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Patients with Amyotrophic lateral sclerosis (ALS) often experience cognitive impairment that accompanies degeneration of the motor system. A valuable tool for assessing cognitive control over behaviour is the antisaccade task which requires: 1) inhibition of the automatic response to look towards an eccentric visual stimulus (prosaccade) to instead 2) redirect gaze in the opposite direction of the stimulus (antisaccade). Psychometric tests were used to quantify the degree of impairment, while eye tracking, functional magnetic resonance imaging (fMRI) and structural MRI were combined to identify the neural correlates of cognitive impairment in ALS. We predict ALS patients will have executive dysfunction and grey matter loss in executive and oculomotor control areas that will affect antisaccade performance and will alter the corresponding brain activation. ALS patients and age-matched controls participated in a rapid-event-related fMRI design with interleaved pro- and antisaccade trials. Catch trials (no stimulus presented after instructional cue to prepare pro- or antisaccade) allowed us to discern the preparatory period from the execution period. ALS patients were biased towards automatic saccade responses, and had greater difficulty with antisaccades relative to controls in terms of correct and timely responses. We found that worsened antisaccade performance in ALS correlated with the degree of cognitive impairment. Generally, we found trends of increased brain activation during the preparatory period of antisaccades in ALS patients compared to controls in most oculomotor areas; meanwhile few differences were seen during execution. Structural analyses revealed ALS patients had decreased grey matter thickness in frontotemporal and oculomotor regions such as the frontal and supplementary eye fields (FEF, SEF) and the dorsolateral prefrontal cortex (DLPFC). These findings suggest that loss of structural integrity and executive dysfunction may elicit compensation mechanisms to improve functional and behavioural performance. Despite this compensation, ALS patients still performed worse on antisaccades than controls. Further investigation to expand the current data set should improve our ability to assuredly identify the neural correlates of cognitive decline in ALS, and may provide a model system to use for critical evaluation of future therapies and interventions for ALS.

Background: The study of impact biomechanics in contact sports has improved our current understanding of concussion mechanisms and the cumulative effects of subconcussive impacts on brain health. Impact exposure is often described by the total insults an athlete sustains or peak magnitude, however, these metrics do not consider underlying properties of the acceleration-time impact profile. It remains unknown whether additional kinematic information can better differentiate impact exposure across positions and session types or characterize subclinical brain changes. Purpose: The objective of this project was to examine potential differences in the biomechanical properties of impacts sustained by collegiate football athletes. These parameters were also used to evaluate changes in functional connectivity and resting perfusion over a season of football. Methods: Helmet accelerometer data were analyzed to characterize subconcussive impact exposure among collegiate football athletes. Impact frequency (per session), peak linear and rotational magnitude, impact duration, area under the acceleration-time curve, impulse, and peak head jerk were used to differentiate mechanical loading events between positional groups, as well as across session types. Resting-state neuroimaging was also used to evaluate the relationship between positional group, impact biomechanics, and concussion history with changes in functional connectivity and resting perfusion in a subset of athletes following subconcussive impact exposure. Results: Biomechanical differences were found in all parameters of interest between session types and positional groups. Several properties of the linear acceleration profile, in addition to rotational velocity, highlighted alterations in regional hemodynamics and functional connectivity within the brain, whereas no such differences were observed using impact count or peak linear acceleration alone. Scaling the functional connectivity data by resting perfusion altered the observed differences in some regions of the brain, highlighting the shared variance that exists between functional network re-organization and perturbations to local physiology following subconcussive impact exposure. Conclusion: These findings indicate that kinematic profile analyses may provide novel insight beyond impact count or peak magnitude that allows for a more complete characterization of impact biomechanics. Altogether, this approach creates a strong paradigm for future studies to examine how these impact parameters relate to injury risk following exposure to repetitive subconcussive head impacts.

