Paired stimulation of the frontal eye fields and the superior colliculus of the rhesus monkey

This chapter discusses the neurophysiology and function of subcortical circuits and cortical areas involved in saccade generation. While cells within the different nuclei of the brainstem reticular formation shape the temporal details of ipsiversive horizontal and vertical/cyclotorsional saccade components, the cerebellar flocculus, vermis and fastigial nucleus are thought to modulate these saccadic waveforms. Burst neurons in the deep layers of the superior colliculus encode the saccade vector in the contralateral field by a localized population in a motor-error map. The complexity of the saccadic system is evident in the different subclasses of SC cells, ranging from purely visual, to visual-motor, purely motor, and quasi-visual cells. Movement-related activity in all SC cells is dissociated from the retinotopic visual activity. The chapter further discusses neurophysiological findings obtained from the substantia nigra (pars reticulata), the medial thalamus, the frontal eye fields, the supplementary motor area and the parietal lobes, discussing the ever more complex response patterns of their neurons in relation to saccades.

A fundamental goal of cognitive neuroscience is to understand how brain activity generates complex mental states and behaviors. While neuronal activity may predict or correlate with behavioral responses in a cognitive task, the use of electrical microstimulation presents the possibility to augment such correlational findings with direct evidence for causal relationships. Although microstimulation has been used for many years as a tool for mapping sensory and motor function, its role in learning, memory and decision-making has emerged only recently. Focal microstimulation of higher cortical areas can produce complex mental states and sequences of action. However, the relationship between the locus of stimulation and the percepts or actions evoked is often stereotyped and inflexible. The challenge is to develop stimulation systems that do not have fixed output but can flexibly contribute to complex cognitive and behavioral tasks. We discuss how microstimulation has been instrumental in manipulating a wide spectrum of cognitive functions including working memory, perceptual decisions and executive control by enhancing attention, re-ordering temporal sequence of saccades, improving associative learning or cognitive performance. For example, stimulation in prefrontal, parietal and sensory cortices may establish causal effects on decision-making, while microstimulation of inferotemporal cortex or caudate nucleus enhances associative learning. Building cognitive prosthetics based on the insights gleaned from such studies may depend on the development of multiple-input, multiple-output (MIMO) devices that allow subjects to control stimulation with their own thoughts in a closed-loop system.

Over the last two centuries, electrical microstimulation has been used to demonstrate causal links between neural activity and specific behaviors and cognitive functions. However, to establish these links it is imperative to characterize the cortical activity patterns that are elicited by stimulation locally around the electrode and in other functionally connected areas. We have developed a technique to record brain activity using the blood oxygen level dependent (BOLD) signal while applying electrical microstimulation to the primate brain. We find that the spread of activity around the electrode tip in macaque area V1 was larger than expected from calculations based on passive spread of current and therefore may reflect functional spread by way of horizontal connections. Consistent with this functional transynaptic spread we also obtained activation in expected projection sites in extrastriate visual areas, demonstrating the utility of our technique in uncovering in vivo functional connectivity maps.

Spatially selective delay activity in the frontal eye field (FEF) is hypothesized to be part of a mechanism for the transformation of visual signals into instructions for voluntary movements. To understand the linkage between FEF activity and eye movement planning, we recorded neuronal responses of FEF neurons while monkeys performed a memory-saccade task. We then electrically stimulated the same sites during the memory-delay epoch of the task. The stimulation currents used were subthreshold for evoking saccades during a gap-fixation task. Microstimulation resulted in changes in the spatial and temporal components of saccade parameters: an increase in latency, and a shift in amplitude and direction. We performed a vector analysis to determine the relative influence of the visual cue and electrical stimulus on the memory-saccade. In general, the memory-saccade was strongly weighted toward the visual cue direction, yet the electrical stimulus introduced a consistent bias away from the receptive/movement field of the stimulation site. The effects of sub-threshold stimulation were consistent with a combination of vector subtraction and averaging, but not with vector summation. Vector subtraction may play a role in spatial updating of movement plans for memory-guided saccades when eye position changes during the memory period.

In exploring the visual scene we make about three saccadic eye movements per second. During each fixation, in addition to analyzing the object at which we are looking, a decision has to be made as to where to look next. Although we perform this task with the greatest of ease, the computations to perform the task are complex and involve numerous brain structures. We have applied several investigative tools that include single-cell recordings, microstimulation, pharmacological manipulations and lesions to learn more about the neural control of visually guided eye saccadic movements. Electrical stimulation of the superior colliculus (SC), areas V1 and V2, the lateral intraparietal sulcus (LIP), the frontal eye fields (FEF) and the medial eye fields (MEF) produces saccadic eye movements at low current levels. After ablation of the SC, electrical microstimulation of V1, V2, and LIP no longer elicits saccadic eye movements whereas stimulation of the FEF and MEF continues to be effective. Ablation of the SC but not of the FEF eliminates short-latency saccadic eye movements to visual targets called “express saccades,” whereas lesions of the FEF selectively interfere with target selection. Bilateral removal of both the SC and the FEF causes major, long lasting deficits: all visually elicited saccadic eye movements are eliminated. In intact monkeys, subthreshold electrical microstimulation of the FEF and MEF as well as the lower layers of V1 and V2 and of some subregions of LIP greatly facilitates the choice of targets presented in the receptive fields of the stimulated neurons. By contrast, stimulation of the upper layers of V1 and V2 and other sub-regions of LIP produces a dramatic interference in target selection. Examination of the role of inhibitory circuits in eye-movement generation reveals that local infusion of muscimol, a GABA (gamma-aminobutyric acid) agonist, or bicuculline, a GABA antagonist, interferes with target selection in V1. On the other hand, infusion of bicuculline into the FEF produces facilitation in target choice and irrepressible saccades. It appears therefore that inhibitory circuits play a central role in visual analysis in V1 and in the generation of saccadic eye movements in the FEF. It is proposed that two major streams can be discerned in visually guided eye-movement control, the posterior from occipital and parietal cortex that reaches the brainstem via the SC and the anterior from the FEF and MEF that has direct access to the brainstem oculomotor centers.

Reviewed is how behavioural context influences saccadic eye movements elicited electrically from the neocortex of monkeys. Factors found to affect stimulation-evoked saccades include (1) motor state, i.e. whether stimulation is delivered during free-viewing, or during or after active fixation, or before an animal is about to execute a saccade to a target location, and (2) reward delivery, i.e. the characteristics and timing of reward, which can promote or inhibit the evocation of saccades. We conclude that anyone using electrical stimulation in neocortex to study sensory and cognitive processes must control for the possibility that stimulation of cortex is merely generating a saccade vector whose expression is being obscured by the behavioural paradigm in use. Areas of neocortex from which saccades can be evoked using low currents (<100 μA) are surprisingly widespread and include regions traditionally considered within the sensory domain (e.g. V1, V2, V4, and MT), in addition to visuomotor regions such as the lateral intraparietal area, the dorsomedial frontal cortex, the frontal eye fields, and the prefrontal cortex. This is especially true once the behavioural state of a stimulated animal is put under experimental control.