Existing knowledge identifies the prefrontal cortex (PFC) as the modulatory area for pain. Previous neuroimaging studies suggest the existence of the cortico-cortical pathway, an alternative pain modulatory pathway distinct from the descending modulatory pathway of pain. However, little is known of the extent, mechanism and underlying substrate of the modulation. The objective of this study is therefore to explore the role of the PFC in pain modulation. To examine the extent of PFC involvement in pain, meta-analyses of imaging studies in healthy volunteers and patients with chronic pain were performed. Using Gaussian-process regression (GPR) analysis, brain maps were produced from foci of activation as reported in the studies. Since structure dictates function, our next study was to performprobabilistic tractography on diffusion-weighted brain images to ascertain the connection probability of lateral PFC subdivisions and pain-related brain regions as well as intrinsic PFC connections. Two behavioural studies were conducted to investigate cognitive modulation of pain. The first was a study to assess the subjective and physiological correlates of cognitive stress, as previously used in stress-induced analgesia studies. The second was to investigate the involvement of the endogenous opioid system inthe cognitive modulation of pain through effortful reappraisal and contextual modulation. Meta-analyses in healthy volunteers and chronic pain patients revealed activation mainly in the lateral aspect of the PFC due to pain. Distinct pattern of activation was demonstrated in patients with significant ventrolateral PFC (VLPFC) activation across subtypes of chronic pain. Probabilistic tractography further illustrate the functional significance of lateral PFC subdivisions by demonstrating differential connection probability to pain-related brain regions; dorsolateral PFC (DLPFC) regions displayed higher connection probability with brain regions serving more sensory-discriminative function while VLPFC showed high connection probability with both sensory-discriminative and affective regions. Behavioural study of stress showed that cognitive stress failed to induce significant increases in biomarkers of stress, and was not affected by increased level of difficulty. Lastly, behavioural study on contextual modulation and reappraisal confirmed opioid mediation for contextual modulation while negating its involvement in effortful reappraisal. Findings from this studyillustrate the extent of PFC involvement in pain modulation especially in chronic pain patients and provide further evidence of an alternative pathway distinct from the opioid-mediated descending inhibitory pathway.

Fragile X syndrome (FXS) is the leading single gene cause of intellectual disability and Autism Spectrum Disorder (ASD). It is caused by epigenetic silencing of the fragile X mental retardation gene (FMR1), causing a loss of Fragile-X Mental Retardation Protein (FMRP). Over the last 2 decades, much has been learned about the pathophysiology related to the loss of FMRP from mouse models of FXS. The recent generation of a rat model of FXS opens the door to: validate phenotypes across mammalian species, address cognitive dysfunction using paradigms that are more difficult to address in mice and explore candidate therapeutics more accurately. This thesis explored the validity of a new rat model for FXS (Fmr1 KO rat). I showed that Fmr1 KO rats exhibit normal spatial navigation memory, social interactions and anxiety levels. On the contrary, when subjects were tested in a battery of spontaneous exploration tasks: object recognition (OR), object-context (OC), object-place (OP), and object-place-context (OPC) recognition, which assess associative memory, Fmr1 KO rats showed a severe deficit in remembering the most complex (episodic-like) associations. Following these results, I sought to explore the development of associative memory from postnatal day 25 (P25) to adulthood (P71). Subjects were tested in the four spontaneous exploration tasks, previously mentioned, 8 times between P25 and P71 to assess the development of their ability to discriminate novel from familiar associations between objects, contexts and places. Fmr1 KO rats’ ability to discriminate novel from familiar object-place (spatial) and object-place-context (episodic-like) associations was significantly impaired (OP was delayed, and OPC ability did not develop). In the last part of this thesis I examined whether early therapeutic intervention with lovastatin can restore the cognitive deficits I observed. Subjects were fed either a diet containing lovastatin (“lovachow”) or an identically looking control diet, between P29 and P64, and tested in the four spontaneous exploration tasks, previously mentioned. Fmr1 KO rats demonstrated a developmental profile of associative memory indistinguishable from that of WT animals. At P64, lovachow was replaced with standard laboratory chow and the animals were tested 1 and 3 months later. Surprisingly, lovastatin treated Fmr1 KO animals maintained the ability to perform the OPC task even at 3 months after the end of treatment, whereas Fmr1 KO animals on control chow showed no improvement with age. The findings of this work indicate that transgenic rats can complement existing mouse models of FXS, providing valuable insights into the effects of FMRP loss on cognitive function. Furthermore, the results from the treatment study show that not only can lovastatin treatment prevent the emergence of cognitive deficits associated with Fragile X Syndrome but also that lovastatin (and perhaps pharmaceutical interventions more generally) may prevent the developmental deficits in neuronal circuit formation which can be maintained into adulthood.

