Compromised reactive but intact proactive inhibitory motor control in Tourette disorder.

Tourette disorder (TD) is characterized by tics, which are sudden repetitive involuntary movements or vocalizations. Deficits in inhibitory control in TD patients remain inconclusive from the traditional method of estimating the ability to stop an impending action, which requires careful interpretation of a metric derived from race model. One possible explanation for these inconsistencies is that race model's assumptions of independent and stochastic rise of GO and STOP process to a fixed threshold are often violated, making the classical metric to assess inhibitory control less robust. Here, we used a pair of metrics derived from a recent alternative model to address why stopping performance in TD is unaffected despite atypical neural circuitry. These new metrics distinguish between proactive and reactive inhibitory control and estimate them separately. When these metrics in adult TD group were contrasted with healthy controls (HC), we identified robust deficits in reactive control, but not in proactive control in TD. The TD group exhibited difficulty in slowing down the speed of movement preparation, which they rectified by their intact ability to postpone the movement.

Pupil dynamics: A potential proxy of neural preparation for goal-directed eye movement.

The pupils reflexively constrict or dilate to regulate the influx of light on the retinae. Pupillary light reflex (PLR) is susceptible to many non-visual cognitive processes including covert orientation of attention and planning rapid saccadic eye movement. The frontal eye field (FEF) and superior colliculus (SC), which also send projections to the PLR pathway, are two important areas in primate's brain for planning saccade and orientation of attention. The saccadic reaction time (SRT) and the rate of increase in activity of movement neurons in these areas are inversely correlated. This study addressed how pupil dynamics, activity in the FEF and SC and SRT are related in a saccadic decision-making task. The rate of visually evoked pupil constriction was found inversely related to SRT. This was further verified by simulating a homeomorphic biomechanical model of pupillary muscle plants, wherein we projected signals similar to build-up activity in the FEF and SC to the parasympathetic (constriction) and sympathetic (dilation) division of the PLR pathway, respectively. A striking similarity between simulated and observed dynamics of pupil constriction suggests that PLR is a potential proxy of saccade planning by movement neurons in the FEF and SC. Indistinguishable pupil dynamics when planned saccades were elicited versus when they were cancelled eliminated the possibility that the obligatory pre-saccadic shift of attention alone influenced the rate of pupil constriction. Our study envisages a mechanism of how the oculomotor system influences the autonomic activity in an attempt to timely minimize saccadic visual transients by regulating the influx of light.

Influence of the Location of a Decision Cue on the Dynamics of Pupillary Light Response.

The pupils of the eyes reflexively constrict in light and dilate in dark to optimize retinal illumination. Non-visual cognitive factors, like attention, arousal, decision-making, etc., also influence pupillary light response (PLR). During passive viewing, the eccentricity of a stimulus modulates the pupillary aperture size driven by spatially weighted corneal flux density (CFD), which is the product of luminance and the area of the stimulus. Whether the scope of attention also influences PLR remains unclear. In this study, we contrasted the pupil dynamics between diffused and focused attentional conditions during decision-making, while the global CFD remained the same in the two conditions. A population of 20 healthy humans participated in a pair of forced choice tasks. They distributed attention to the peripheral decision cue in one task, and concentrated at the center in the other to select the target from four alternatives for gaze orientation. The location of this cue did not influence participants' reaction time (RT). However, the magnitude of constriction was significantly less in the task that warranted attention to be deployed at the center than on the periphery. We observed similar pupil dynamics when participants either elicited or canceled a saccadic eye movement, which ruled out pre-saccadic obligatory attentional orientation contributing to PLR. We further addressed how the location of attentional deployment might have influenced PLR. We simulated a biomechanical model of PLR with visual stimulation of different strengths as inputs corresponding to the two attentional conditions. In this homeomorphic model, the computational characteristic of each element was derived from the physiological and/or mechanical properties of the corresponding biological element. The simulation of this model successfully mimicked the observed data. In contrast to common belief that the global ambient luminosity drives pupillary response, the results of our study suggest that the effective CFD (eCFD) determined via the luminance multiplied by the size of the stimulus at the location of deployed attention in the visual space is critical for the magnitude of pupillary constriction.

Efficacy of inhibitory control depends on procrastination and deceleration in saccade planning.

