduce SRT and elicit pre-target responses in the SCi. To dissociate warning and sensory effects, we altered the luminance of the FP during the gap period (renamed warning period) such that it could increase, decrease, or stay the same. Faster SRTs resulted with larger decrements in FP luminance. Different categories of SCi warning period activity were evaluated: (1) always increasing or decreasing or (2) sensory-linked responses to changes in FP luminance. In the caudal SCi (at the location coding the target), all activity correlated negatively with SRT (i.e., saccade facilitation), and two categories of activity were observed (always increasing or opposing FP luminance changes). In the rostral SCi, four categories of activity were observed: activity that increased or followed the change in FP luminance correlated positively with SRT (i.e., saccade inhibition), while activity that decreased or opposed FP luminance changes correlated negatively with SRT. Such SCi activity reflected both goal-driven saccade preparation signals and FP sensory properties.

Pupil size reflects a proxy for neural activity associated with global luminance, arousal, and cognitive processing. Microsaccades are also modulated by arousal and cognitive processing. Are these effects of arousal and cognitive signals on pupil size and microsaccades coordinated? If so, via what neural mechanisms? We hypothesized that if pupil size and microsaccades are coordinately modulated by these processes, pupil size immediately before microsaccade onset, as an index for ongoing cognitive and arousal processing, should correlate with microsaccade responses during tasks alternating these signals. Here, we examined the relationship between pupil size and microsaccade responses in tasks that included variations in global luminance, arousal, and inhibitory control. Higher microsaccade peak velocities correlated with larger pre-microsaccade pupil response related to arousal and inhibitory control signals. In contrast, pupil responses evoked by global luminance signals did not correlate with microsaccade responses. Given the central role of the superior colliculus in microsaccade generation, these results suggest the critical involvement of the superior colliculus to coordinate pupil and microsaccade responses for arousal and inhibitory control modulations, but not for the pupil luminance modulation.

The pupil responds to a salient stimulus appearing in the environment, in addition to its modulation by global luminance. These pupillary responses can be evoked by visual or auditory stimuli, scaled with stimulus salience, and enhanced by multisensory presentation. In addition, pupil size is modulated by various visual stimulus attributes, such as color, area, and motion. However, research that concurrently examines the influence of different factors on pupillary responses is limited. To explore how presentation of multiple visual stimuli influences human pupillary responses, we presented arrays of visual stimuli and systematically varied their luminance, color, and set size. Saliency level, computed by the saliency model, systematically changed with set size across all conditions, with higher saliency levels in larger set sizes. Pupillary constriction responses were evoked by the appearance of visual stimuli, with larger pupillary responses observed in larger set size. These effects were pronounced even though the global luminance level was unchanged using isoluminant chromatic stimuli. Furthermore, larger pupillary constriction responses were obtained in the blue, compared to other color conditions. Together, we argue that both cortical and subcortical areas contribute to the observed pupillary constriction modulated by set size and color.

Emerging evidence indicates that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), can cause neurological complications. We provide a brief overview of these recent observations and discuss some of their possible implications. In particular, given the global dimension of the current pandemic, we highlight the need to consider the possible long-term impact of COVID-19, potentially including neurological and neurodegenerative disorders.

When presented with a periodic stimulus, humans spontaneously adjust their movements from reacting to predicting the timing of its arrival, but little is known about how this sensorimotor adaptation changes across development. To investigate this, we analyzed saccade behavior in 114 healthy humans (ages 6–24 years) performing the visual metronome task, who were instructed to move their eyes in time with a visual target that alternated between two known locations at a fixed rate, and we compared their behavior to performance in a random task, where target onsets were randomized across five interstimulus intervals (ISIs) and thus the timing of appearance was unknown. Saccades initiated before registration of the visual target, thus in anticipation of its appearance, were labeled predictive [saccade reaction time (SRT) < 90 ms] and saccades that were made in reaction to its appearance were labeled reactive (SRT > 90 ms). Eye-tracking behavior including saccadic metrics (e.g., peak velocity, amplitude), pupil size following saccade to target, and blink behavior all varied as a function of predicting or reacting to periodic targets. Compared with reactive saccades, predictive saccades had a lower peak velocity, a hypometric amplitude, smaller pupil size, and a reduced probability of blink occurrence before target appearance. The percentage of predictive and reactive saccades changed inversely from ages 8–16, at which they reached adult-levels of behavior. Differences in predictive saccades for fast and slow target rates are interpreted by differential maturation of cerebellar-thalamic-striatal pathways.SIGNIFICANCE STATEMENTFrom the first moments of life, humans are exposed to rhythm (i.e., mother's heartbeatin utero), but the timeline of brain development to promote the identification and anticipation of a rhythmic stimulus, known as temporal prediction, remains unknown. Here, we used saccade reaction time (SRT) in the visual metronome task to differentiate between temporally predictive and reactive responses to a target that alternated at a fixed rate in humans aged 6–24. Periods of age-related change varied little by target rate, with matured predictive performance evident by mid-adolescence for fast and slow rates. A strong correlation among saccade, pupil, and blink responses during target prediction provides evidence of oculomotor coordination and dampened noradrenergic neuronal activity when generating rhythmic motor responses.

Background The lack of effective treatments for Alzheimer’s disease (AD) reflects an incomplete understanding of disease mechanisms. Alterations in proteins involved in mitochondrial dynamics, an essential process for mitochondrial integrity and function, have been reported in AD brains. Impaired mitochondrial dynamics causes mitochondrial dysfunction and has been associated with cognitive impairment in AD. Here, we investigated a possible link between pro-inflammatory interleukin-1 (IL-1), mitochondrial dysfunction, and cognitive impairment in AD models. Methods We exposed primary hippocampal cell cultures to amyloid-β oligomers (AβOs) and carried out AβO infusions into the lateral cerebral ventricle of cynomolgus macaques to assess the impact of AβOs on proteins that regulate mitochondrial dynamics. Where indicated, primary cultures were pre-treated with mitochondrial division inhibitor 1 (mdivi-1), or with anakinra, a recombinant interleukin-1 receptor (IL-1R) antagonist used in the treatment of rheumatoid arthritis. Cognitive impairment was investigated in C57BL/6 mice that received an intracerebroventricular (i.c.v.) infusion of AβOs in the presence or absence of mdivi-1. To assess the role of interleukin-1 beta (IL-1β) in AβO-induced alterations in mitochondrial proteins and memory impairment, interleukin receptor-1 knockout (Il1r1−/−) mice received an i.c.v. infusion of AβOs. Results We report that anakinra prevented AβO-induced alteration in mitochondrial dynamics proteins in primary hippocampal cultures. Altered levels of proteins involved in mitochondrial fusion and fission were observed in the brains of cynomolgus macaques that received i.c.v. infusions of AβOs. The mitochondrial fission inhibitor, mdivi-1, alleviated synapse loss and cognitive impairment induced by AβOs in mice. In addition, AβOs failed to cause alterations in expression of mitochondrial dynamics proteins or memory impairment in Il1r1−/− mice. Conclusion These findings indicate that IL-1β mediates the impact of AβOs on proteins involved in mitochondrial dynamics and that strategies aimed to prevent pathological alterations in those proteins may counteract synapse loss and cognitive impairment in AD.

