Differential Effects of Macaque Dorsolateral Prefrontal Deactivations During Uncued and Cued Role Conditions

Cognitive control enables us to guide our behaviour in an appropriate, context-dependent manner. This behavioral flexibility is probed by task-switching paradigms, which require working memory to maintain relevant rules and flexibility to switch between rules. The dorsolateral prefrontal cortex (DLPFC) has been implicated in rule maintenance by neuroimaging and electrophysiological studies. While these studies have identified a correlation between DLPFC activity and rule maintenance, deactivation studies allow us to establish a causal relationship. Here we have examined the effect of bilateral deactivation of areas 46 and 9/46d on rule maintenance, while a monkey (Macacca mulatta) performed blocks of pro- and anti-saccades. Areas 46 and 9/46d were deactivated by pumping chilled methanol through bilaterally implanted cryoloops. Rule maintenance was tested while monkeys performed blocks of pro- and anti-saccades with and without instruction cues. Monkeys had to look toward the stimulus on pro-saccade trials and away from the stimulus to its mirror location on anti-saccade trials. After 15-25 correct responses, the task switched (e.g. from pro-saccades to anti-saccades) without any explicit signal to the monkey. Bilateral area 46 deactivation impaired performance throughout both blocks, while bilateral area 9/46d deactivation did not affect performance. Surprisingly, bilateral deactivation of both areas (46 and 9/46d) impaired performance on anti-saccade trials but recovered performance on pro-saccade trials. These results present a causal relationship between area 46 and rule maintenance and provide evidence for functional dissociation between subregions in the dorsolateral PFC for rule-guided behavior

Unique and shared roles of the posterior parietal and dorsolateral prefrontal cortex in cognitive functions

The dorsolateral prefrontal cortex (PFC) and posterior parietal cortex (PPC) are two parts of a broader brain network involved in the control of cognitive functions such as working-memory, spatial attention, and decision-making. The two areas share many functional properties and exhibit similar patterns of activation during the execution of mental operations. However, neurophysiological experiments in non-human primates have also documented subtle differences, revealing functional specialization within the fronto-parietal network. These differences include the ability of the PFC to influence memory performance, attention allocation, and motor responses to a greater extent, and to resist interference by distracting stimuli. In recent years, distinct cellular and anatomical differences have been identified, offering insights into how functional specialization is achieved. This article reviews the common functions and functional differences between the PFC and PPC, and their underlying mechanisms

The cognitive neuroscience of visual working memory

Visual working memory allows us to temporarily maintain and manipulate visual information in order to solve a task. The study of the brain mechanisms underlying this function began more than half a century ago, with Scoville and Milner’s (1957) seminal discoveries with amnesic patients. This timely collection of papers brings together diverse perspectives on the cognitive neuroscience of visual working memory from multiple fields that have traditionally been fairly disjointed: human neuroimaging, electrophysiological, behavioural and animal lesion studies, investigating both the developing and the adult brain

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

Role of cholinergic receptors in prefrontal activity of nonhuman primates during an oculomotor rule-based working memory task

The ability to flexibly react to our dynamic environment is a cardinal component of cognition and our human identity. Millions across the globe are affected by disorders of cognition, affecting their ability to live independently. Prefrontal cortex is required for optimal cognitive functioning, but its circuitry is often disrupted in conditions of impaired cognition. In addition, the cholinergic system is vital to optimal executive function, but this is disrupted in a number of conditions, including Alzheimer’s disease and schizophrenia. The actions of cholinergic receptors were explored in this project with local application of cholinergic compounds onto prefrontal neurons as rhesus monkeys performed a rule-based saccadic task that requires working memory maintenance. The antisaccade task is a useful probe of prefrontal cortex function that elicits errors in neuropsychiatric conditions. Some prefrontal neurons respond to different task aspects of the antisaccade task, e.g., discharging preferentially for one task rule over the other (pro- or antisaccades), and are thought to be involved in the circuitry for correct behavioural responses. Chapter 2 explored the effect of general stimulation of cholinergic receptors on rhesus PFC neuronal activity during antisaccade performance. In Chapter 3, newly developed cholinergic receptor subtype-specific compounds were utilized to examine the actions of muscarinic M1 receptor stimulation on prefrontal activity. Cortical oscillations are emerging as an important aspect of cognitive circuitry, such as during working memory maintenance. Chapter 4 examined the influence of local cholinergic receptor stimulation and blockade on the power of local field potential in different frequency bands. This project characterized the role of cholinergic receptors in prefrontal cortical neurons that were actively involved in cognitive circuitry. This and future work on the cholinergic influence on prefrontal cortex will provide insights into the altered cognitive functioning in Alzheimer’s disease and schizophrenia, which are also affected by disrupted cholinergic systems

