Masayuki Watanabe

Executive impairment in Parkinson's disease: Response automaticity and task switching

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

Neural Correlates of Fine Depth Discrimination in Monkey Inferior Temporal Cortex

Binocular disparity is an important visual cue that gives rise to the perception of depth. Disparity signals are widely spread across the visual cortex, but their relative role is poorly understood. Here, we addressed the correlation between the responses of disparity-selective neurons in the occipitotemporal (ventral) visual pathway and the behavioral discrimination of stereoscopic depth. We recorded activity of disparity-selective neurons in the inferior temporal cortex (IT) while monkeys were engaged in a fine stereoscopic depth discrimination (stereoacuity) task. We found that trial-to-trial fluctuations in neuronal responses correlated with the monkeys perceptual choice. We suggest that disparity signals in the IT, located in the ventral visual pathway, are functionally linked to the discrimination of fine-grain depth.

Probing basal ganglia functions by saccade eye movements

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.

Neural correlates of conflict resolution between automatic and volitional actions by basal ganglia.

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

Presetting Basal Ganglia for Volitional Actions

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.

Saccade suppression by electrical microstimulation in monkey caudate nucleus.

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.

Threshold mechanism for saccade initiation in frontal eye field and superior colliculus

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

Role of the basal ganglia in switching a planned response

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.

Saccade reaction times are influenced by caudate microstimulation following and prior to visual stimulus appearance

Several cognitive models suggest that saccade RTs are controlled flexibly not only by mechanisms that accumulate sensory evidence after the appearance of a sensory stimulus (poststimulus mechanisms) but also by mechanisms that preset the saccade control system before the sensory event (prestimulus mechanisms). Consistent with model predictions, neurons in structures tightly related to saccade initiation, such as the superior colliculus and FEF, have poststimulus and prestimulus activities correlated with RTs. It has been hypothesized that the BG influence the saccade initiation process by controlling both poststimulus and prestimulus activities of superior colliculus and FEF neurons. To examine this hypothesis directly, we delivered electrical microstimulation to the caudate nucleus, the input stage of the oculomotor BG, while monkeys performed a prosaccade (look toward a visual stimulus) and antisaccade (look away from the stimulus) paradigm. Microstimulation applied after stimulus appearance (poststimulus microstimulation) prolonged RTs regardless of saccade directions (contra/ipsi) or task instructions (pro/anti). In contrast, microstimulation applied before stimulus appearance (prestimulus microstimulation) shortened RTs, although the effects were limited to several task conditions. The analysis of RT distributions using the linear approach to threshold with ergodic rate model revealed that poststimulus microstimulation prolonged RTs by reducing the rate of rise to the threshold for saccade initiation, whereas fitting results for prestimulus microstimulation were inconsistent across different task conditions. We conclude that both poststimulus and prestimulus activities of caudate neurons are sufficient to control saccade RTs.

Effects of caudate microstimulation on spontaneous and purposive saccades

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.