Impulsivity and emotional dysregulation are two core features of borderline personality disorder (BPD), and the neural mechanisms recruited during mixed-strategy interactions overlap with frontolimbic networks that have been implicated in BPD. We investigated strategic choice patterns during the classic two-player game, Matching Pennies, where the most efficient strategy is to choose each option randomly from trial-to-trial to avoid exploitation by one’s opponent. Twenty-seven female adolescents with BPD (mean age: 16 years) and twenty-seven age-matched female controls (mean age: 16 years) participated in an experiment that explored the relationship between strategic choice behavior and impulsivity in both groups and emotional dysregulation in BPD. Relative to controls, BPD participants showed marginally fewer reinforcement learning biases, particularly decreased lose-shift biases, increased variability in reaction times (coefficient of variation; CV), and a greater percentage of anticipatory decisions. A subset of BPD participants with high levels of impulsivity showed higher overall reward rates, and greater modulation of reaction times by outcome, particularly following loss trials, relative to control and BPD participants with lower levels of impulsivity. Additionally, BPD participants with higher levels of emotional dysregulation showed marginally increased reward rate and increased entropy in choice patterns. Together, our preliminary results suggest that impulsivity and emotional dysregulation may contribute to variability in mixed-strategy decision-making in female adolescents with BPD.

Eye movement desensitization and reprocessing (EMDR), a form of psychotherapy for individuals with post-traumatic stress disorder (PTSD), has long been a controversial topic, hampered in part by a lack of understanding of the neural mechanisms that contribute to its remedial effect. Here, we review current theories describing EMDR's potential neurobiological mechanisms of action involving working memory, interhemispheric communication, de-arousal, and memory reconsolidation. We then discuss recent studies describing the temporal and spatial aspects of smooth pursuit and predictive saccades, which resemble those made during EMDR, and their neural correlates within the default mode network (DMN) and cerebellum. We hypothesize that if the production of bilateral predictive eye movements is supportive of DMN and cerebellum activation, then therapies that shift the brain towards this state correspondingly would benefit the processes regulated by these structures (i.e., memory retrieval, relaxation, and associative learning), all of which are essential components for PTSD recovery. We propose that the timing of sensory stimulation may be relevant to treatment effect and could be adapted across different patients depending on their baseline saccade metrics. Empirical data in support of this model are reviewed and experimental predictions are discussed.

During competitive interactions, such as predator-prey or team sports, the outcome of one's actions is dependent on both their own choices and those of their opponents. Success in these rivalries requires that individuals choose dynamically and unpredictably, often adopting a mixed strategy. Understanding the neural basis of strategic decision making is complicated by the fact that it recruits various cognitive processes that are often shared with non-strategic forms of decision making, such as value estimation, working memory, response inhibition, response selection, and reward processes. Although researchers have explored neural activity within key brain regions during mixed-strategy games, how brain activity differs in the context of strategic interactions versus non-strategic choices is not well understood. We developed a novel behavioral paradigm to dissociate choice behavior during mixed-strategy interactions from non-strategic choices, and we used task-based functional magnetic resonance imaging (fMRI) to contrast brain activation. In a block design, participants competed in the classic mixed-strategy game, "matching pennies," against a dynamic computer opponent designed to exploit predictability in players' response patterns. Results were contrasted with a non-strategic task that had comparable sensory input, motor output, and reward rate; thus, differences in behavior and brain activation reflect strategic processes. The mixed-strategy game was associated with activation of a distributed cortico-striatal network compared to the non-strategic task. We propose that choosing in mixed-strategy contexts requires additional cognitive demands present to a lesser degree during the control task, illustrating the strength of this design in probing function of cognitive systems beyond core sensory, motor, and reward processes.

The saliency map has played a long-standing role in models and theories of visual attention, and it is now supported by neurobiological evidence from several cortical and subcortical brain areas. While visual saliency is computed during moments of active fixation, it is not known whether the same is true while engaged in smooth pursuit of a moving stimulus, which is very common in real-world vision. Here, we examined extrafoveal saliency coding in the superior colliculus, a midbrain area associated with attention and gaze, during smooth pursuit eye movements. We found that SC neurons from the superficial visual layers showed a robust representation of peripheral saliency evoked by a conspicuous stimulus embedded in a wide-field array of goal-irrelevant stimuli. In contrast, visuomotor neurons from the intermediate saccade-related layers showed a poor saliency representation, even though most of these neurons were visually responsive during smooth pursuit. These results confirm and extend previous findings that place the SCs in a unique role as a saliency map that monitors peripheral vision during foveation of stationary and now moving objects.

Recent advances in movement neuroscience have consistently highlighted that the nervous system performs sophisticated feedback control over very short time scales (

A salient stimulus can trigger a coordinated orienting response consisting of a saccade, pupil, and microsaccadic responses. Saliency models predict that the degree of visual conspicuity of all visual stimuli guides visual orienting. By presenting a multiple-item array that included an oddball colored item (pop-out), randomly mixed colored items (mixed-color), or single-color items (single-color), we examined the effects of saliency and priority (saliency + relevancy) on pupil size and microsaccade responses. Larger pupil responses were produced in the pop-out compared to the mixed-color or single-color conditions after stimulus presentation. However, the saliency modulation on microsaccades was not significant. Furthermore, although goal-relevancy information did not modulate pupil responses and microsaccade rate, microsaccade direction was biased toward the pop-out item when it was the subsequent saccadic target. Together, our results demonstrate saliency modulation on pupil size and priority effects on microsaccade direction during visual pop-out.