In our pilot study investigating Texas Hold ‘em poker, we found that players bluffing (with a losing hand) elicits a similar physiological arousal response (as measured by skin conductance levels) to those in a position of strength and poised to win. Since arousal has been suggested to be a reinforcing factor in problematic gambling behaviour, we sought to replicate the findings of our pilot study in the current investigation. We aimed to extend our previous findings further by: isolating truthful betting (strong betting) to disambiguate deception when players are in positions of strength (i.e. trapping), measuring subjective excitement levels and risk assessments, investigating the physiological arousal responses following wins versus losses, and finally, exploring group differences (i.e. problem gambling status, experience levels). 71 participants played 20 naturalistic rounds of Texas Hold ‘em poker for monetary rewards. We were able to replicate our previous findings that bluffing triggers a physiological arousal (as measured by skin conductance responses) similar to truthful strong betting. Trapping was also found to elicit a skin conductance response similar to both bluffing and strong betting. Measures of subjective excitement revealed a pattern that converged with physiological data. Furthermore, wins were found to be more arousing than losses. Finally, our exploratory analysis of group differences (i.e. problem gambling status, experience) proved to be an insignificant factor with all measures. We conclude that the effect of bluffing on physiological arousal is so powerful that it pervades all participants; which is problematic due to its risky nature and potential to be self-triggered. With its ever increasing popularity and availability, more research on Texas Hold ‘em poker is warranted for treatment implications.

The following two studies examined the influence of spatial regularities on our ability to learn and predict frequencies and sequences of events. Research into statistical and sequence learning has demonstrated that we can learn the statistical properties of events and use this knowledge to make predictions about future events. Research has also demonstrated that redundant spatial features associated with events can influence our ability to respond to and discriminate between different stimuli. The goal of this thesis was to test whether redundant spatial features could influence our ability to notice non-spatial regularities in an environment. Using a computerized version of the children’s game ‘rock-paper-scissors’ (RPS), undergraduates were instructed to win as often as possible against a computer that played varying strategies. For each strategy, the computer’s plays were either presented with spatial regularity (i.e., ‘rock’ would always appear on the left of the screen, ‘paper’ in the middle, and ‘scissors’ on the right) or without spatial regularity (i.e., the items were equally likely to appear in any of the three screen locations). The results showed that, although irrelevant to the task itself, spatial regularities had a moderate influence when participants learned to exploit easy strategies, and a more pronounced influence when learning to exploit harder strategies. This research suggests that redundant spatial features can influence our ability to learn and represent distributions of events.

Superior parietal cortex has been implicated in visuomotor guidance and is proposed to be specialised for action in the lower visual field and peripersonal space. Two patients, one with a right superior parietal lesion leading to optic ataxia (ME), and one with a lesion affecting right inferior parietal cortex (LH), were compared to elderly controls (n=8) and young controls (n=8) on a reciprocal pointing task with movements made in the near-far direction (i.e., sagittal plane) or right-left direction (i.e., fronto-parallel plane). In contrast to both control groups, who demonstrated a speed-accuracy trade-off in movement time and peak velocity, neither of the patients did. When the time spent post-peak velocity (represented as a percentage of total movement time) was examined, both patients demonstrated larger times post-peak velocity than controls for all movement directions. Furthermore, while rightward movements of the right hand had higher times post-peak velocity than leftward movements there were no directional patterns for near-far movements which contrasted with controls who had larger times post-peak velocity for near movements. The patient with the more superior lesion (ME) had the greatest difficulty with movements made back toward the body suggestive of a role for superior parietal cortex in the fine tuning of movements made in this region of space (i.e., personal or peripersonal space). In contrast, all directions of movement seemed to be equally affected in the patient with a more inferior lesion. These results are discussed in terms of the different roles played by inferior and superior parietal cortex in the control of visually guided movements.

