Cognitive deficits are highly prevalent in multiple sclerosis (MS) and have a negative impact on daily life. Impairments in information processing speed are among the most commonly reported deficits in MS and are generally assessed by evaluating mean-level performance on time-limited tests. However, this approach to assessing performance ignores potential within-subject differences that may be useful for characterizing cognitive difficulties in MS. An alternative method of measuring performance on timed cognitive tasks is to examine the degree of within-subject variability, termed intraindividual variability (IIV). IIV provides information about the characteristics of an individual’s performance and may provide novel information about cognitive functioning in MS and other neurodegenerative disorders. The research presented in this dissertation examined IIV in performance as an indicator of cognitive functioning in persons with MS and explored the relations of performance variability to measures of neuronal connectivity derived from resting state functional magnetic resonance imaging (rsfMRI). Individuals with MS were found to be both slower and more variable on tests of information processing speed and attention. This variability was observed even when controlling for sensorimotor confounds and other systematic variables that may influence variability, such as practice and learning effects. IIV in performance was found to better distinguish MS patients from matched groups of healthy control subjects when compared to common clinical measures of cognitive performance or average response speed. These differences in IIV were also found consistently across six monthly assessments in a group with MS who remained clinically stable over this period. This stability in IIV suggests its feasibility as a measure of changes in longitudinal cognitive or clinical status. Using rsfMRI, greater stability in performance (i.e., lower IIV) was associated with greater functional connectivity between frontal lobe regions (i.e., ventral medial prefrontal cortex and frontal pole) in persons with MS. This increased connectivity appears to represent potential compensatory processes within mildly affected MS individuals. Together the findings demonstrate that IIV is an important characteristic of cognitive performance that may provide new insights into the cognitive deficits present in MS.

Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) is the dominant tool used for mapping human brain function because it is non-invasive, does not use ionizing radiation, and offers relatively high spatial and temporal resolution compared to other neuroimaging techniques. Unfortunately, conventional fMRI techniques cannot map brain function in the inferior temporal cortex (ITC) and orbitofrontal cortex (OFC). These brain regions experience severe magnetic field distortions due to magnetic susceptibility mismatch with the neighboring air-filled ear-canals (ITC) or sinus cavities (OFC), causing loss of the fMRI signal. Functional imaging capability is important for gaining a better understanding of these brain regions and the diseases that commonly affect them (Alzheimer’s disease and epilepsy (ITC), Parkinson’s disease and schizophrenia (OFC)). Balanced steady state free precession (balanced SSFP) is a relatively new fMRI technique that can measure function in all brain regions. Rather than diffuse signal loss, balanced SSFP images exhibit signal loss in spatially periodic, narrow bands. Banding artifacts cannot be eliminated in a single scan, but the phase of the banding artifacts can be controlled by the experimenter, permitting the combination of two antiphase balanced SSFP images to produce a single image free of banding artifacts. Unfortunately, image-corrupting transient signal oscillations limit the rate at which the banding artifact phase can be modified, such that the banding-artifact-free image acquisition rate is prohibitively slow for most clinical and neuroscience applications. This work describes the development of a modified balanced SSFP fMRI technique, alternating SSFP, which permits rapid, banding-artifact-free balanced SSFP fMRI. Theoretical modeling was used to find a rapid transition between antiphase balanced SSFP images with minimal transient signal oscillations. Monte Carlo simulations were used to optimize alternating SSFP acquisition parameters for BOLD sensitivity, with comparison to established balanced SSFP acquisitions. Rat fMRI was used to confirm these predictions. Finally, the ability of alternating SSFP to provide rapid, banding-artifact-free balanced SSFP fMRI in humans at 4 T was demonstrated.

Models of speech production postulate that, in order to facilitate rapid and precise control of articulation, the predicted auditory feedback is sent to the auditory system to be compared with incoming sensory data. If this is so, an 'error' signal may be observed when the predicted auditory feedback and the sensory consequences of vocalization do not match. I used event-related fMRI to look for the neural concomitants of such an error signal. In two conditions volunteers whispered 'ted'. In one of these, voice-gated noise implemented in our real-time processing system was used to mask the auditory feedback, which should result in an error signal. Two other conditions were yoked to the production conditions (either clearly heard or masked), but were listen-only and therefore no error signal would be expected. I acquired whole-brain EPI data from 21 subjects using a fast-sparse design. Activity in the superior temporal gyrus bilaterally was significantly greater for clear than masked speech during the listen-only trials (F(1,20)≥12.84, p<0.002), and significantly higher for masked than for clear speech in the production trials (F(1,20)≥6.68, p<0.02). This crossover interaction indicates that speech production results in corollary discharge in the auditory system and furthermore suggests that this corollary discharge reflects expectations about the sensory concomitants of speech acts. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2007-09-26 10:02:35.972