The pupil constricts or dilates in response to a luminance increase or decrease, and these transient pupillary responses are controlled by the parasympathetic and sympathetic pathways. Although pupillary responses of the two eyes are highly correlated, they are not always identical (referred to as anisocoria). For example, there are unequal direct and consensual pupillary constriction responses after an increase in luminance to one eye. While contraction anisocoria (i.e. constriction) has been demonstrated in the pupillary light reflex, it is not yet known if there is also dilation anisocoria in the pupillary darkness reflex. Unlike previous studies that focused on the pupillary light reflex, we examined response anisocoria in both pupillary light and darkness reflexes. While requiring participants to maintain central fixation, we presented a light or dark stimulus to either the right or left visual field to induce transient pupillary constriction or dilation. Both the pupillary light and darkness reflexes had significantly larger ipsilateral responses compared to the contralateral responses relative to the stimulated visual field. The observed ipsilateral effects occurred significantly faster in the light than darkness reflex, suggesting that larger ipsilateral pupillary dilation after a luminance decrease cannot be only attributed to the inhibition of the parasympathetic system, but is also mediated by the excitation of the sympathetic system. Together, our results demonstrated a larger ipsilateral pupil response in both the pupillary light and darkness reflex, indicating an asymmetry in ipsilateral and contralateral neural circuitry of the pupillary darkness reflex.

The ability to generate flexible behaviors to accommodate changing goals in response to identical sensory stimuli is a signature that is inherited in humans and higher-level animals. In the oculomotor system, this function has often been examined with the anti-saccade task, in which subjects are instructed, prior to stimulus appearance, to either automatically look at the peripheral stimulus (pro-saccade) or to suppress the automatic response and voluntarily look in the opposite direction from the stimulus (anti-saccade). Distinct neural preparatory activity between the pro-saccade and anti-saccade conditions has been well documented, particularly in the superior colliculus (SC) and the frontal eye field (FEF), and this has shown higher inhibition-related fixation activity in preparation for anti-saccades than in preparation for pro-saccades. Moreover, the level of preparatory activity related to motor preparation is negatively correlated with reaction times. We hypothesised that preparatory signals may be reflected in pupil size through a link between the SC and the pupil control circuitry. Here, we examined human pupil dynamics during saccade preparation prior to the execution of pro-saccades and anti-saccades. Pupil size was larger in preparation for correct anti-saccades than in preparation for correct pro-saccades and erroneous pro-saccades made in the anti-saccade condition. Furthermore, larger pupil dilation prior to stimulus appearance accompanied saccades with faster reaction times, with a trial-by-trial correlation between dilation size and anti-saccade reaction times. Overall, our results demonstrate that pupil size is modulated by saccade preparation, and neural activity in the SC, together with the FEF, supports these findings, providing unique insights into the neural substrate coordinating cognitive processing and pupil diameter.

Background The association of cognitive and motor impairments in Alzheimer's disease and other neurodegenerative diseases is thought to be related to damage in the common brain networks shared by cognitive and cortical motor control processes. These common brain networks play a pivotal role in selecting movements and postural synergies that meet an individual's needs. Pathology in this "highest level" of motor control produces abnormalities of gait and posture referred to as highest-level gait disorders. Impairments in cognition and mobility, including falls, are present in almost all neurodegenerative diseases, suggesting common mechanisms that still need to be unraveled. Objective To identify motor-cognitive profiles across neurodegenerative diseases in a large cohort of patients. Methods Cohort study that includes up to 500 participants, followed every year for three years, across five neurodegenerative disease groups: Alzheimer's disease/mild cognitive impairment, frontotemporal degeneration, vascular cognitive impairment, amyotrophic lateral sclerosis, and Parkinson's disease. Gait and balance will be assessed using accelerometers and electronic walkways, evaluated at different levels of cognitive and sensory complexity, using the dual-task paradigm. Results Comparison of cognitive and motor performances across neurodegenerative groups will allow the identification of motor-cognitive phenotypes through the standardized evaluation of gait and balance characteristics. Conclusions As part of the Ontario Neurodegenerative Research Initiative (ONDRI), the gait and balance platform aims to identify motor-cognitive profiles across neurodegenerative diseases. Gait assessment, particularly while dual-tasking, will help dissect the cognitive and motor contribution in mobility and cognitive decline, progression to dementia syndromes, and future adverse outcomes including falls and mortality.

International audience; 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 agematched 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.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and a major medical problem. Here, we have investigated the impact of amyloid-β (Aβ) oligomers, AD-related neurotoxins, in the brains of rats and adult nonhuman primates (cynomolgus macaques). Soluble Aβ oligomers are known to accumulate in the brains of AD patients and correlate with disease-associated cognitive dysfunction. When injected into the lateral ventricle of rats and macaques, Aβ oligomers diffused into the brain and accumulated in several regions associated with memory and cognitive functions. Cardinal features of AD pathology, including synapse loss, tau hyperphosphorylation, astrocyte and microglial activation, were observed in regions of the macaque brain where Aβ oligomers were abundantly detected. Most importantly, oligomer injections induced AD-type neurofibrillary tangle formation in the macaque brain. These outcomes were specifically associated with Aβ oligomers, as fibrillar amyloid deposits were not detected in oligomer-injected brains. Human and macaque brains share significant similarities in terms of overall architecture and functional networks. Thus, generation of a macaque model of AD that links Aβ oligomers to tau and synaptic pathology has the potential to greatly advance our understanding of mechanisms centrally implicated in AD pathogenesis. Furthermore, development of disease-modifying therapeutics for AD has been hampered by the difficulty in translating therapies that work in rodents to humans. This new approach may be a highly relevant nonhuman primate model for testing therapeutic interventions for AD.

