Neurophysiology and neuroanatomy of reflexive and voluntary saccades in non-human primates

A multitude of cognitive functions can easily be tested by a number of relatively simple saccadic eye movement tasks. This approach has been employed extensively with patient populations to investigate the functional deficits associated with psychiatric disorders. Neurophysiological studies in non-human primates performing the same tasks have begun to provide us with insights into the neural mechanisms underlying many cognitive functions. Here, we review studies that have investigated single neuron activity in the superior colliculus (see glossary), frontal eye field, supplementary eye field, dorsolateral prefrontal cortex, anterior cingulate (see glossary) cortex and lateral intraparietal area associated with the performance of visually guided saccades, anti-saccades and memory-guided saccades in awake behaving monkeys.     

Neurophysiology and neuroanatomy of reflexive and volitional saccades: evidence from studies of humans

This review provides a summary of the contributions made by human functional neuroimaging studies to the understanding of neural correlates of saccadic control. The generation of simple visually guided saccades (redirections of gaze to a visual stimulus or pro-saccades) and more complex volitional saccades require similar basic neural circuitry with additional neural regions supporting requisite higher level processes. The saccadic system has been studied extensively in non-human (e.g., single-unit recordings) and human (e.g., lesions and neuroimaging) primates. Considerable knowledge of this system’s functional neuroanatomy makes it useful for investigating models of cognitive control. The network involved in pro-saccade generation (by definition largely exogenously-driven) includes subcortical (striatum, thalamus, superior colliculus, and cerebellar vermis) and cortical (primary visual, extrastriate, and parietal cortices, and frontal and supplementary eye fields) structures. Activation in these regions is also observed during endogenously-driven voluntary saccades (e.g., anti-saccades, ocular motor delayed response or memory saccades, predictive tracking tasks and anticipatory saccades, and saccade sequencing), all of which require complex cognitive processes like inhibition and working memory. These additional requirements are supported by changes in neural activity in basic saccade circuitry and by recruitment of additional neural regions (such as prefrontal and anterior cingulate cortices). Activity in visual cortex is modulated as a function of task demands and may predict the type of saccade to be generated, perhaps via top-down control mechanisms. Neuroimaging studies suggest two foci of activation within FEF - medial and lateral - which may correspond to volitional and reflexive demands, respectively. Future research on saccade control could usefully (i) delineate important anatomical subdivisions that underlie functional differences, (ii) evaluate functional connectivity of anatomical regions supporting saccade generation using methods such as ICA and structural equation modeling, (iii) investigate how context affects behavior and brain activity, and (iv) use multi-modal neuroimaging to maximize spatial and temporal resolution.     

Neurophysiology and neuroanatomy of reflexive and volitional saccades: Evidence from studies of humans

This review provides a summary of the contributions made by human functional neuroimaging studies to the understanding of neural correlates of saccadic control. The generation of simple visually guided saccades (redirections of gaze to a visual stimulus or pro-saccades) and more complex volitional saccades require similar basic neural circuitry with additional neural regions supporting requisite higher level processes. The saccadic system has been studied extensively in non-human (e.g., single-unit recordings) and human (e.g., lesions and neuroimaging) primates. Considerable knowledge of this system’s functional neuroanatomy makes it useful for investigating models of cognitive control. The network involved in pro-saccade generation (by definition largely exogenously-driven) includes subcortical (striatum, thalamus, superior colliculus, and cerebellar vermis) and cortical (primary visual, extrastriate, and parietal cortices, and frontal and supplementary eye fields) structures. Activation in these regions is also observed during endogenously-driven voluntary saccades (e.g., anti-saccades, ocular motor delayed response or memory saccades, predictive tracking tasks and anticipatory saccades, and saccade sequencing), all of which require complex cognitive processes like inhibition and working memory. These additional requirements are supported by changes in neural activity in basic saccade circuitry and by recruitment of additional neural regions (such as prefrontal and anterior cingulate cortices). Activity in visual cortex is modulated as a function of task demands and may predict the type of saccade to be generated, perhaps via top-down control mechanisms. Neuroimaging studies suggest two foci of activation within FEF - medial and lateral - which may correspond to volitional and reflexive demands, respectively. Future research on saccade control could usefully (i) delineate important anatomical subdivisions that underlie functional differences, (ii) evaluate functional connectivity of anatomical regions supporting saccade generation using methods such as ICA and structural equation modeling, (iii) investigate how context affects behavior and brain activity, and (iv) use multi-modal neuroimaging to maximize spatial and temporal resolution.     