Resting-state functional MRI examines activity of the central nervous system in the absence of a specific task or stimulus, and has been used to investigate coordinated activity within the cerebral hemispheres, as well as the brainstem and spinal cord. While previous research has shown coordinated resting-state BOLD fluctuations in the brainstem and cord, the extent of resting-state networks (RSNs) and their function are still unclear. Characterizing these networks is an important step towards understanding the complex processing that occurs in the spinal cord and brainstem outside of a reaction to a stimulus. The overall aim of this thesis was to investigate the function of spinal cord and brainstem RSNs, by examining how these networks change when participants are experiencing different cognitive states. If a person’s cognitive/emotional state can be shown to influence resting-state BOLD signal fluctuations in the brainstem/cord, then we can infer that a function of these RSNs is to modulate the excitability of spinal cord neurons. We first aimed to confirm the presence of RSNs in the brainstem and spinal cord. After doing so, we present evidence that, while RSNs are largely consistent across 3 conditions (a resting-state condition, an audio presentation, and a video), watching a video or listening to an audio presentation alters these networks in specific ways. Combined with prior evidence, these results show that the observed networks likely help integrate homeostatic autonomic functions. Building on this evidence, we investigated how connectivity in the previously-identified networks is altered when a participant is specifically expecting pain. We provide evidence that coordinated brainstem and spinal cord networks are affected by the expectation of pain differently than by other distracting situations such as focusing on a video. We conclude that these networks may serve to integrate autonomic regulatory functions with pain processing. Linking the function of these networks to homeostatic autonomic control and pain modulation is an important step in understanding the complex brainstem/spinal cord activity that occurs aside from a reaction to a painful stimulus. Findings of this thesis will help provide a deeper understanding of pain modulation and subjective experiences of pain, such as placebo/nocebo effects.

Provoked Vestibulodynia (PVD) is the most common form of chronic vulvar pain, affecting 12% of women in the general population. Research has demonstrated that women with PVD display both allodynia and hyperalgesia to pain at vulvar and non-vulvar sites, as well as reduced psychosocial functioning. The goal of this study was to use a multi-method approach (interview, questionnaires, sensory testing, and fMRI) to examine group differences between women with PVD (N=15) and healthy control women (N=15). Results will allow for improved understanding of the interaction between psychosocial and neurobiological underpinnings of this disorder, which can contribute to the creation of better treatment strategies. Variables included psychophysical and psychosocial measures, as well as neural activations associated with painful pressure, painful words, and psychosocial functioning. Differences between subgroups of PVD, based on temporal onset, were also examined. There were no robust group differences in neural activation during the application of pain or pain words. This finding is consistent with many studies that match groups on pain intensity ratings, as opposed to amount of pressure applied. Painful pressures and painful words resulted in greater neural activation than neutral words or touch; however, there were no group differences for the word conditions. Women with PVD reported increased psychosocial dysfunction, including higher levels of anxiety and catastrophizing. Significant correlations were found between these psychosocial variables and areas of the brain associated with pain modulation and attention (e.g., PFC). Examination of PVD subgroups revealed differences in neural correlates of anxiety and catastrophizing during painful stimulation. This finding adds to the literature suggesting that women with primary PVD experience greater dysfunction than women with secondary PVD. Overall, these studies support findings of pain processing in the general pain literature, as well as supporting PVD as a chronic pain condition. They also add to the development of a greater understanding of the interaction between psychophysical and psychosocial components of chronic pain by examining their relationship with neural activations. Future research should examine brain functioning in PVD women pre- and post-treatment as well as examining neural correlates of other psychosocial variables that contribute to the pain experience (e.g., somatization).