Altered sexual function is one of the most devastating consequences of spinal cord trauma (SCT). Despite this fact, current knowledge of the neural circuitry regulating sexual response in the spinal cord (SC) in healthy humans is remarkably incomplete. In order to better understand the changes that occur to sexual responses following SCT, we must elucidate the neural transmission of sexual function in healthy humans. Functional magnetic resonance imaging (fMRI) techniques to map neuronal function have been adapted for the SC and can now reveal this neural circuitry. We mapped, with spinal fMRI, neuronal activity in the lower thoracic, lumbar and sacral SC in healthy men (n = 10) and women (n = 9) that occurs in response to intermittent audiovisual stimulation (AVS), intermittent genital self-stimulation (GSS) and the combination of the former and latter, applied continuously and simultaneously until orgasm (AVGSS). MR images revealed predominantly increased signal intensity changes (ΔS+) in the autonomic preganglionic nuclei of the lower thoracic, lumbar and sacral SC in women and mostly decreased signal intensity changes (ΔS-) in comparable regions in men. In functional MR images, ΔS+ are related to increased neuronal input while ΔS- are associated with diminished neuronal input to a particular region. Linear regression analyses uncovered a greater number of inverse correlations between SC ΔS and scores of sexual function in women than in men indicating greater descending modulation of SC circuits regulating sexual responses in women than in men. Taken together, our results demonstrate that spinal fMRI is an effective and sensitive technique that can reveal signal intensity changes in the lower thoracic, lumbar and sacral SC associated with AVS, GSS and AVGSS in healthy men and women. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2009-10-06 21:26:15.011

Brain tumours, even though rare, are one of the deadliest types of cancer. The five year survival rate for the most malignant type of brain tumours is below 5%. Modern medicine provides many options for treating brain cancer such as radiotherapy and chemotherapy. However, one of the most effective ways of fighting the disease is surgical resection. During such a procedure the tumour is partially or completely removed. Unfortunately, even after a complete resection some tumourous tissue is left behind and can grow back or metastasise to a different location in the brain. It has been shown, however, that more aggressive resections lead to longer life expectancy. This does not come without risks. Depending on tumour location, extensive resections can lead to transient or permanent post-operative neurological deficits. Therefore, when planning a procedure, the neurosurgeon needs to find balance between extending patients life and maintaining its quality. Recent developments in Magnetic Resonance Imaging (MRI) fueled by the field of human cognitive neuroscience have led to improved methods of non-invasive imaging of the brain function. Such methods allow the creation of functional brain maps of populations or individual subjects. Adapting this technique to the clinical environment enables the assessment of the risks and to plan surgical procedures. The following work aims at improving the use of functional MRI with a specific clinical goal in mind. The thesis begins with description of etiology, epidemiology and treatment options for brain tumours. This is followed by a description of MRI and related data processing methods, which leads to introduction of a new technique for thresholding statistical maps which improves upon existing solutions by adapting to the nature of the problem at hand. In contrast to methods used in cognitive neuroscience our approach is optimized to work on single subjects and maintain a balance between false positive and false negative errors. This balance is crucial for accurate assessment of the risk of a surgical procedure. Using this method a test-retest reliability study was performed to assess five different behavioural paradigms and scanning parameters. This experiment was performed on healthy controls and was aimed at selecting which paradigms produce reliable results and therefore can be used for presurgical planning. This allowed the creation of a battery of task that was applied to glioma patients. Functional maps created before the surgeries were compared with electrocortical stimulation performed during the surgeries. The final contribution of this work focuses on technical aspects of performing neuroimaging data analysis. A novel data processing framework which provides means for rapid prototyping and easy translation and adaptation of already existing methods taken from cognitive neuroscience field is introduced. The framework enables fully automatic processing of patient data and therefore greatly reduced costs while maintaining quality control. A discussion of future directions and challenges in using functional MRI for presurgical planning concludes the thesis.