Control of reflexive and voluntary saccades in the gap effect

In two experiments, we examined whether voluntary and reflexive saccades shared a common fixation disengagement mechanism, Participants were required to perform a variety of tasks, each requiring a different level of information processing of the display prior to execution of the saccade. In Experiment 1, participants executed either a prosaccade or an antisaccade upon detecting a stimulus array. In Experiment 2, participants executed a prosaccade to a stimulus array only if the array contained a target item. The target could be a line (easy search) or a digit (difficult search). The critical manipulation in both experiments was the relative timing between the removal of the fixation stimulus and the onset of the stimulus array. In both experiments, it was found that saccadic latencies were shortest when the fixation stimulus was removed before the onset of the stimulus array—a gap effect. It was concluded that reflexive and voluntary saccades share a common fixation disengagement mechanism that is largely independent of higher level cognitive processes.     

Control' of reflexive and voluntary saccades in the gap effect.

In two experiments, we examined whether voluntary and reflexive saccades shared a common fixation disengagement mechanism. Participants were required to perform a variety of tasks, each requiring a different level of information processing of the display prior to execution of the saccade. In Experiment 1, participants executed either a prosaccade or an antisaccade upon detecting a stimulus array. In Experiment 2, participants executed a prosaccade to a stimulus array only if the array contained a target item. The target could be a line (easy search) or a digit (difficult search). The critical manipulation in both experiments was the relative timing between the removal of the fixation stimulus and the onset of the stimulus array. In both experiments, it was found that saccadic latencies were shortest when the fixation stimulus was removed before the onset of the stimulus array--a gap effect. It was concluded that reflexive and voluntary saccades share a common fixation disengagement mechanism that is largely independent of higher level cognitive processes.     

Neurophysiology and neuroanatomy of reflexive and volitional saccades as revealed by lesion studies with neurological patients and transcranial magnetic stimulation (TMS)

This review discusses the neurophysiology and neuroanatomy of the cortical control of reflexive and volitional saccades in humans. The main focus is on classical lesion studies and studies using the interference method of transcranial magnetic stimulation (TMS). To understand the behavioural function of a region, it is essential to assess oculomotor deficits after a focal lesion using a variety of oculomotor paradigms, and to study the oculomotor consequences of the lesion in the chronic phase. Saccades are controlled by different cortical regions, which could be partially specialised in the triggering of a specific type of saccade. The division of saccades into reflexive visually guided saccades and intentional or volitional saccades corresponds to distinct regions of the neuronal network, which are involved in the control of such saccades.TMS allows to specifically interfere with the functioning of a region within an intact oculomotor network. TMS provides advantages in terms of temporal resolution, allowing to interfere with brain functioning in the order of milliseconds, thereby allowing to define the time course of saccade planning and execution.In the first part of the paper, we present an overview of the cortical structures important for saccade control, and discuss the pro’s and con’s of the different methodological approaches to study the cortical oculomotor network. In the second part, the functional network involved in reflexive and volitional saccades is presented. Finally, studies concerning recovery mechanisms after a lesion of the oculomotor cortex are discussed.     