A goal-directed flexible behavior warrants our ability to timely inhibit impending movements deemed inappropriate due to an abrupt change in the context. Race model of countermanding rapid saccadic eye movement posits a competition between a preparatory GO process and an inhibitory STOP process rising to reach a fixed threshold. Stop-signal response time (SSRT), which is the average time STOP takes to rise to the threshold, is widely used as a metric to assess the ability to revoke a movement. A reliable estimation of SSRT critically depends on the assumption of independence between GO and STOP process, which has been violated in many studies. In addition, the physiological correlate of stochastic rise of STOP process to a threshold remains unsubstantiated thus far. Here, we introduce a method to estimate the efficacy of inhibitory control on the premise of an alternative model that assumes deceleration of GO process following the stop-signal onset. The average reaction time increased exponentially with the increase in the maximum duration available to attenuate GO process by the stop-signal. Our method estimates saccade procrastination in anticipation of the stop-signal, and the rate of increase in attenuation on GO process. Unlike SSRT, these new metrics are independent of how the stopping performance varies with the delay between go- and stop-signal onsets. We reckon that these metrics together qualify to be considered as an efficient alternative to SSRT for the estimation of individuals' ability to countermand saccades, especially in cases when the assumptions of race model are no longer valid.

Detectability of stop-signal determines magnitude of deceleration in saccade planning.

An inhibitory control is exerted when the context in which a movement has been planned changes abruptly making the impending movement inappropriate. Neurons in the frontal eye field and superior colliculus steadily increase activity before a saccadic eye movement, but cease the rise below a threshold when an impending saccade is withheld in response to an unexpected stop-signal. This type of neural modulation has been majorly considered as an outcome of a race between preparatory and inhibitory processes ramping up to reach a decision criterion. An alternative model claims that the rate of saccade planning is diminished exclusively when the stop-signal is detected within a stipulated period. However, due to a dearth of empirical evidence in support of the latter model, it remains unclear how the detectability of the stop-signal influences saccade inhibition. In our study, human participants selected a visual target to look at by discriminating a go-cue. Infrequently they cancelled saccade and reported whether they saw the stop-signal. The go-cue and stop-signal both were embedded in a stream of irrelevant stimuli presented in rapid succession. Participants exhibited difficulty in detection of the stop-signal when presented almost immediately after the go-cue. We found a robust relationship between the detectability of the stop-signal and the odds of saccade inhibition. Saccade latency increased exponentially with the maximum time available for processing the stop-signal before gaze shifted. A model in which the stop-signal onset spontaneously decelerated progressive saccade planning with the magnitude proportional to its detectability accounted for the data.

A mechanism for decision rule discrimination by supplementary eye field neurons.

A decision to select an action from alternatives is often guided by rules that flexibly map sensory inputs to motor outputs when certain conditions are satisfied. However, the neural mechanisms underlying rule-based decision making remain poorly understood. Two complementary types of neurons in the supplementary eye field (SEF) of macaques have been identified that modulate activity differentially to interpret rules in an ocular go-nogo task, which stipulates that the animal either visually pursue a moving object if it intersects a visible zone ('go'), or maintain fixation if it does not ('nogo'). These neurons discriminate between go and nogo rule-states by increasing activity to signal their preferred (agonist) rule-state and decreasing activity to signal their non-preferred (antagonist) rule-state. In the current study, we found that SEF neurons decrease activity in anticipation of the antagonist rule-state, and do so more rapidly when the rule-state is easier to predict. This rapid decrease in activity could underlie a process of elimination in which trajectories that do not invoke the preferred rule-state receive no further computational resources. Furthermore, discrimination between difficult and easy trials in the antagonist rule-state occurs prior to when discrimination within the agonist rule-state occurs. A winner-take-all like model that incorporates a pair of mutually inhibited integrators to accumulate evidence in favor of either the decision to pursue or the decision to continue fixation accounts for the observed neural phenomena.

Is saccade averaging determined by visual processing or movement planning?