The sudden appearance of a novel stimulus initiates a series of responses to orient the body for appropriate actions, including not only shifts of gaze and attention, but also transient pupil dilation. Modulation of pupil dynamics by stimulus properties is less understood, although its effects on other components of orienting have been extensively explored. Microstimulation of the superior colliculus evoked transient pupil dilation, and the initial component of pupil dilation evoked by microstimulation was similar to that elicited by the presentation of salient sensory stimuli, suggesting a coordinated role of the superior colliculus on this behavior, although evidence in humans is yet to be established. To examine pupil orienting responses in humans, we presented visual stimuli while participants fixated on a central visual spot. Transient pupil dilation in humans was elicited after presentation of a visual stimulus in the periphery. The evoked pupil responses were modulated systematically by stimulus contrast, with faster and larger pupil responses triggered by higher contrast stimuli. The pupil response onset latencies for high contrast stimuli were similar to those produced by the light reflex and significantly faster than the darkness reflex, suggesting that the initial component of pupil dilation is probably mediated by inhibition of the parasympathetic pathway. The contrast modulation was pronounced under different levels of baseline pupil size. Together, our results demonstrate visual contrast modulation on the orienting pupil response in humans.

A distributed network of cortical and subcortical brain areas controls our oculomotor behavior. This network includes the superior colliculus (SC), which coordinates an ancient visual grasp reflex via outputs that ramify widely within the brainstem and spinal cord, accessing saccadic and other premotor and autonomic circuits. In this Review, we discuss recent results correlating subliminal SC activity in the absence of saccades with diverse components of the visual grasp reflex, including neck and limb muscle recruitment, pupil dilation, and microsaccade propensity. Such subtle manifestations of covert orienting are accessible in the motor periphery and may provide the next generation of oculomotor biomarkers in health and disease.

The sudden appearance of a novel stimulus in the environment initiates a series of orienting responses that include coordinated shifts of gaze and attention, and also transient changes in pupil size. Although numerous studies have identified a significant effect of stimulus saliency on shifts of gaze and attention, saliency effects on pupil size are less understood. To examine salience-evoked pupil responses, we presented visual, auditory, or audiovisual stimuli while monkeys fixated a central visual spot. Transient pupil dilation was elicited after visual stimulus presentation regardless of target luminance relative to background, and auditory stimuli also evoked similar pupil responses. Importantly, the evoked pupil response was modulated by contrast-based saliency, with faster and larger pupil responses following the presentation of more salient stimuli. The initial transient component of pupil dilation was qualitatively similar to that evoked by weak microstimulation of the midbrain superior colliculus. The pupil responses elicited by audiovisual stimuli were well predicted by a linear summation of each modality response. Together, the results suggest that the transient pupil response, as one component of orienting, is modulated by contrast-based saliency, and the superior colliculus is likely involved in its coordination.

Signals from different sensory modalities are integrated in the brain to optimize behavior. Although multisensory integration has been demonstrated in saccadic eye movements, its influence on other orienting responses, including pupil size and microsaccades, is still poorly understood. We examined human gaze orienting responses following presentation of visual, auditory, or combined audiovisual stimuli. Transient pupil dilation and microsaccade inhibition were evoked shortly after the appearance of a salient stimulus. Audiovisual stimuli evoked larger pupil dilation, greater microsaccade inhibition, and faster saccade reaction times compared to unimodal conditions. Trials with faster saccadic reaction times were accompanied with greater pupil dilation responses. Similar modulation of pre-stimulus pupil-size-change rate was observed between stimulus-evoked saccadic and pupillary responses. Thus, multisensory integration impacts multiple components of orienting, with coordination between saccade and pupil responses, implicating the superior colliculus in coordinating these responses because of its central role in both orienting behavior and multisensory integration.

Electrical stimulation has been delivered to the basal ganglia (BG) to treat intractable symptoms of a variety of clinical disorders. However, it is still unknown how such treatments improve behavioral symptoms. A difficulty of this problem is that artificial signals created by electrical stimulation interact with intrinsic signals before influencing behavior, thereby making it important to understand how such interactions between artificial and intrinsic signals occur. We addressed this issue by analyzing the effects of electrical stimulation under the following two behavioral conditions that induce different states of intrinsic signals: 1) subjects behave spontaneously without task demands; and 2) subjects perform a behavioral paradigm purposefully. We analyzed saccadic eye movements in monkeys while delivering microstimulation to the head and body of the caudate nucleus, a major input stage of the oculomotor BG. When monkeys generated spontaneous saccades, caudate microstimulation biased saccade vector endpoints toward the contralateral direction of stimulation sites. However, when caudate microstimulation was delivered during a purposive prosaccade (look toward a visual stimulus) or an antisaccade (look away from a stimulus) paradigm, it created overall ipsilateral biases by suppressing contralateral saccades more strongly than ipsilateral saccades. These results suggest that the impact of BG electrical stimulation changes dynamically depending on the state of intrinsic signals that vary under a variety of behavioral demands in everyday life.

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.

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 basal ganglia (BG) are a group of subcortical structures involved in diverse functions, such as motor, cognition and emotion. However, the BG do not control these functions directly, but rather modulate functional processes occurring in structures outside the BG. The BG form multiple functional loops, each of which controls different functions with similar architectures. Accordingly, to understand the modulatory role of the BG, it is strategic to uncover the mechanisms of signal processing within specific functional loops that control simple neural circuits outside the BG, and then extend the knowledge to other BG loops. The saccade control system is one of the best-understood neural circuits in the brain. Furthermore, sophisticated saccade paradigms have been used extensively in clinical research in patients with BG disorders as well as in basic research in behaving monkeys. In this review, we describe recent advances of BG research from the viewpoint of saccade control. Specifically, we account for experimental results from neuroimaging and clinical studies in humans based on the updated knowledge of BG functions derived from neurophysiological experiments in behaving monkeys by taking advantage of homologies in saccade behavior. It has become clear that the traditional BG network model for saccade control is too limited to account for recent evidence emerging from the roles of subcortical nuclei not incorporated in the model. Here, we extend the traditional model and propose a new hypothetical framework to facilitate clinical and basic BG research and dialogue in the future.

Eye movement recordings are useful for assessing neurological disorders, the prevalence of which increases with age. However, there is little rigorous quantitative data on describing oculomotor changes that occur during healthy aging. Here, we measured the ability of 81 normal elderly subjects (60-85 years) to perform two saccadic eye movement tasks: a pro-saccade task, requiring an automatic response to look towards a stimulus and an anti-saccade task, requiring inhibition of the automatic response to instead initiate a voluntary saccade away from the stimulus. Saccadic ability decreased with age: the oldest subjects were slower to initiate saccades and they made more direction errors (i.e., erroneous pro-saccades) in the anti-saccade task. Intra-subject variability in reaction time also correlated positively with age in both saccade tasks. Voluntary saccade control, as assessed by the anti-saccade task, was far more affected by aging than automatic control, as assessed by the pro-saccade task, suggesting that the mechanisms driving voluntary and automatic saccade performance deteriorate at different rates in the aging brain, and therefore likely involves different neural substrates. Our data provide insight into deficits due to normal brain changes in aging as well as a baseline to evaluate deficits caused by neurological disorders common in this age range.

