Douglas P. Munoz

Look away: the anti-saccade task and the voluntary control of eye movement

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.

Maturation of widely distributed brain function subserves cognitive development.

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

Salience, relevance, and firing: a priority map for target selection

The salience map is a crucial concept for many theories of visual attention. On this map, each object in the scene competes for selection - the more conspicuous the object, the greater its representation, and the more likely it will be chosen. In recent years, the firing patterns of single neurons have been interpreted using this framework. Here, we review evidence showing that the expression of salience is remarkably similar across structures, remarkably different across tasks, and modified in important ways when the salient object is consistent with the goals of the participant. These observations have important ramifications for theories of attention. We conclude that priority--the combined representation of salience and relevance--best describes the firing properties of neurons.

Age-related performance of human subjects on saccadic eye movement tasks

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

An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers

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

A Model of Saccade Initiation Based on the Competitive Integration of Exogenous and Endogenous Signals in the Superior Colliculus

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

Human fMRI evidence for the neural correlates of preparatory set

We used functional magnetic resonance imaging (fMRI) to study readiness and intention signals in frontal and parietal areas that have been implicated in planning saccadic eye movements—the frontal eye fields (FEF) and intraparietal sulcus (IPS). To track fMRI signal changes correlated with readiness to act, we used an event-related design with variable gap periods between disappearance of the fixation point and appearance of the target. To track changes associated with intention, subjects were instructed before the gap period to make either a pro-saccade (look at target) or an anti-saccade (look away from target). FEF activation increased during the gap period and was higher for anti- than for pro-saccade trials. No signal increases were observed during the gap period in the IPS. Our findings suggest that within the frontoparietal networks that control saccade generation, the human FEF, but not the IPS, is critically involved in preparatory set, coding both the readiness and intention to perform a particular movement.

Contribution of the Primate Superior Colliculus to Inhibition of Return

The phenomenon of inhibition of return (IOR) has generated considerable interest in cognitive neuroscience because of its putative functional role in visual search, that of placing inhibitory tags on objects that have been recently inspected so as to direct further search to novel items. Many behavioral parameters of this phenomenon have been clearly delineated, and based on indirect but converging evidence, the widely held consensus is that the midbrain superior colliculus (SC) is involved in the generation of IOR. We had previously trained monkeys on a saccadic IOR task and showed that they displayed IOR in a manner similar to that observed in humans. Here we recorded the activity of single neurons in the superficial and intermediate layers of the SC while the monkeys performed this IOR task. We found that when the target was presented at a previously cued location, the stimulus-related response was attenuated and the magnitude of this response was correlated with subsequent saccadic reaction times. Surprisingly, this observed attenuation of activity during IOR was not caused by active inhibition of these neurons because (a) they were, in fact, more active following the presentation of the cue in their response field, and (b) when we repeated the same experiment while using the saccadic response time induced by electrical micro-stimulation of the SC to judge the level of excitability of the SC circuitry during the IOR task, we found faster saccades were elicited from the cued location. Our findings demonstrate that the primate SC participates in the expression of IOR; however, the SC is not the site of the inhibition. Instead, the reduced activity in the SC reflects a signal reduction that has taken place upstream.

On your mark, get set: Brainstem circuitry underlying saccadic initiation

Saccades are rapid eye movements that are used to move the visual axis toward targets of interest in the visual field. The time to initiate a saccade is dependent upon many factors. Here we review some of the recent advances in our understanding of the these processes in primates. Neurons in the superior colliculus and brainstem reticular formation are organised into a network to control saccades. Some neurons are active during visual fixation, while others are active during the preparation and execution of saccades. Several factors can influence the excitability levels of these neurons prior to the appearance of a new saccadic target. These pre-target changes in excitability are correlated to subsequent changes in behavioural performance. Our results show how neuronal signals in the superior colliculus and brainstem reticular formation can be shaped by contextual factors and demonstrate how situational experience can expedite motor behaviour via the advanced preparation of motor programs.

Deficits in saccadic eye-movement control in Parkinson's disease

In contrast to their slowed limb movements, individuals with Parkinsons disease (PD) produce rapid automatic eye movements to sensory stimuli and show an impaired ability to generate voluntary eye movements in cognitive tasks. Eighteen PD patients and 18 matched control volunteers were instructed to look either toward (pro-saccade) or away from (anti-saccade) a peripheral stimulus as soon as it appeared (immediate, gap and overlap conditions) or after a variable delay; or, they made sequential saccades to remembered targets after a variable delay. We found that PD patients made more express saccades (correct saccades in the latency range of 90-140 ms) in the immediate pro-saccade task, more direction errors (automatic pro-saccades) in the immediate anti-saccade task, and were less able to inhibit saccades during the delay period in all delay tasks. PD patients also made more directional and end-point errors in the memory-guided sequential task. Their inability to plan eye movements to remembered target locations suggests that PD patients have a deficit in spatial working memory which, along with their deficit in automatic saccade suppression, is consistent with a disorder of the prefrontal-basal ganglia circuit. Impairment of this pathway may release the automatic saccade system from top-down inhibition and produce deficits in volitional saccade control. Parallel findings across various motor, cognitive and oculomotor tasks suggest a common mechanism underlying a general deficit in automatic response suppression.