Saccadic averaging that causes subjects' gaze to land between the location of two targets when faced with simultaneously or sequentially presented stimuli has been often used as a probe to investigate the nature of computations that transform sensory representations into an oculomotor plan. Since saccadic movements involve at least two processing stages-a visual stage that selects a target and a movement stage that prepares the response-saccade averaging can either occur due to interference in visual processing or movement planning. By having human subjects perform two versions of a saccadic double-step task, in which the stimuli remained the same, but different instructions were provided (REDIRECT gaze to the later-appearing target vs. FOLLOW the sequence of targets in their order of appearance), we tested two alternative hypotheses. If saccade averaging were due to visual processing alone, the pattern of saccade averaging is expected to remain the same across task conditions. However, whereas subjects produced averaged saccades between two targets in the FOLLOW condition, they produced hypometric saccades in the direction of the initial target in the REDIRECT condition, suggesting that the interaction between competing movement plans produces saccade averaging.

Mutual inhibition and capacity sharing during parallel preparation of serial eye movements.

Many common activities, like reading, scanning scenes, or searching for an inconspicuous item in a cluttered environment, entail serial movements of the eyes that shift the gaze from one object to another. Previous studies have shown that the primate brain is capable of programming sequential saccadic eye movements in parallel. Given that the onset of saccades directed to a target are unpredictable in individual trials, what prevents a saccade during parallel programming from being executed in the direction of the second target before execution of another saccade in the direction of the first target remains unclear. Using a computational model, here we demonstrate that sequential saccades inhibit each other and share the brain's limited processing resources (capacity) so that the planning of a saccade in the direction of the first target always finishes first. In this framework, the latency of a saccade increases linearly with the fraction of capacity allocated to the other saccade in the sequence, and exponentially with the duration of capacity sharing. Our study establishes a link between the dual-task paradigm and the ramp-to-threshold model of response time to identify a physiologically viable mechanism that preserves the serial order of saccades without compromising the speed of performance.

Trans-saccadic processing of visual and motor planning during sequential eye movements.

How the brain maintains perceptual continuity across eye movements that yield discontinuous snapshots of the world is still poorly understood. In this study, we adapted a framework from the dual-task paradigm, well suited to reveal bottlenecks in mental processing, to study how information is processed across sequential saccades. The pattern of RTs allowed us to distinguish among three forms of trans-saccadic processing (no trans-saccadic processing, trans-saccadic visual processing and trans-saccadic visual processing and saccade planning models). Using a cued double-step saccade task, we show that even though saccade execution is a processing bottleneck, limiting access to incoming visual information, partial visual and motor processing that occur prior to saccade execution is used to guide the next eye movement. These results provide insights into how the oculomotor system is designed to process information across multiple fixations that occur during natural scanning.

Functional distinction between visuomovement and movement neurons in macaque frontal eye field during saccade countermanding.

In the previous studies on the neural control of saccade initiation using the countermanding paradigm, movement and visuomovement neurons in the frontal eye field were grouped as movement-related neurons. The activity of both types of neurons was modulated when a saccade was inhibited in response to a stop signal, and this modulation occurred early enough to contribute to the control of the saccade initiation. We now report a functional difference between these two classes of neurons when saccades are produced. Movement neurons exhibited a progressive accumulation of discharge rate following target presentation that triggered a saccade when it reached a threshold. When saccades were inhibited with lower probability in response to a stop signal appearing at longer delays, this accumulating activity was interrupted at levels progressively closer to the threshold. In contrast, visuomovement neurons exhibited a maintained elevated discharge rate following target presentation that was followed by a further enhancement immediately before the saccade initiation. When saccades were inhibited in response to a stop signal, the late enhancement was absent and the maintained activity decayed regardless of stop-signal delay. These results demonstrate that the activity of movement neurons realizes the progressive commitment to the saccade initiation modeled by the activation of the go unit in computational models of countermanding performance. The lack of correspondence of the activity of visuomovement neurons with any elements of these models indicates that visuomovement neurons perform a function other than the saccade preparation such as a corollary discharge to update visual processing.

Attention for action during error correction.