Previous studies have demonstrated that humans are sometimes capable of initiating arm movements towards visual stimuli at extremely short latencies, implying the presence of a short-latency neural pathway linking visual input to limb motor output. However, little is known about the neural mechanisms that underlie such hastened arm responses. One clue may come from recent demonstrations that the appearance of a visual target can elicit a rapid response in neck muscles that is time-locked to target appearance and functionally relevant for orienting gaze (head and eye) towards the target. Because oculomotor structures thought to contribute to ‘visual responses’ on neck muscles also target some arm muscles via a tecto-reticulo-spinal pathway, we hypothesized that a similar visual response would be present in arm muscles. Our results were consistent with this hypothesis as we observed the presence of rapid arm muscle activity (< 100 ms latency) that was time-locked to target appearance and not movement onset. We further found that the visual response in arm muscles: (i) was present only when an immediate reach towards the target was required; (ii) had a magnitude that was predictive of reaction time; (iii) was tuned to target location in a manner appropriate for moving the arm towards the target; and (iv) was more prevalent in shoulder muscles than elbow muscles. These results provide evidence for a rapid neural pathway linking visual input to arm motor output and suggest the presence of a common neural mechanism for hastening eye, head and arm movements.

The basal ganglia (BG) have been considered as a key structure for volitional action preparation. Neurons in the striatum, the main BG input stage, increase activity gradually before volitional action initiation. However, because of the diversity of striatal motor commands, such as automatic (sensory driven) and volitional (internally driven) actions, it is still unclear whether an appropriate set of neurons encoding volitional actions are activated selectively for volitional action preparation. Here, using the antisaccade paradigm (look away from a visual stimulus), we dissociated neurons in the caudate nucleus, the oculomotor striatum, encoding predominantly automatic saccades toward the stimulus and volitional saccades in the opposite direction of the stimulus in monkeys. We found that before actual saccade directions were defined by visual stimulus appearance, neurons encoding volitional saccades increased activity with elapsed time from fixation initiation and by a temporal gap between fixation point disappearance and stimulus appearance. Their activity was further enhanced by an antisaccade instruction and correlated with antisaccade behavior. Neurons encoding automatic saccades also increased activity with elapsed time from fixation initiation and by a fixation gap. However, the activity of this type of neuron was not enhanced by an antisaccade instruction nor correlated with antisaccade behavior. We conclude that caudate neurons integrate nonspatial signals, such as elapsed time from fixation initiation, fixation gap, and task instructions, to preset BG circuits in favor of volitional actions to compete against automatic actions even before automatic and volitional commands are programmed with spatial information.

It has been suggested that the caudate nucleus, the input stage of the basal ganglia, facilitates and suppresses saccade initiation based on its anatomical characteristics. Although the involvement of the caudate nucleus in saccade facilitation has been shown previously, it is still unclear whether the caudate nucleus is also involved in saccade suppression. Here, we revealed the direct involvement of the caudate nucleus in saccade suppression by electrical microstimulation in behaving monkeys. We delivered microstimulation to the caudate nucleus while monkeys performed the prosaccade (look toward a peripheral visual stimulus) and antisaccade (look away from the stimulus) paradigm. The reaction times of contralateral saccades were prolonged on both prosaccade and antisaccade trials. The suppression effects on reaction times were stronger on prosaccade trials compared with antisaccade trials. The analysis of reaction time distributions using the linear approach to threshold with ergodic rate model (LATER model) revealed that microstimulation prolonged reaction times by reducing the rate of rise to the threshold for saccade initiation. Microstimulation also worsened correct performance rates for contralateral saccades. The same microstimulation prolonged and/or shortened the reaction times of ipsilateral saccades, although the effects were not as consistent as those on contralateral saccades. We conclude that caudate signals are sufficient to suppress contralateral saccades and influence saccadic decision by controlling contralateral and ipsilateral saccade commands at the same time.

Saccadic reaction times (SRT) are composed of the sum of multiple processes, including bottom-up sensory processing, top-down goal oriented processing, and afferent and efferent conduction delays. In order to determine the timing dependencies and potential interactions between bottom-up and top-down processes on SRTs, we trained monkeys to perform several variants of visually guided saccade tasks. Bottom-up components of SRT were manipulated by varying target luminance from near detection threshold to supra-threshold ranges (i.e., 0.001-42.5 cd/m(2)). There was a significant reduction of mean SRT with increases in target luminance up to 3.5-17.5 cd/m(2). Luminance increases above these ranges produced significant increases in SRT when the target was within 6 degrees from the fovea. Top-down components were assessed by manipulating spatial target predictability across blocks of trials using either 1, 2, 4 or 8 possible target locations. Decreasing spatial target predictability increased SRT across target luminances from 1 to 4 targets in the gap task, but then paradoxically decreased SRT again when there were 8 possible targets in both the gap and step tasks. Finally, a gap task (200 ms gap) was used to determine the dependence of target luminance on the magnitude of the gap effect. Decreasing target luminance significantly reduced the magnitude of the gap effect indicating that the gap effect is strongly influenced by bottom-up factors.

The ability to perform an appropriate response in the presence of competing alternatives is a critical facet of human behavioral control. This is especially important if a response is prepared for execution but then has to be changed suddenly. A popular hypothesis of basal ganglia (BG) function suggests that its direct and indirect pathways could provide a neural mechanism to rapidly switch from one planned response to an alternative. However, if one response is more dominant or 'automatic' than the other, the BG might have a different role depending on switch direction. We built upon the pro- and antisaccade tasks, two models of automatic and voluntary behavior, respectively, and investigated whether the BG are important for switching any planned response in general, or if they are more important for switching from a more automatic response to a response that is more difficult to perform. Subjects prepared either a pro- or antisaccade but then had to switch it unexpectedly on a subset of trials. The results revealed increased striatal activation for switching from a pro- to an antisaccade but this did not occur for switching from an anti- to a prosaccade. This activation pattern depended on the relative difficulty in switching, and it was distinct from frontal eye fields, an area shown to be more active for antisaccade trials than for prosaccade trials. This suggests that the BG are important for compensating for differences in response difficulty, facilitating the rapid switching of one response for another.