Neurophysiology and neuroanatomy of reflexive and volitional saccades as revealed by lesion studies with neurological patients and transcranial magnetic stimulation (TMS)

This review discusses the neurophysiology and neuroanatomy of the cortical control of reflexive and volitional saccades in humans. The main focus is on classical lesion studies and studies using the interference method of transcranial magnetic stimulation (TMS). To understand the behavioural function of a region, it is essential to assess oculomotor deficits after a focal lesion using a variety of oculomotor paradigms, and to study the oculomotor consequences of the lesion in the chronic phase. Saccades are controlled by different cortical regions, which could be partially specialised in the triggering of a specific type of saccade. The division of saccades into reflexive visually guided saccades and intentional or volitional saccades corresponds to distinct regions of the neuronal network, which are involved in the control of such saccades.TMS allows to specifically interfere with the functioning of a region within an intact oculomotor network. TMS provides advantages in terms of temporal resolution, allowing to interfere with brain functioning in the order of milliseconds, thereby allowing to define the time course of saccade planning and execution.In the first part of the paper, we present an overview of the cortical structures important for saccade control, and discuss the pro’s and con’s of the different methodological approaches to study the cortical oculomotor network. In the second part, the functional network involved in reflexive and volitional saccades is presented. Finally, studies concerning recovery mechanisms after a lesion of the oculomotor cortex are discussed.     

Neurophysiology and neuroanatomy of smooth pursuit in humans

Smooth pursuit eye movements enable us to focus our eyes on moving objects by utilizing well-established mechanisms of visual motion processing, sensorimotor transformation and cognition. Novel smooth pursuit tasks and quantitative measurement techniques can help unravel the different smooth pursuit components and complex neural systems involved in its control. The maintenance of smooth pursuit is driven by a combination of the prediction of target velocity and visual feedback about performance quality, thus a combination of retinal and extraretinal information that has to be integrated in various networks. Different models of smooth pursuit with specific in- and output parameters have been developed for a better understanding of the underlying neurophysiological mechanisms and to make quantitative predictions that can be tested in experiments. Functional brain imaging and neurophysiological studies have defined motion sensitive visual area V5, frontal (FEF) and supplementary (SEF) eye fields as core cortical smooth pursuit regions. In addition, a dense neural network is involved in the adjustment of an optimal smooth pursuit response by integrating also extraretinal information. These networks facilitate interaction of the smooth pursuit system with multiple other visual and non-visual sensorimotor systems on the cortical and subcortical level. Future studies with fMRI advanced techniques (e.g., event-related fMRI) promise to provide an insight into how smooth pursuit eye movements are linked to specific brain activation. Applying this approach to neurological and also mental illness can reveal distinct disturbances within neural networks being present in these disorders and also the impact of medication on this circuitry.     

Neurophysiology and neuroanatomy of smooth pursuit in humans

Smooth pursuit eye movements enable us to focus our eyes on moving objects by utilizing well-established mechanisms of visual motion processing, sensorimotor transformation and cognition. Novel smooth pursuit tasks and quantitative measurement techniques can help unravel the different smooth pursuit components and complex neural systems involved in its control. The maintenance of smooth pursuit is driven by a combination of the prediction of target velocity and visual feedback about performance quality, thus a combination of retinal and extraretinal information that has to be integrated in various networks. Different models of smooth pursuit with specific in- and output parameters have been developed for a better understanding of the underlying neurophysiological mechanisms and to make quantitative predictions that can be tested in experiments. Functional brain imaging and neurophysiological studies have defined motion sensitive visual area V5, frontal (FEF) and supplementary (SEF) eye fields as core cortical smooth pursuit regions. In addition, a dense neural network is involved in the adjustment of an optimal smooth pursuit response by integrating also extraretinal information. These networks facilitate interaction of the smooth pursuit system with multiple other visual and non-visual sensorimotor systems on the cortical and subcortical level. Future studies with fMRI advanced techniques (e.g., event-related fMRI) promise to provide an insight into how smooth pursuit eye movements are linked to specific brain activation. Applying this approach to neurological and also mental illness can reveal distinct disturbances within neural networks being present in these disorders and also the impact of medication on this circuitry.     