Muscarinic attenuation of mnemonic rule representation in macaque dorsolateral prefrontal cortex during a pro- and anti-saccade task

Maintenance of context is necessary for execution of appropriate responses to diverse environmental stimuli. The dorsolateral prefrontal cortex (DLPFC) plays a pivotal role in executive function, including working memory and representation of abstract rules, and is modulated by the ascending cholinergic system through nicotinic and muscarinic receptors. Muscarinic receptors’ effect on local primate DLPFC neural activity in vivo during cognitive tasks remains poorly understood. Here we examined the effects of muscarinic receptor blockade on rule-related activity in the macaque prefrontal cortex by combining iontophoretic application of the general muscarinic receptor antagonist scopolamine with single-unit recordings while monkeys performed a rule-guided saccade task. We found that scopolamine reduced overall neuronal firing rate and impaired rule discriminability of task-selective cells. Saccade and visual direction selectivity measures were also reduced by muscarinic antagonism. These results demonstrate that blockade of muscarinic receptors in dorsolateral prefrontal cortex creates deficits in working memory representation of rules in primates

Dorsolateral prefrontal lesions do not impair tests of scene learning and decision-making that require frontal–temporal interaction

Theories of dorsolateral prefrontal cortex (DLPFC) involvement in cognitive function variously emphasize its involvement in rule implementation, cognitive control, or working and/or spatial memory. These theories predict broad effects of DLPFC lesions on tests of visual learning and memory. We evaluated the effects of DLPFC lesions (including both banks of the principal sulcus) in rhesus monkeys on tests of scene learning and strategy implementation that are severely impaired following crossed unilateral lesions of frontal cortex and inferotemporal cortex. Dorsolateral lesions had no effect on learning of new scene problems postoperatively, or on the implementation of preoperatively acquired strategies. They were also without effect on the ability to adjust choice behaviour in response to a change in reinforcer value, a capacity that requires interaction between the amygdala and frontal lobe. These intact abilities following DLPFC damage support specialization of function within the prefrontal cortex, and suggest that many aspects of memory and strategic and goal-directed behaviour can survive ablation of this structure

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

The role of the ventrolateral frontal cortex in inhibitory oculomotor control

It has been proposed that the inferior/ventrolateral frontal cortex plays a critical role in the inhibitory control of action during cognitive tasks.However, the contribution of this region to the control of eye movements has not been clearly established.Here, we describe the performance of a group of 23 frontal lobe damaged patients in an oculomotor rule switching task for which the association between a centrally presented visual cue and the direction of a saccade could change from trial to trial. A subset of 16 patients also completed the standard antisaccade task.Ventrolateral damage was found to be a significant predictor of errors in both tasks. Analysis of the rate at which patients corrected errors in the rule switching task also revealed an important dissociation between left and right hemisphere damaged patients.Whilst patients with left ventrolateral damage usually corrected response errors with secondary saccades, those with right hemisphere lesions often failed to do so. The results suggest that the inferior frontal cortex forms part of a wider frontal network mediating inhibitory control over stimulus elicited eye movements. The critical role played by the right ventrolateral region in cognitive tasks may arise due to an additional functional specialization for the monitoring and updating of task rules