A salient event in the environment can initiate a complex orienting response that includes a shift in gaze. The midbrain superior colliculus (SC) contains the appropriate circuitry to generate and distribute a signal of the priority of this event, and co-ordinate the orienting response. The magnitude and timing of the short-latency transient visual response in the SC, when combined with cortical inputs signaling stimulus relevance and expectation, influences the type and latency of the orienting response. This signal in the SC is distributed to higher cortical areas to influence visual processing, to the reinforcement learning system to influence future actions, and to premotor circuits, including neck and shoulder muscles, to influence immediate action.

Huntington's disease (HD), a progressive neurological disorder involving degeneration in basal ganglia structures, leads to abnormal control of saccadic eye movements. We investigated whether saccadic impairments in HD (N = 9) correlated with clinical disease severity to determine the relationship between saccadic control and basal ganglia pathology. HD patients and age/sex-matched controls performed various eye movement tasks that required the execution or suppression of automatic or voluntary saccades. In the "immediate" saccade tasks, subjects were instructed to look either toward (pro-saccade) or away from (anti-saccade) a peripheral stimulus. In the "delayed" saccade tasks (pro-/anti-saccades; delayed memory-guided sequential saccades), subjects were instructed to wait for a central fixation point to disappear before initiating saccades towards or away from a peripheral stimulus that had appeared previously. In all tasks, mean saccadic reaction time was longer and more variable amongst the HD patients. On immediate anti-saccade trials, the occurrence of direction errors (pro-saccades initiated toward stimulus) was higher in the HD patients. In the delayed tasks, timing errors (eye movements made prior to the go signal) were also greater in the HD patients. The increased variability in saccadic reaction times and occurrence of errors (both timing and direction errors) were highly correlated with disease severity, as assessed with the Unified Huntington's Disease Rating Scale, suggesting that saccadic impairments worsen as the disease progresses. Thus, performance on voluntary saccade paradigms provides a sensitive indicator of disease progression in HD.

When observers initiate responses to visual targets, they do so sooner when a preceding stimulus indicates that the target will appear shortly. This consequence of a warning signal may change neural activity in one of four ways. On the sensory side, the warning signal may speed up the rate at which the target is registered by the brain or enhance the magnitude of its signal. On the motor end, the warning signal may lower the threshold required to initiate a response or speed up the rate at which activity accumulates to reach threshold. Here, we describe which explanation is better supported. To accomplish this end, monkeys performed different versions of a cue-target task while we monitored the activity of visuomotor and motor neurons in the superior colliculus. Although the cue target task was designed to measure the properties of reflexive spatial attention, there are two events in this task that produce nonspecific warning effects: a central reorienting event (brightening of central fixation marker) that is used to direct attention away from the cue, and the presentation of the cue itself. Monopolizing on these tendencies, we show that warning effects are associated with several changes in neural activity: the target-related response is enhanced, the threshold for initiating a saccade is lowered, and the rate at which activity accumulates toward threshold rises faster. Ultimately, the accumulation of activity toward threshold predicted behavior most closely. In the discussion, we describe the implications and limitations of these data for theories of warning effects and potential avenues for future research.

Express saccades represent the fastest possible eye movements to visual targets with reaction times that approach minimum sensory-motor conduction delays. Previous work in monkeys has identified two specific neural signals in the superior colliculus (SC: a midbrain sensorimotor integration structure involved in gaze control) that are required to execute express saccades: 1) previsual activity consisting of a low-frequency increase in action potentials in sensory-motor neurons immediately before the arrival of a visual response; and 2) a transient visual-sensory response consisting of a high-frequency burst of action potentials in visually responsive neurons resulting from the appearance of a visual target stimulus. To better understand how these two neural signals interact to produce express saccades, we manipulated the arrival time and magnitude of visual responses in the SC by altering target luminance and we examined the corresponding influences on SC activity and express saccade generation. We recorded from saccade neurons with visual-, motor-, and previsual-related activity in the SC of monkeys performing the gap saccade task while target luminance was systematically varied between 0.001 and 42.5 cd/m2 against a black background (∼0.0001 cd/m2). Our results demonstrated that 1) express saccade latencies were linked directly to the arrival time in the SC of visual responses produced by abruptly appearing visual stimuli; 2) express saccades were generated toward both dim and bright targets whenever sufficient previsual activity was present; and 3) target luminance altered the likelihood of producing an express saccade. When an express saccade was generated, visuomotor neurons increased their activity immediately before the arrival of the visual response in the SC and saccade initiation. Furthermore, the visual and motor responses of visuomotor neurons merged into a single burst of action potentials, while the visual response of visual-only neurons was unaffected. A linear combination model was used to test which SC signals best predicted the likelihood of producing an express saccade. In addition to visual response magnitude and previsual activity of saccade neurons, the model identified presaccadic activity (activity occurring during the 30-ms epoch immediately before saccade initiation) as a third important signal for predicting express saccades. We conclude that express saccades can be predicted by visual, previsual, and presaccadic signals recorded from visuomotor neurons in the intermediate layers of the SC.

As we have limited processing abilities with respect to the plethora of visual information entering our brain, spatial selection mechanisms are crucial. These mechanisms result in both enhancing processing at a location of interest and in suppressing processing at other locations; together, they enable successful further processing of locations of interest. It has been suggested that saccade planning modulates these spatial selection mechanisms; however, the precise influence of saccades on the distribution of spatial resources underlying selection remains unclear. To this end, we compared discrimination performance at different locations (six) within a work space during different saccade tasks. We used visual discrimination performance as a behavioral measure of enhancement and suppression at the different locations. A total of 14 participants performed a dual discrimination/saccade countermanding task, which allowed us to specifically isolate the consequences of saccade execution. When a saccade was executed, discrimination performance at the cued location was never better than when fixation was maintained, suggesting that saccade execution did not enhance processing at a location more than knowing the likelihood of its appearance. However, discrimination was consistently lower at distractor (uncued) locations in all cases where a saccade was executed compared with when fixation was maintained. Based on these results, we suggest that saccade execution specifically suppresses distractor locations, whereas attention shifts (with or without an accompanying saccade) are involved in enhancing perceptual processing at the goal location.