Neurophysiology and neuroanatomy of smooth pursuit: Lesion studies

Smooth pursuit impairment is recognized clinically by the presence of saccadic tracking of a small object and quantified by reduction in pursuit gain, the ratio of smooth eye movement velocity to the velocity of a foveal target. Correlation of the site of brain lesions, identified by imaging or neuropathological examination, with defective smooth pursuit determines brain structures that are necessary for smooth pursuit. Paretic, low gain, pursuit occurs toward the side of lesions at the junction of the parietal, occipital and temporal lobes (area V5), the frontal eye field and their subcortical projections, including the posterior limb of the internal capsule, the midbrain and the basal pontine nuclei. Paresis of ipsiversive pursuit also results from damage to the ventral paraflocculus and caudal vermis of the cerebellum. Paresis of contraversive pursuit is a feature of damage to the lateral medulla. Retinotopic pursuit paresis consists of low gain pursuit in the visual hemifield contralateral to damage to the optic radiation, striate cortex or area V5. Craniotopic paresis of smooth pursuit consists of impaired smooth eye movement generation contralateral to the orbital midposition after acute unilateral frontal or parietal lobe damage. Omnidirectional saccadic pursuit is a most sensitive sign of bilateral or diffuse cerebral, cerebellar or brainstem disease. The anatomical and physiological bases of defective smooth pursuit are discussed here in the context of the effects of lesion in the human brain.     

Ultra-rapid categorisation in non-human primates

The visual system of primates is remarkably efficient for analysing information about objects present in complex natural scenes. Recent work has demonstrated that they perform this at very high speeds. In a choice saccade task, human subjects can initiate a first reliable saccadic eye movement response to a target (the image containing an animal) in only 120 ms after image onset. Such fast responses impose severe time constraints if one considers neuronal responses latencies in high-level ventral areas of the macaque monkey. The question then arises: are non-human primates able to perform the task? Two rhesus macaque monkeys (Macaca mulatta) were trained to perform the same forced-choice categorization task as the one used in humans. Both animals performed the task with a high accuracy and generalized to new stimuli that were introduced everyday: accuracy levels were comparable both with new and well-known images (84% vs. 94%). More importantly, reaction times were extremely fast (minimum reaction time 100 ms and median reaction time 152 ms). Given that typical single units onset times in Inferotemporal cortex (IT) are about as long as the shortest behavioural responses measured here, we conclude that visual processing involved in ultra rapid categorisations might be based on rather simple shape cue analysis that can be achieved in areas such as extrastriate cortical area V4. The present paper demonstrates for the first time, that rhesus macaque monkeys (Macaca mulatta) are able to match human performance in a forced-choice saccadic categorisation task of animals in natural scenes.     

Neurophysiology and neuroanatomy of smooth pursuit: Lesion studies

Smooth pursuit impairment is recognized clinically by the presence of saccadic tracking of a small object and quantified by reduction in pursuit gain, the ratio of smooth eye movement velocity to the velocity of a foveal target. Correlation of the site of brain lesions, identified by imaging or neuropathological examination, with defective smooth pursuit determines brain structures that are necessary for smooth pursuit. Paretic, low gain, pursuit occurs toward the side of lesions at the junction of the parietal, occipital and temporal lobes (area V5), the frontal eye field and their subcortical projections, including the posterior limb of the internal capsule, the midbrain and the basal pontine nuclei. Paresis of ipsiversive pursuit also results from damage to the ventral paraflocculus and caudal vermis of the cerebellum. Paresis of contraversive pursuit is a feature of damage to the lateral medulla. Retinotopic pursuit paresis consists of low gain pursuit in the visual hemifield contralateral to damage to the optic radiation, striate cortex or area V5. Craniotopic paresis of smooth pursuit consists of impaired smooth eye movement generation contralateral to the orbital midposition after acute unilateral frontal or parietal lobe damage. Omnidirectional saccadic pursuit is a most sensitive sign of bilateral or diffuse cerebral, cerebellar or brainstem disease. The anatomical and physiological bases of defective smooth pursuit are discussed here in the context of the effects of lesion in the human brain.     