Listening to music is rated as one of the most pleasurable activities in human life and,in fact, listeners report the emotional impact of music to be one of the main motivatorsas to why they listen to music. This thesis focuses on the positive affective statesexperienced when listening to music and their underlying neural substrates. Despite thefact that research on the neural correlates of music-induced positive affect is arelatively recent undertaking our understanding has significantly improved during thelast decades. The aim of the current thesis is to give an overview of the neuralcorrelates of music-induced positive affect in healthy individuals. As such,psychophysiological, neuroimaging and electrophysiological studies are reviewed.Across studies the consistent involvement of brain regions, such as the orbitofrontalcortex, the striatum and the amygdala and left hemisphere frontal regions in response tomusic-induced positive affect has been found. These structures constitute an importantpart of the mesolimbocortical reward circuitry found to be involved in the processing ofa wide range of pleasures. The thesis also discusses conceptual and methodologicallimitations inherent in the studies reviewed. Understanding the nature and underlyingneural basis of music-induced positive affect is important because of the implications itmay have for psychological and physical wellbeing.

Maternal smoking during pregnancy has often been associated with numerous adverse outcomes for the offspring. However, its long-term effects are not well established. Given the high prevalence of maternal smoking during pregnancy, an understanding of these effects is essential. Therefore, the aim of the present dissertation was to shed light on the long-term neurophysiological effects of prenatal nicotine exposure on three different executive functioning processes by assessing participants in young adulthood, using functional magnetic resonance imaging (fMRI). Participants imaged were members of the Ottawa Prenatal Prospective Study, a longitudinal study that collected a unique body of information on participants from infancy to young adulthood, which allowed for the measurement of an unprecedented number of potentially confounding drug exposure variables. The dissertation consists of three separate original manuscripts. In manuscript 1, participants completed a response inhibition task, in manuscript 2 participants completed a verbal working memory task and in manuscript 3 participants completed a visuospatial working memory task. Taken together, results from all three manuscripts showed that prenatal nicotine exposure leads to altered neural functioning during executive functioning processing that continues into young adulthood. These significant results highlight the need for education about the repercussions of women smoking during pregnancy.

Human behavior relies on the accumulation of task-relevant information to narrow the range of possible responses to a single response. How do we utilize advance information that can help us select and prepare responses to a task? How is this performance benefit facilitated in the brain? Previous literature suggests a subset of brain regions involved in cue-specific processing. We investigated how informative cues affect brain processing. Specifically, to what extent is activity modulated for stimulus-related and response-related cues versus neutral cues in control- and processing-related regions? Participants made manual responses to the identity of face or place stimuli in a variation of the response cuing paradigm while fMRI BOLD signal was recorded. Prior to the stimulus, a letter cue indicating the upcoming stimulus type (face or place) or response hand (left or right) or a neutral cue was presented. We proposed three hypotheses: 1) control-related activity (e.g., prefrontal, parietal) would increase for cued vs. uncued trials; 2) activity in face and place processing regions and left and right premotor regions would activate for their respective cues, although all cues were letters; and 3) stimulus processing regions would also be activated by response cues, and vice versa.