The intermediate layers of the superior colliculus (SC) contain neurons that clearly play a major role in regulating the production of saccadic eye movements: a burst of activity from saccade neurons (SNs) is thought to provide a drive signal to set the eyes in motion, whereas the tonic activity of fixation neurons (FNs) is thought to suppress saccades during fixation. The exact contribution of these neurons to saccade control is, however, unclear because the nature of the signals sent by the SC to the brain stem saccade generation circuit has not been studied in detail. Here we tested the hypothesis that the SC output signal is sufficient to control saccades by examining whether antidromically identified tectoreticular neurons (TRNs: 33 SNs and 13 FNs) determine the end of saccades. First, TRNs had discharge properties similar to those of nonidentified SC neurons and a proportion of output SNs had visually evoked responses, which signify that the saccade generator must receive and process visual information. Second, only a minority of TRNs possessed the temporal patterns of activity sufficient to terminate saccades: Output SNs did not cease discharging at the time of saccade end, possibly continuing to drive the brain stem during postsaccadic fixations, and output FNs did not resume their activity before saccade end. These results argue against a role for SC in regulating the timing of saccade termination by a temporal code and suggest that other saccade centers act to thwart the extraneous SC drive signal, unless it controls saccade termination by a spatial code.

Performance in a reaction time task can be strongly influenced by the physical properties of the stimuli used (e.g., position and intensity). The reduction in reaction time observed with higher-intensity visual stimuli has been suggested to arise from reduced processing time along the visual pathway. If this hypothesis is correct, activity should be registered in neurons sooner for higher-intensity stimuli. We evaluated this hypothesis by measuring the onset of neural activity in the intermediate layers of the superior colliculus while monkeys generated saccades to high or low-intensity visual stimuli. When stimulus intensity was high, the response onset latency was significantly reduced compared to low-intensity stimuli. As a result, the minimum time for visually triggered saccades was reduced, accounting for the shorter saccadic reaction times (SRTs) observed following high-intensity stimuli. Our results establish a link between changes in neural activity related to stimulus intensity and changes to SRTs, which supports the hypothesis that shorter SRTs with higher-intensity stimuli are due to reduced processing time.

Pupil size, as a component of orienting, changes rapidly in response to local salient events in the environment, in addition to its well-known illumination-dependent modulation. Recent research has shown that visual, auditory, or audiovisual stimuli can elicit transient pupil dilation, and the timing and size of the evoked responses are systematically modulated by stimulus salience. Moreover, weak microstimulation of the superior colliculus (SC), a midbrain structure involved in eye movements and attention, evokes similar transient pupil dilation, suggesting that the SC coordinates the orienting response which includes transient pupil dilation. Projections from the SC to the pupil control circuitry provide a novel neural substrate underlying pupil modulation by various cognitive processes.

Variation in response latency to identical sensory stimuli has been attributed to variation in neural activity mediating preparatory set. Here we report evidence for a relationship between saccadic reaction time (SRT) and set-related brain activity measured with event-related functional magnetic resonance imaging. We measured hemodynamic activation time-courses during a preparatory “gap” period, during which no visual stimulus was present and no saccades were made. The subjects merely anticipated appearance of the target. Saccade direction and latency were recorded during scanning, and trials were sorted according to SRT. Both the frontal (FEF) and supplementary eye fields showed pretarget preparatory activity, but only in the FEF was this activity correlated with SRT. Activation in the intraparietal sulcus did not show any preparatory activity. These data provide evidence that the human FEF plays a central role in saccade initiation; pretarget activity in this region predicts both the type of eye movement (whether the subject will look toward or away from the target) and when a future saccade will occur.

Express saccades promote the acquisition of visual targets at extremely short reaction times. Because of the head's considerable inertia, it is unknown whether express saccades are accompanied by a parallel command to the head. Here, by recording electromyographic (EMG) activity from monkey neck muscles, we demonstrate that visual target presentation elicits time-locked, lateralized recruitment of neck muscles at extremely short latencies (55–95 ms). Remarkably, such recruitment not only accompanies express saccades, but also precedes nonexpress saccades, occasionally by up to 150 ms. These results demonstrate selective gating of components of descending commands from the superior colliculus to prevent express saccades yet permit recruitment of a head orienting synergy. We conclude that such selective gating aids eye-head coordination by permitting force development at neck muscles while a decision to commit to a gaze shift is being made, optimizing the contribution of the more inertial head to the ensuing gaze shift.

Reflexively orienting toward a peripheral cue can influence subsequent responses to a target, depending on when and where the cue and target appear relative to each other. At short delays between the cue and target [cue-target onset asynchrony (CTOA)], subjects are faster to respond when they appear at the same location, an effect referred to as reflexive attentional capture. At longer CTOAs, subjects are slower to respond when the two appear at the same location, an effect referred to as inhibition of return (IOR). Recent evidence suggests that these phenomena originate from sensory interactions between the cue- and target-related responses. The capture of attention originates from a strong target-related response, derived from the overlap of the cue- and target-related activities, whereas IOR corresponds to a weaker target-aligned response. If such interactions are responsible, then modifying their nature should impact the neuronal and behavioral outcome. Monkeys performed a cue-target saccade task featuring visual and auditory cues while neural activity was recorded from the superior colliculus (SC). Compared with visual stimuli, auditory responses are weaker and occur earlier, thereby decreasing the likelihood of interactions between these signals. Similar to previous studies, visual stimuli evoked reflexive attentional capture at a short CTOA (60 ms) and IOR at longer CTOAs (160 and 610 ms) with corresponding changes in the target-aligned activity in the SC. Auditory cues used in this study failed to elicit either a behavioral effect or modification of SC activity at any CTOA, supporting the hypothesis that reflexive orienting is mediated by sensory interactions between the cue and target stimuli.

The anti-saccade task has emerged as an important task for investigating the flexible control that we have over behaviour. In this task, participants must suppress the reflexive urge to look at a visual target that appears suddenly in the peripheral visual field and must instead look away from the target in the opposite direction. A crucial step involved in performing this task is the top-down inhibition of a reflexive, automatic saccade. Here, we describe recent neurophysiological evidence demonstrating the presence of this inhibitory function in single-cell activity in the frontal eye fields and superior colliculus. Patients diagnosed with various neurological and/or psychiatric disorders that affect the frontal lobes or basal ganglia find it difficult to suppress the automatic pro-saccade, revealing a deficit in top-down inhibition.

