An Investigation of the Neural Mechanism by which the Prefrontal Cortex Facilitates Anti-saccade Task Performance

Cognitive control enables us to guide our behaviour in an appropriate manner, such as rapid eye movements (saccades) toward a location or object of interest. A well-established test of cognitive control is the anti-saccade task, which instructs subjects to look away from a suddenly-appearing stimulus. The dorsolateral prefrontal cortex (dlPFC) and anterior cingulate cortex (ACC) are part of a cortical saccade control network that influences the superior colliculus (SC), which sends saccade commands to the brainstem saccade generator. To compare and contrast the roles of the dlPFC and ACC in saccade control, the cryoloop method of reversible cryogenic deactivation was used to identify the effects of dlPFC and ACC deactivation on pro-saccades and anti-saccades. Both dlPFC and ACC deactivation increased the incidence of ipsilateral saccades, but only dlPFC deactivation impaired contralateral saccades. An inhibitory model of prefrontal function has been proposed by which the prefrontal cortex suppresses the activity of SC saccade neurons on anti-saccade trials, to inhibit an unwanted saccade toward the stimulus. A direct test of this inhibitory model was performed by deactivating the dlPFC and recording the activity of SC saccade neurons. Unilateral dlPFC deactivation delayed the onset of saccade-related activity in the SC ipsilateral to deactivation, which suggests that the dlPFC has an excitatory influence on SC saccade neurons. There was also an increase of activity in the contralateral SC, which suggests that unilateral dlPFC deactivation caused a neural imbalance at the SC. Bilateral dlPFC deactivation, on the other hand, should not cause a neural imbalance, and thus was used to identify the effects of dlPFC deactivation that were caused by cognitive control impairments. Bilateral dlPFC deactivation increased the stimulus-related activity, and decreased the saccade-related activity, of SC saccade neurons. An increase of anti-saccade errors was more substantial in a “rule memorized” condition, which suggests that the dlPFC plays an important role in rule maintenance. Given an excitatory influence of the dlPFC on SC saccade neurons, I propose that the dlPFC facilitates anti-saccade task performance by first maintaining the relevant rule in working memory, then implementing the rule by enhancing the saccade-generating signal at the SC

ELECTRICAL MICROSTIMULATION OF THE MONKEY DORSOLATERAL PREFRONTAL CORTEX IMPAIRS ANTISACCADE PERFORMANCE

The dorsolateral prefrontal cortex (DLPFC) has been implicated in response suppression. This function is frequently investigated with the antisaccade task, which requires suppression of the automatic tendency to look toward a flashed peripheral stimulus (prosaccade) and generation of a voluntary saccade to the mirror location. To test the functional relationship between DLPFC activity and antisaccade performance, we applied electrical microstimulation to the DLPFC of two monkeys while they performed randomly interleaved pro- and anti-saccade trials. Microstimulation increased the number of direction errors and slowed saccadic reaction times (SRTs) on antisaccade trials when the visual stimulus is presented on the side contralateral to the stimulated hemisphere. Also, we observed shorter SRTs for contralateral prosaccades and longer SRTs for ipsilateral prosaccades on microstimulation trials. These findings do not support a role for the DLPFC in response suppression, but suggest a more general role in attentional selection of the contralateral field

Contribution of the dorsolateral prefrontal cortex to attentional and mnemonic processes in visual search

A key characteristic of selective visual attention is that it may be deployed on the basis of our knowledge or goals of the task at hand. Here, we used cryogenic deactivation to investigate the contribution of the dorsolateral PFC to cognitive flexibility and working memory, as well as their relation to the deployment of attention. Macaque monkeys performed visual search tasks requiring them to foveate a target in an array of stimuli. These included a feature search, a constant-target conjunction search, a variable-target search and variable-target with delay search task, with each being more cognitively demanding than the last. Bilateral deactivation of the DLPFC during more demanding tasks resulted in increased reaction time and decreased accuracy. These effects on visual search performance suggest that the DLPFC is involved in the deployment of attention to a target, and also contributes to the flexible and mnemonic processes needed when task demands increase

Contribution of the Primate Frontal Cortex to Eye Movements and Neuronal Activity in the Superior Colliculus