The prevalence of chronic pain is known to increase with advancing age, with over 50% of community dwelling older adults (aged 65 years and over) and up to 80% of those residing in nursing homes estimated to be suffering some form of persistent or recurring pain complaint. In addition to a greater likelihood of pain, advancing age is associated with increased reports of pain interference. It is possible to ascribe age-related changes in pain report and impact to increased disease prevalence and severity in older people. However, there is also evidence that ageing has effects on pain perception, central pain processing, and plasticity of pain responses that are not explained by co-morbid disease. / The increased prevalence of chronic pain in older adults represents a major public health concern. As a result of increased life expectancy and the post-World War II baby boom, there will be a dramatic change in the demographic structure of our population over the coming decades, with older adults representing the fastest-growing segment of our communities. The proportion of the total population over the age of 65 in Australia has risen from 9% in 1976, to 12% in 2001, and is predicted to reach 16% by the year 2016. Pain that is undetected or under-treated can adversely affect quality of life for older adults, leading to diminished mood, impaired cognition, behavioural problems, as well as increased functional dependence. This in turn contributes to greater demands for daily personal care and a resultant increase in health-care costs. / Pain management is a particularly salient issue in the case of older adults with dementia, who are at increased risk of undetected pain on account of impaired cognition and communication skills. Indeed, clinical reports show that patients with Alzheimer’s disease (AD) are routinely administered fewer pain-relief medications compared with their cognitively-intact peers. Understandably, reports of reduced analgesia in AD have sparked considerable research interest, and over recent years there has been a marked increase in the number of studies aimed at better characterising the experience of pain in patients with AD. However, despite these efforts, the effects of neurodegeneration on pain processing, and the specific ways in which the disease process impacts on brain responses to noxious stimulation and the ensuing experience of pain have not been previously determined. / Improved management of pain is fundamental to the clinical care of older adults, particularly those with dementia. However, the potential to adequately counteract pro-nociceptive processes and facilitate endogenous inhibitory mechanisms in the treatment of ongoing pain in older adults will only become possible once the effects of ageing and age-related neurodegeneration on central pain processing are identified and described. The overarching goal of this thesis was therefore to improve current understanding of the ways in which normal ageing and Alzheimer’s disease impact on the perception and central nervous system processing of pain. The findings of this thesis provide valuable new insights into the impact of ageing and AD on the central mechanisms contributing to pain perception, and may therefore contribute toward better management and treatment of pain in this vulnerable and rapidly growing sector of our community. / Thesis outline: Chapter 2 provides a review of the background literature and rationale for the thesis. The chapter begins with a discussion of current understanding of pain as a multidimensional phenomenon shaped by sensory, emotional and cognitive components, and leads into a description of neural mechanisms of nociception, as well as the supraspinal processes involved in the elaboration of nociceptive signals into these aspects of pain. The impact of ageing on the structure and function of central nervous system regions underlying these processes are discussed, along with the findings from previous clinical and empirical data which suggest age-related changes in pain perception. Current understanding of the neuropathological and clinical aspects of AD is reviewed, with particular emphasis on potential ways in which the disease may impact on central nociceptive processing and the behavioural response to pain. This is followed by a review of the previous clinical and empirical literature examining pain perception in AD. Finally, the aims of the current thesis are outlined. / Chapter 3 describes the general methods which were employed in the subsequent empirical chapters in order to address the aims of the thesis. The equipment and psychophysical procedures used to assess pain perception in healthy young and older adults and patients with AD are described. The basic principals of magnetic resonance imaging (MRI) are then outlined, and the utility of structural and functional MRI for assessing age-related and disease-related changes to brain regions involved in pain perception and processing are discussed. The empirical studies which were undertaken to identify the impact of ageing and AD on central pain processing are presented in the next three chapters. / Chapter 4 begins with psychophysical studies comparing sensory and emotional responses to pain in healthy young and older adults, and follows with MRI investigations of age-related differences in brain volumetry and pain-related brain activity. Studies of pain sensitivity and pain-evoked brain activity in patients with AD compared with age-matched controls are presented in Chapter 5. Following on from these findings of AD-related differences in pain-evoked brain activation, the study described in Chapter 6 used functional connectivity analysis in order to assess the impact of AD on the functional integration of brain regions underlying the sensory, emotional, and cognitive aspects of pain. / The key findings presented in the preceding three chapters are summarized in a general discussion in Chapter 7. The implications of the findings, in terms of the clinical management of pain in older adults with and without Alzheimer’s disease are discussed. The opportunity is also taken to discuss some of the limitations of the present research, and finally, recommendations are made for future research directions.

Parkinson’s disease (PD) is a neurodegenerative disorder commonly presenting with perceptual and cognitive dysfunction. Whereas previous work in PD suggests that abnormal basal ganglia activity has profound effects on integrated functioning of widespread cortical networks, the relation of specific network functions to the perceptual and cognitive impairments is still poorly understood. Here, I present a series of fMRI investigations of network-level functioning in non-demented individuals with PD with the aim of elucidating these associations. Study 1 examined the neural correlates of optic flow processing in 23 individuals with PD and 17 age-matched control participants (MC). An optic flow network comprising visual motion areas V6, V3A, MT+ and visuo-vestibular areas PIVC and CSv is known to be important for parsing egomotion depth cues in humans. The hypothesis was that individuals with PD would show less activation in these regions than MC when processing optic flow. While MC participants showed robust activation in this network, PD participants showed diminished activity within MT+ and CSv. Diminished CSv activity also correlated with greater disease severity. Study 2 investigated intrinsic network organization in PD with a focus on the functional coupling among three neurocognitive networks: the default-mode network (DMN), the salience network (SN), and the central executive network (CEN). Twenty-four individuals with PD and 20 MC participants were scanned at rest. The hypothesis was that PD participants would demonstrate dysfunctional SN coupling with the DMN and CEN. Relative to MC, in PD the CEN was less positively coupled with the SN and less anti-correlated with the DMN. Study 3 investigated the association between functional coupling and cognition in the same group that participated in Study 2. As hypothesized, anti-correlated functional coupling between the SN and DMN was related to successful performance on tests of executive function, psychomotor speed, and memory retrieval in MC but not in PD, suggesting that dysfunction within these networks could underlie early cognitive deficits in PD. Together, the results from the three studies suggest that dysfunctional activity in cortical networks important for visual motion processing and neurocognitive efficiency may underlie aspects of perceptual and cognitive impairment in PD. / 2017-12-06T00:00:00Z