While the role of attention in selecting visual attributes is well acknowledged, relatively less is known about the mechanisms that facilitate the selection of actions during goal-directed behaviors. The notion of an executive attention has provided a particularly fruitful framework to understand how the brain coordinates the selection of appropriate modules in a sequence that optimizes behavior. However, to do this, theorists have recognized the need to parcel out this unitary system into subcomponents. Two modules that have been commonly invoked are performance monitoring and response inhibition. Visuomotor control of eye movements provides an elegant model system to investigate these mechanisms of selection and control specially occurring during "double-step" tasks in which goals are suddenly changed, demanding inhibition and error detection/correction. Here, we describe our work that has focused on the executive mechanisms that regulate the production of saccadic movements during double-step tasks in different cognitive contexts and target-shift double-step tasks. By examining the pattern of response in the context of quantitative models of saccadic reaction times, we provide behavioral evidence of predictive error correction that produces fast, corrective responses. The predictions from these behavioral experiments were also tested and supported by analyzing neural data from the frontal cortex of monkeys performing similar tasks. Finally, we present data that tested the possibility of an interaction between the inhibitory control and error correction and suggest a model in which predictive error correction may be engaged when the likelihood of error is high. We propose that these results when used in conjunction with electrophysiological recordings, may provide an important approach to understand how error detection/correction and inhibition, two vital cogs in the functioning of executive control, may interact to govern goal-directed behaviors.

Neural control of visual search by frontal eye field: effects of unexpected target displacement on visual selection and saccade preparation.

The dynamics of visual selection and saccade preparation by the frontal eye field was investigated in macaque monkeys performing a search-step task combining the classic double-step saccade task with visual search. Reward was earned for producing a saccade to a color singleton. On random trials the target and one distractor swapped locations before the saccade and monkeys were rewarded for shifting gaze to the new singleton location. A race model accounts for the probabilities and latencies of saccades to the initial and final singleton locations and provides a measure of the duration of a covert compensation process-target-step reaction time. When the target stepped out of a movement field, noncompensated saccades to the original location were produced when movement-related activity grew rapidly to a threshold. Compensated saccades to the final location were produced when the growth of the original movement-related activity was interrupted within target-step reaction time and was replaced by activation of other neurons producing the compensated saccade. When the target stepped into a receptive field, visual neurons selected the new target location regardless of the monkeys' response. When the target stepped out of a receptive field most visual neurons maintained the representation of the original target location, but a minority of visual neurons showed reduced activity. Chronometric analyses of the neural responses to the target step revealed that the modulation of visually responsive neurons and movement-related neurons occurred early enough to shift attention and saccade preparation from the old to the new target location. These findings indicate that visual activity in the frontal eye field signals the location of targets for orienting, whereas movement-related activity instantiates saccade preparation.

Frontal eye field contributions to rapid corrective saccades.

Visually guided movements can be inaccurate, especially if unexpected events occur while the movement is programmed. Often errors of gaze are corrected before external feedback can be processed. Evidence is presented from macaque monkey frontal eye field (FEF), a cortical area that selects visual targets, allocates attention, and programs saccadic eye movements, for a neural mechanism that can correct saccade errors before visual afferent or performance monitoring signals can register the error. Macaques performed visual search for a color singleton that unpredictably changed position in a circular array as in classic double-step experiments. Consequently, some saccades were directed in error to the original target location. These were followed frequently by unrewarded, corrective saccades to the final target location. We previously showed that visually responsive neurons represent the new target location even if gaze shifted errantly to the original target location. Now we show that the latency of corrective saccades is predicted by the timing of movement-related activity in the FEF. Preceding rapid corrective saccades, the movement-related activity of all neurons began before explicit error signals arise in the medial frontal cortex. The movement-related activity of many neurons began before visual feedback of the error was registered and that of a few neurons began before the error saccade was completed. Thus movement-related activity leading to rapid corrective saccades can be guided by an internal representation of the environment updated with a forward model of the error.

Programming of double-step saccade sequences: modulation by cognitive control.

The capacity to detect and correct errors is thought to engage cognitive control. To probe the nature of such control in relation to eye movements, subjects performed a double-step task under different instructions: to FOLLOW the appearance of successive targets; or to cancel the initial saccade and REDIRECT gaze to the final target location. Saccade sequences occurred in the FOLLOW and REDIRECT conditions where they represented correct and corrective behaviour, respectively. We observed that corrective responses were faster than correct responses, and concurrent preparation of saccades was facilitated during error correction. These results are consistent with psychological theories that posit supervisory cognitive control over action during error correction.