Humans and non-human primates must precisely align the eyes on an object to view it with high visual acuity. An important role of the oculomotor system is to generate accurate eye movements, such as saccades, toward a target. Given that each eye has only six muscles that rotate the eye in three degrees of freedom, this relatively simple volitional movement has allowed researchers to well-characterize the brain areas involved in their generation. In particular, the midbrain Superior Colliculus (SC), is recognized as having a primary role in the generation of visually-guided saccades via the integration of sensory and cognitive information. One important source of sensory and cognitive information to the SC is the Frontal Eye Fields (FEF). The role of the FEF and SC in visually-guided saccades has been well-studied using anatomical and functional techniques, but only a handful of studies have investigated how these areas work together to produce saccades. While it is assumed that the FEF exerts its influence on saccade generation though the SC, it remains unknown what happens in the SC when the FEF is suddenly inactivated. To test this prediction, I use the combined approach of FEF cryogenic inactivation and SC neuronal recordings, although it also provides a valuable opportunity to understand how FEF inputs to the SC govern saccade preparation. Nonetheless, it was first necessary to characterize the eye movement deficits following FEF inactivation, as it was unknown how a large and reversible FEF inactivation would influence saccade behaviour, or whether cortical areas influence fixational eye movements (e.g. microsaccades). Four major results emerged from this thesis. First, FEF inactivation delayed saccade reaction times (SRT) in both directions. Second, FEF inactivation impaired microsaccade generation and also selectively reduced microsaccades following peripheral cues. Third, FEF inactivation decreased visual, cognitive, and saccade-related activity in the ipsilesional SC. Fourth, the delayed onset of saccade-related SC activity best explained SRT increases during FEF inactivation, implicating one mechanism for how FEF inputs govern saccade preparation. Together, these results provide new insights into the FEF\u27s role in saccade and microsaccade behaviour, and how the oculomotor system commits to a saccade

Spatial Transformations in Frontal Cortex During Memory-Guided Head-Unrestrained Gaze Shifts

We constantly orient our line of sight (i.e., gaze) to external objects in our environment. One of the central questions in sensorimotor neuroscience concerns how visual input (registered on retina) is transformed into appropriate signals that drive gaze shift, comprised of coordinated movement of the eyes and the head. In this dissertation I investigated the function of a node in the frontal cortex, known as the frontal eye field (FEF) by investigating the spatial transformations that occur within this structure. FEF is implicated as a key node in gaze control and part of the working memory network. I recorded the activity of single FEF neurons in head-unrestrained monkeys as they performed a simple memory-guided gaze task which required delayed gaze shifts (by a few hundred milliseconds) towards remembered visual stimuli. By utilizing an elaborate analysis method which fits spatial models to neuronal response fields, I identified the spatial code embedded in neuronal activity related to vision (visual response), memory (delay response), and gaze shift (movement response). First (Chapter 2), spatial transformations that occur within the FEF were identified by comparing spatial codes in visual and movement responses. I showed eye-centered dominance in both neuronal responses (and excluded head- and space-centered coding); however, whereas the visual response encoded target position, the movement response encoded the position of the imminent gaze shift (and not its independent eye and head components), and this was observed even within single neurons. In Chapter 3, I characterized the time-course for this target-to-gaze transition by identifying the spatial code during the intervening delay period. The results from this study highlighted two major transitions within the FEF: a gradual transition during the visual-delay-movement extent of delay-responsive neurons, followed by a discrete transition between delay-responsive neurons and pre-saccadic neurons that exclusively fire around the time of gaze movement. These results show that the FEF is involved in memory-based transformations in gaze control; but instead of encoding specific movement parameters (eye and head) it encodes the desired gaze endpoint. The representations of the movement goal are subject to noise and this noise accumulates at different stages related to different mechanisms

Physiology of Higher Central Auditory Processing and Plasticity

Binaural cue processing requires central auditory function as damage to the auditory cortex and other cortical regions impairs sound localization. Sound localization cues are initially extracted by brainstem nuclei, but how the cerebral cortex supports spatial sound perception remains unclear. This chapter reviews the evidence that spatial encoding within and beyond the auditory cortex supports sound localization, including the integration of information across sound frequencies and localization cues. In particular, this chapter discusses the role of brain regions across the cerebral cortex that may be specialized for extracting and transforming the spatial aspects of sounds and extends from sensory to parietal and prefrontal cortices. The chapter considers how the encoding of spatial information changes with attention and how spatial processing fits within the broader context of auditory scene analysis by cortical networks. The importance of neural plasticity in binaural processing is outlined, including a discussion of how changes in the mapping of localization cues to spatial position allow listeners to adapt to changes in auditory input throughout life and after hearing loss. The chapter ends by summarizing some of the open questions about the central processing of binaural cues and how they may be answered

Investigating the Primate Prefrontal Cortex Correlates of Cognitive Deficits In the Ketamine Model of Schizophrenia

The World Health Organization has classified schizophrenia as one of the five leading causes of disability worldwide. Afflicting almost 1% of the world’s population, the disease’s greatest impact stems from its reduction in patients’ cognitive faculties. In order to better study these impairments, a pharmacological model has been developed using the NMDA antagonist, ketamine. This disease model successfully recreates the cognitive dysfunction of schizophrenia, allowing researchers to search for associated electrophysiological changes. In this project I examined the behavioural and neurophysiological effects of ketamine on non-human primates performing the anti-saccade task. Success in this task requires a degree of cognitive control over behaviour and previous studies have described poor performance in both patients with schizophrenia and healthy controls administered ketamine. Our intracranial recordings are localized in the prefrontal cortex (PFC), a region associated with many of the cognitive functions impaired in schizophrenia. The first study shows that neurons in the PFC exhibit selectivity for the task rule. This rule selectivity is lost after ketamine administration due to an indiscriminate increase in the neuronal firing rate. These changes were also associated with an increased error rate and longer reaction times. The second study shows that neurons in the PFC are also sensitive to the outcome of the trial, firing more for either correct or erroneous responses. Once again, selectivity is lost following ketamine administration and the neurons show increased, nonspecific activity. Lastly, we recorded the local field potential of the PFC and found changes in the oscillatory patterns during the anti-saccade task. Prior to ketamine there was a significantly stronger beta-band activity after correct trials compared to error trials, but this selective activity was lost due to an overall decrease in the outcome selective oscillatory events. These findings show that ketamine’s effect on the PFC is one of selectivity reduction. Patients with schizophrenia have been shown to require increased PFC activity but only reach moderate performance levels in cognitive challenges. It is possible that their brains suffer the same changes highlighted in this research. Although the signals are still present in their PFC, they are being lost amongst the noise