Walking around in dynamically changing environments require the integration of three of our sensory systems: visual, vestibular, and kinesethic. Vision is the only modality of these three sensory systems that provides information at a distance for proactively controlling locomotion (Gibson, 1958). The visual system provides information about self-motion, about body position and body segments relative to one another and the environment, and environmental information at a distance (Patla, 1998). Gibson (1979) developed the idea that everyday behaviour is controlled by perception-action coupling between an action and some specific information picked up from the optic flow that is generated by that action. Such that visual perception guides the action required to navigate safely through an environment and the action in turn alters perception. The objective of my thesis was to determine how well perception and action are coupled when approaching and walking through moving doors with dynamically changing apertures. My first two studies were grouped together and here I found that as the level of threat increased, the parameters of control changed and not the controlling mechanism. The two dominant action control parameters observed were a change in approach velocity and a change in posture (i.e. shoulder rotation). These findings add to previous work done in this area using a similar set-up in virtual reality, where after much practice participants increased success rate by decreasing velocity prior to crossing the doors. In my third study I found that visual fixation patterns and action parameters were similar when the location of the aperture was predictable and when it was not. Previous work from other researchers has shown that vision and a subsequent action are tightly coupled with a latency of about 1second. I have found that vision only tightly couples action when a specific action is required and the threat of a collision increases. My findings also point in the same direction as previous work that has shown that individuals look where they are going. My last study was designed to determine if we go where we are looking. Here I found that action does follow vision but is only loosely correlated. The most important and common finding from all the studies is that at 2 seconds prior to crossing the moving doors (any type of movement) vision seems to have the most profound effect on action. At this time variability in action is significantly lower than at prior times. I believe that my findings will help to understand how individuals use vision to modify actions in order to avoid colliding with other people or other moving objects within the environment. And this knowledge will help elderly individuals to be better able to cope with walking in cluttered environments and avoid contacting other objects.

In this dissertation, the effect of mild sleep deprivation on attentional allocation and performance monitoring was investigated using a variety of event-related potential (ERP) paradigms with ecologically realistic periods of sleep deprivation. Seventeen female young adults completed several tasks under alert and sleepy conditions, after 3 and 20 hours of wakefulness, respectively. Objective behavioural measures of response times and error rates indicated virtually no decrements that could be attributed exclusively to sleepiness; however, there were consistent alterations in the ERPs indicative of subtly reduced attentional resources and performance monitoring. The first study (Chapter 2) examined the effect of distraction on the P300, an ERP component related to attention and stimulus processing. Participants performed an auditory oddball task with and without a secondary visual working memory task. Response times (RTs) and P300 amplitudes were affected by the addition of the secondary working memory task. However, an interaction showed that the P300 latency was significantly increased by the secondary task only in the sleepy condition, indicating that processing speed is impaired by a secondary task only when the participant is sleepy. The next study (Chapter 3) used a Go/NoGo contingent negative variation (CNV) task. The CNV is reflective of sustained attention, and is known to be associated with frontal lobe functioning. This task was performed twice, with and without a financial incentive for fast responses, to assess the effect of motivation. The P300 amplitude to the first stimulus and CNV prior to the second were clearly larger to Go stimuli for both levels of alertness when the participant was motivated by the financial incentive. However, with no incentive in the sleepy condition, there was reduced differentiation of the two types of stimuli, indicating a reduced ability to discriminate between important and less important information. In chapters 4 and 5, performance monitoring was examined using two tasks, the Eriksen Flanker task and the Anti-Saccade task, producing an ERP related to errors with two basic components: the error-negativity (Ne/ERN) and error-positivity (Pe), thought to be related to error recognition and error evaluation, respectively. In both data sets, the amplitude of the Ne/ERN was not significantly reduced by sleep deprivation, but the amplitude of the Pe was. In addition, smaller anti-saccade errors produced reduced Ne/ERN amplitudes compared to larger anti-saccade errors. Another marker of performance monitoring is post-error slowing, which was present in the flanker task only during the alert condition. These results indicate that error detection or recognition (Ne/ERN) appears to be relatively preserved during sleep deprivation, but further error evaluation (Pe) and compensation (post-error slowing) are impaired. Taken together, the findings demonstrate that even mild sleep deprivation has a subtle but reliable effect on electrocortical activity associated with attention and performance monitoring despite an absence of behavioural changes, indicating deleterious effects before behavioural changes are observed. Therefore, relying on behavioural tests to determine at what point an individual becomes unsafe to operate machinery or perform various tasks may be misleading.