Neurons in the intermediate and deep layers of the superior colliculus (SC) often exhibit sensory-related activity in addition to discharging for saccadic eye movements. These two patterns of activity can combine so that modifications of the sensory response can lead to changes in orienting behaviour. Can behavioural factors, however, influence sensory activity? In this study of rhesus monkeys, we isolate one behavioural factor, the state of visual fixation, and examine its influences on sensory processing and multisensory integration in the primate SC. Two interleaved fixation conditions were used: a FIX condition requiring exogenous fixation of a visible fixation point; and a FIX-BLINK condition, requiring endogenous fixation in the absence of a visible fixation point. Neurons of the SC were influenced by fixation state, exhibiting both lower levels of sensory activity and reduced multisensory interactions when fixation was exogenously engaged on a visible fixation point. These results are consistent with active visual fixation suppressing responses to extraneous stimuli, and thus demonstrate that sensory processing and multisensory responses in the SC are not dependent solely on the physical properties of the sensory environment, but are also dynamically influenced by the behavioural state of the animal.

Children with attention-deficit hyperactivity disorder (ADHD) are impulsive, and that impulsiveness can be measured using a countermanding task. Although the overt behaviors of ADHD attenuate with age, it is not clear how well impulsiveness is controlled in adults with ADHD. We tested ADHD adults with an oculomotor countermanding task. The task included two conditions: on 75% of the trials, participants viewed a central fixation marker and then looked to an eccentric target that appeared simultaneous with the disappearance of the fixation marker; on 25% of the trials, a signal was presented at variable delays after target appearance. The signal instructed subjects to stop, or countermand, an eye movement to the target. A correct movement in this case would be to hold gaze at the central fixation location. We expected ADHD participants to be impulsive in their countermanding performance. Additionally, we expected that a visual stop signal at the central fixation location would assist oculomotor countermanding because the signal is presented in the "stop" location, at fixation. To test whether a central stop signal positively biased countermanding, we used a three types of stop signal to instruct the stop: a central visual marker, a peripheral visual signal, and a non-localized sound. All subjects performed best with the central visual stop signal. Subjects with ADHD were less able to countermand eye movements and were influenced more negatively by the non-central signals. Oculomotor countermanding may be useful for quantifying impulsive dysfunction in adults with ADHD especially if a non-central stop signal is applied.

The attentional blink paradigm tests attention by overloading it: a list of stimuli is presented very rapidly one after another at the same location on a computer screen, each item overwriting the last, and participants monitor the list using two criteria [e.g. detect the target (red letter) and identify the probe (letter p)]. If the interval between the target and the probe is greater than about 500 ms, both are usually reported correctly, but, when the interval between the target and the probe is within 200-500 ms, report of the probe declines. This decline is the attentional blink, an interval of time when attention is supposedly switching from the first criterion to the second. The attentional blink paradigm should be difficult to perform correctly without vigilantly attending to the rapidly presented list. Vigilance tasks are often used to assess attention-deficit hyperactivity disorder (ADHD). Symptoms of the disorder include hyperactivity and attentional dysfunction; however, some people with ADHD also have difficulty maintaining gaze at a fixed location. We tested 15 adults with ADHD and their age- and sex-matched controls, measuring accuracy and gaze stability during the attentional blink task. ADHD participants reported fewer targets and probes, took longer to recover from the attentional blink, made more eye movements, and made identification errors consistent with non-perception of the letter list. In contrast, errors made by control participants were consistent with guessing (i.e., report of a letter immediately preceding or succeeding the correct letter). Excessive eye movements result in poorer performance for all participants; however, error patterns confirm that the weak performance of ADHD participants may be related to gaze instability as well as to attentional dysfunction.

Attention-deficit hyperactivity disorder (ADHD) is characterized by the overt symptoms of impulsiveness, hyperactivity, and inattention. A frontostriatal pathophysiology has been hypothesized to produce these symptoms and lead to reduced ability to inhibit unnecessary or inappropriate behavioral responses. Oculomotor tasks can be designed to probe the ability of subjects to generate or inhibit reflexive and voluntary responses. Because regions of the frontal cortex and basal ganglia have been identified in the control of voluntary responses and saccadic suppression, we hypothesized that children and adults diagnosed with ADHD may have specific difficulties in oculomotor tasks requiring the suppression of reflexive or unwanted saccadic eye movements. To test this hypothesis, we measured eye movement performance in pro- and anti-saccade tasks of 114 ADHD and 180 control participants ranging in age from 6 to 59 yr. In the pro-saccade task, participants were instructed to look from a central fixation point toward an eccentric visual target. In the anti-saccade task, stimulus presentation was identical, but participants were instructed to suppress the saccade to the stimulus and instead look from the central fixation point to the side opposite the target. The state of fixation was manipulated by presenting the target either when the central fixation point was illuminated (overlap condition) or at some time after it disappeared (gap condition). In the pro-saccade task, ADHD participants had longer reaction times, greater intra-subject variance, and their saccades had reduced peak velocities and increased durations. In the anti-saccade task, ADHD participants had greater difficulty suppressing reflexive pro-saccades toward the eccentric target, increased reaction times for correct anti-saccades, and greater intra-subject variance. In a third task requiring prolonged fixation, ADHD participants generated more intrusive saccades during periods when they were required to maintain steady fixation. The results suggest that ADHD participants have reduced ability to suppress unwanted saccades and control their fixation behavior voluntarily, a finding that is consistent with a fronto-striatal pathophysiology. The findings are discussed in the context of recent neurophysiological data from nonhuman primates that have identified important control signals for saccade suppression that emanate from frontostriatal circuits.

In tasks that are designed to explore cognitive functioning, the response on each trial is a function of the combination of experimental conditions that occurred on that and the previous trial. Because the previous trial influences performance, the event presented during or the action required by the previous trial must leave an imprint on the brain's activity that carries through to the next trial. These imprints are manifest in the activity of single neurons that participate in producing the response. Previous trial effects address disparate cognitive phenomena, such as response priming, task switching and inhibition of return, and the neural bases of previous trial effects can be envisioned as changes in salience of the target or the goal of the action on a spatial map.