Prefrontal Cortex Deactivation in Macaques Alters Activity in the Superior Colliculus and Impairs Voluntary Control of Saccades

The cognitive control of action requires both the suppression of automatic responses to sudden stimuli and the generation of behavior specified by abstract instructions. Though patient, functional imaging and neurophysiological studies have implicated the dorsolateral prefrontal cortex (dlPFC) in these abilities, the mechanism by which the dlPFC exerts this control remains unknown. Here we examined the functional interaction of the dlPFC with the saccade circuitry by deactivating area 46 of the dlPFC and measuring its effects on the activity of single superior colliculus neurons in monkeys performing a cognitive saccade task. Deactivation of the dlPFC reduced preparatory activity and increased stimulus-related activity in these neurons. These changes in neural activity were accompanied by marked decreases in task performance as evidenced by longer reaction times and more task errors. The results suggest that the dlPFC participates in the cognitive control of gaze by suppressing stimulus-evoked automatic saccade programs

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

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

Top-down control of visual sensory processing during an ocular motor response inhibition task

The study addressed whether top-down control of visual cortex supports volitional behavioral control in a novel antisaccade task. The hypothesis was that anticipatory modulations of visual cortex activity would differentiate trials on which subjects knew an anti- versus a pro-saccade response was required. Trials consisted of flickering checkerboards in both peripheral visual fields, followed by brightening of one checkerboard (target) while both kept flickering. Neural activation related to checkerboards before target onset (bias signal) was assessed using electroencephalography. Pretarget visual cortex responses to checkerboards were strongly modulated by task demands (significantly lower on antisaccade trials), an effect that may reduce the predisposition to saccade generation instigated by visual capture. The results illustrate how top-down sensory regulation can complement motor preparation to facilitate adaptive voluntary behavioral control

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

Prefrontal Neurons Predict Choices during an Auditory Same-Different Task

SummaryThe detection of stimuli is critical for an animal's survival [1]. However, it is not adaptive for an animal to respond automatically to every stimulus that is present in the environment [2–5]. Given that the prefrontal cortex (PFC) plays a key role in executive function [6–8], we hypothesized that PFC activity should be involved in context-dependent responses to uncommon stimuli. As a test of this hypothesis, monkeys participated in a same-different task, a variant of an oddball task [2]. During this task, a monkey heard multiple presentations of a “reference” stimulus that were followed by a “test” stimulus and reported whether these stimuli were the same or different. While they participated in this task, we recorded from neurons in the ventrolateral prefrontal cortex (vPFC; a cortical area involved in aspects of nonspatial auditory processing [9, 10]). We found that vPFC activity was correlated with the monkeys' choices. This finding demonstrates a direct link between single neurons and behavioral choices in the PFC on a nonspatial auditory task

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

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

Collicular circuits for flexible sensorimotor routing

Context-based sensorimotor routing is a hallmark of executive control. Pharmacological inactivations in rats have implicated the midbrain superior colliculus (SC) in this process. But what specific role is this, and what circuit mechanisms support it? Here we report a subset of rat SC neurons that instantiate a specific link between the representations of context and motor choice. Moreover, these neurons encode animals’ choice far earlier than other neurons in the SC or in the frontal cortex, suggesting that their neural dynamics lead choice computation. Optogenetic inactivations revealed that SC activity during context encoding is necessary for choice behavior, even while that choice behavior is robust to inactivations during choice formation. Searches for SC circuit models matching our experimental results identified key circuit predictions while revealing some a priori expected features as unnecessary. Our results reveal circuit mechanisms within the SC that implement response inhibition and context-based vector inversion during executive control