Sequential learning in non-human primates

Sequential learning plays a role in a variety of common tasks, such as human language processing, animal communication, and the learning of action sequences. In this article, we investigate sequential learning in non-human primates from a comparative perspective, focusing on three areas: the learning of arbitrary, fixed sequences; statistical learning; and the learning of hierarchical structure. Although primates exhibit many similarities to humans in their performance on sequence learning tasks, there are also important differences. Crucially, non-human primates appear to be limited in their ability to learn and represent the hierarchical structure of sequences. We consider the evolutionary implications of these differences and suggest that limitations in sequential learning may help explain why non-human primates lack human-like language.     

Suppression of reflexive saccades in younger and older adults: Age comparisons on an antisaccade task

Inhibitory control of prepotent responses has been examined by using the antisaccade task, during which a reflexive saccade toward a peripheral onset must be suppressed before an eye movement in the opposite direction from the onset can be executed. In the present experiments, we sought to determine whether older and younger adults would perform similarly on this task. Older adults had a harder time suppressing their reflexive responses, as measured by an increase in the proportion of saccade direction errors. Despite an age-related decline in saccade direction accuracy, the increase in saccade latency associated with the antisaccade condition was the same for both younger and older adults. These results support the view that the effectiveness of inhibitory control declines with age (Hasher & Zacks, 1988; Hasher, Zacks, & May, 1999).     

Variable foreperiod deficits in Parkinson's disease: dissociation across reflexive and voluntary behaviors

The effect of a visual warning signal (1.0-6.5 s random foreperiod, FP) on the latency of voluntary (hand-grip) and reflexive (startle-eyeblink) reactions was investigated in Parkinson's disease (PD) patients and in young and aged control subjects. Equivalent FP effects on blink were observed across groups. By contrast, FP effects diverged for voluntary responses across groups with no effect of foreperiod duration for PD patients. The convergence of these results with findings from animal research suggests that interval-timing processes associated with higher level voluntary behaviors are dependent upon intact dopaminergic pathways, while those associated with lower level reflexive behaviors are spared in PD.     

Inhibition of return generated by voluntary saccades is independent of attentional momentum

Summoning attention to a peripheral location, either by a peripheral cue with the eyes fixed or when a voluntary saccade is made to it and gaze is then returned to the centre, delays detection of subsequent targets at that location compared to a location in the opposite visual field. It has been proposed that oculomotor activation generates this inhibition of return (IOR). This account presupposes that the asymmetry in detection results from inhibition at the cued location rather than facilitation at the uncued location. This has been confirmed for exogenously generated IOR. However, it has not, heretofore, been confirmed for “IOR” generated by voluntary saccades. The current study investigated whether the asymmetry in target detection, elicited either by a peripheral flash or by an eye movement generated in response to a central arrowhead, reflects facilitation at the opposite location due to the path of attentional momentum. Reaction times at the cued location were slower than reaction times at the opposite or perpendicular locations, which did not differ. Opposite facilitation due to attentional momentum requires that opposite be faster than perpendicular, which was not obtained. The results were the same whether IOR was generated by an exogenous cue or by a saccade executed endogenously to a central arrow.     

Brain structures playing a crucial role in the representation of tools in humans and non-human primates

The cortical representation of concepts varies according to the information critical for their development. Living categories, being mainly based upon visual information, are bilaterally represented in the rostral parts of the ventral stream of visual processing; whereas tools, being mainly based upon action data, are unilaterally represented in a left-sided fronto-parietal network. The unilateral representation of tools results from involvement in actions of the right side of the body.