Superior parietal cortex has been implicated in visuomotor guidance and is proposed to be specialised for action in the lower visual field and peripersonal space. Two patients, one with a right superior parietal lesion leading to optic ataxia (ME), and one with a lesion affecting right inferior parietal cortex (LH), were compared to elderly controls (n=8) and young controls (n=8) on a reciprocal pointing task with movements made in the near-far direction (i.e., sagittal plane) or right-left direction (i.e., fronto-parallel plane). In contrast to both control groups, who demonstrated a speed-accuracy trade-off in movement time and peak velocity, neither of the patients did. When the time spent post-peak velocity (represented as a percentage of total movement time) was examined, both patients demonstrated larger times post-peak velocity than controls for all movement directions. Furthermore, while rightward movements of the right hand had higher times post-peak velocity than leftward movements there were no directional patterns for near-far movements which contrasted with controls who had larger times post-peak velocity for near movements. The patient with the more superior lesion (ME) had the greatest difficulty with movements made back toward the body suggestive of a role for superior parietal cortex in the fine tuning of movements made in this region of space (i.e., personal or peripersonal space). In contrast, all directions of movement seemed to be equally affected in the patient with a more inferior lesion. These results are discussed in terms of the different roles played by inferior and superior parietal cortex in the control of visually guided movements.

Synaesthesia is a fascinating condition in which ordinary stimuli elicit extraordinary sensory experiences. For example, specific tastes may elicit unusual tactile sensations and standard black letters may elicit highly specific colour experiences. These unusual experiences have been shown to have substantial impact on cognition, emotion, perception, and covert attention. Two experiments are presented which show that synaesthesia also influences overt visual attention. In these experiments two grapheme-colour synaesthetes viewed coloured letters while their eye movements were tracked. Letters were presented in colours that were either congruent or incongruent with the synaesthetes' colours. Eye tracking analysis showed that synaesthetes exhibited a colour congruity bias – a propensity to fixate congruently coloured letters more often and for longer durations than incongruently coloured letters – in a naturalistic free viewing task. In a more structured visual search task, this congruity bias caused synaesthetes to rapidly fixate and identify congruently coloured target letters, but led to problems in identifying incongruently coloured target letters. The results are discussed in terms of their implications for perception in synaesthesia.

Some authors have argued that the primary function of the posterior parietal cortex is to control visual attention and awareness, whereas others have argued that the posterior parietal cortex is specialized for controlling actions. The purpose of the present thesis was to examine the influence of prism adaptation – a visuomotor adaptation technique – on visual attention deficits in patients with lesions of parietal cortex. Lesions to dorsal regions of the posterior parietal cortex lead to optic ataxia – a disorder in which visually guided reaching is disrupted. In contrast lesions to ventral (i.e. inferior) regions of the posterior parietal cortex of the right hemisphere lead to spatial neglect – a disorder in which patients are unaware of people or objects in contralesional (left) space. Chapter 1 presents an overview of the organization of the posterior parietal cortex, as well as an introduction to the disorders of spatial neglect and optic ataxia and the use of prism adaptation as a treatment for spatial neglect. Chapter 2 examined the influence of prism adaptation on attentional deficits in patients with right brain damage. Results demonstrated that prism adaptation reduced both the disengage deficit and the rightward attentional bias, two of the classic attentional deficits in neglect. Chapter 3 investigated the role of the dorsal posterior parietal cortex in controlling both reflexive and voluntary attention in two patients with optic ataxia. Lesions to the dorsal posterior parietal cortex led to both a disengage deficit and a rightward attentional bias, similar to patients with neglect, even though neither of the patients had any clinical symptoms of neglect. Contrary to previous work these results indicated that dorsal portions of the posterior parietal cortex – a region not commonly damaged in neglect – are important for controlling the orienting and reorienting of both reflexive and voluntary attention. Furthermore, these results indicated that optic ataxia is not purely a visuomotor disorder that is independent of any perceptual or attentional deficits as was previously assumed. Based on the results of Chapters 2 and 3 it was hypothesized that the beneficial effects of prism adaptation on attention may operate via the superior parietal lobe, a region which is typically undamaged in neglect, and is known to be important for controlling attention and action. Chapter 4 provided support for this hypothesis by demonstrating that a patient with lesions to the superior parietal lobe, who had the same attentional deficits as the right brain damaged patients tested in Chapter 2, failed to demonstrate any beneficial effects of prism adaptation on his attentional performance. Specifically, prism adaptation had no influence on his disengage deficit or his rightward attentional bias. Therefore, these data provide direct evidence that the beneficial effects of prisms on attention rely, at least in part, on the superior parietal lobe. Finally, Chapter 5 concludes with a summary of the research findings from the present thesis, and puts forward a new theory to conceptualize the mechanisms underlying the beneficial effects of prisms in patients with neglect.