Investigating Cognitive Control And Task Switching Using The Macaque Oculomotor System

Cognitive control is crucial to voluntary behaviour. It is required to select appropriate goals and guide behaviour to achieve the desired outcomes. Cognitive control is particularly important for the ability to adapt behaviour to changes in the external environment and internal goals, and to quickly switch between different tasks. Successful task switching involves a network of brain areas to select, maintain, implement, and execute the appropriate task. Uncovering the neural mechanisms of this goal-directed behaviour using lesions, functional neuroimaging, and neurophysiology studies is central to cognitive neuroscience. The oculomotor system provides a valuable framework for understanding the neural mechanisms of cognitive control, as it is anatomically and functionally well characterized. In this project, pro-saccade and anti-saccade tasks were used to investigate the contributions of oculomotor and cognitive brain areas to different stages of task processing. In Chapter 2, non-human primates performed cued and randomly interleaved pro-saccade and anti-saccade tasks while neural activity was recorded in the superior colliculus (SC). In Chapter 3, non-human primates performed cued and randomly interleaved pro-saccade and anti-saccade tasks while local field potential activity was recorded in the SC and reversible cryogenic deactivation was applied to the dorsolateral prefrontal cortex (DLPFC). In Chapter 4, non-human primates performed uncued and cued pro-saccade and anti-saccade switch tasks while reversible cryogenic deactivation was applied to the dorsal anterior cingulate cortex (dACC). The first study clarifies that macaque monkeys demonstrate similar error rate and reaction time switch costs to humans performing cued and randomly interleaved pro-saccade and anti-saccade tasks. These switch costs were associated with switch-related differences in stimulus-related activity in the SC that were resolved by the time of saccade onset. The second study shows that bilateral DLPFC deactivation decreases preparatory beta and gamma power in the superior colliculus. In addition, the correlation of gamma power with spike rate in the SC was attenuated by DLPFC deactivation. Lastly, bilateral dACC deactivation in the third study impairs anti-saccade performance and increases saccadic reaction times for pro-saccades and anti-saccades. Deactivation of the dACC also impairs the ability to integrate feedback from the previous trial. Overall, these findings suggest unique roles for the dACC, DLPFC, and SC in cognitive control and task switching. The dACC may monitor feedback to select the appropriate task and implement cognitive control, the DLPFC may maintain the current task-set and modulate the activity of other brain areas, and the SC may be modulated by task switching processes and contribute to the production of switch costs

Functional and Structural Brain Reorganization After Unilateral Prefrontal Cortex Lesions In Macaques

Visually exploring the surrounding environment relies on attentional selection of behaviourally relevant stimuli for further processing. The prefrontal cortex contributes to target selection as part of a frontoparietal network that controls shifts of gaze and attention towards relevant stimuli. Evidence from stroke patients and nonhuman primate lesion studies have shown that unilateral damage to the prefrontal cortex commonly impairs the ability to allocate attention toward stimuli in the contralesional visual hemifield. Although these impairments often exhibit a gradual improvement over time, the neural plasticity that underlies recovery of function remains poorly understood. The main objective of this dissertation was to study the relationship between large-scale network reorganization and the recovery of lateralized target selection deficits. To that aim, endothelin-1 was used to produce unilateral ischemic lesions in the caudal lateral prefrontal cortex of four rhesus macaques. Longitudinal behavioural and neuroimaging data were collected before and after the lesions, including eye-tracking while monkeys performed free-choice and visually guided saccades, resting-state fMRI, and diffusion-weighted imaging. Chapter 2 investigated the effects of unilateral prefrontal cortex lesions on saccade target selection and oculomotor parameters to disentangle attentional and motor impairments in the lasting contralesional target selection deficit. Chapter 3 examined the resting-state functional reorganization in a frontoparietal network during recovery of contralesional target selection. Finally, Chapter 4 investigated microstructural changes in cortical white matter tracts from diffusion-weighted imaging after behavioural recovery compared to pre-lesion. In general, spatiotemporal patterns of functional and structural network reorganization differed based on the extent of prefrontal damage. Altogether, these studies characterized the recovery of lateralized target selection deficits in a macaque model of focal cerebral ischemia and demonstrated involvement of both contralesional and ipsilesional networks throughout behavioural recovery. The broad implication of this research is that a network perspective is fundamental to understanding compensatory mechanisms of brain reorganization underlying recovery of function