Quantitative measures of gray matter (GM) and white matter (WM) can be derived from structural and diffusion Magnetic Resonance Imaging (MRI) to study the cerebral cortex and WM projections. Previous multimodal research in patient populations suggests that changes in GM or WM properties propagate to the other tissue type in anatomically connected regions. The association between GM and WM measures is poorly understood, especially in healthy subjects. Addressing this gap is important because the relationship between GM and WM measures may vary over the lifespan where MRI measures may reflect different underlying mechanisms. The primary purpose of this research was to determine the relationship between GM and associated WM in healthy young adults. It was hypothesized that lower cortical morphometric measures would be associated with lower tract volume and WM micro-structural integrity. These relationships were examined using a surface and tract based approach with a subset of the Human Connectome Project dataset. The cortical surface and 16 known WM pathways were reconstructed. The two WM tract endings for each pathway were projected onto the cortical surface to identify associated GM regions. The WM volume and average fractional anisotropy (FA) were computed for each reconstructed tract of interest (TOI). The cortical thickness, surface area, GM volume and curvature measures were extracted for each corresponding GM region of interest (ROI). The magnitude, direction and significance of the Spearman's Rank Correlation coefficients were used to evaluate the association between GM and WM measures from structurally connected TOIs and ROIs. The most noteworthy findings were the relationships between surface area and WM properties and GM volume and WM properties. Surface area and GM volume were consistently positively correlated with WM volume. These correlations varied from weak to strong and reached significance in nearly all regions examined across the brain. Surface area and GM volume also demonstrated a weak to moderate negative correlation with tract average FA which was significant in over 40\% of the brain regions examined. The relationships between other GM and WM measures were inconclusive with a lack of supporting evidence. Characterizing these relationships may lead to easier detection of abnormal relationships.

Generalized Anxiety Disorder (GAD) is a highly prevalent anxiety disorder, characterized by chronic, excessive worry. Physical symptoms are prevalent in GAD, but physiological data are often inconsistent. The goal of the present research is to investigate the neural responses to threat in GAD versus healthy controls (HC). To achieve this goal, we collected data from the largest span of the central nervous system to-date, using functional magnetic resonance imaging (fMRI). This work was broken down into the following three aims: to identify neural activity differences between GAD and HC groups in response to threat in Aim 1) the brain, Aim 2) the cervical spinal cord, and Aim 3) the thoracic spinal cord. All three aims use data acquired from a single sample of 16 participants with GAD and 14 HC. The thesis begins with an introduction to relevant topics including GAD, physiology, and MRI technology. Aim 1) is addressed in two parts. Aim 1a is an in-depth systematic review and meta-analysis on previous neuroimaging research to identify the known neural correlates of GAD, yielding results from the dorsolateral prefrontal cortex, anterior cingulate cortex, amygdala, hippocampus, and culmen of the cerebellum, among others. Aim 1b includes a brain fMRI study in which GAD and HC participants view emotion-evoking images. First, region-of-interest analyses are conducted using regions identified in the systematic review, but results are not significant for these analyses. A follow-up whole brain analysis yields significant results for the main effect of group, corroborating many of the findings from the systematic review. Aims 2 and 3 are considered together in an identical fMRI task as Aim 1b, this time looking at the cervical and thoracic spinal cord. Spinal cord results include increased activity in ventral rostral cervical cord (innervating the neck, shoulders, and trapezius muscles) and mediolateral thoracic cord (innervating the adrenal medulla and gut) for the GAD group as compared to HC. These results provide neurological evidence for increased muscle tension and autonomic activity in the gut and adrenal glands for those with GAD. This work provides the most comprehensive fMRI study of the neurophysiological underpinnings of GAD to-date.

A Brain Computer Interface (BCI) system can bypass impaired systems in the brain, nervous system, and muscles to enable alternate function and allow the user to reconnect with the outside environment. Measurements for these systems usually include the collection of brain signal activity from sensors mounted on the surface of the scalp. Electroencephalography (EEG) and functional near infrared spectroscopy (fNIRS) are two commonly used non-invasive brain imaging modalities in BCI systems. EEG records the electrical activity produced by neuronal activations whereas fNIRS measures the concentration changes of oxy- (HbO) and deoxyhemoglobin (HbR) molecules in the brain cortex. In this thesis, both EEG and fNIRS data collected during a bilateral right- and left-hand motor imagery task were used to detect brain signals that suggest intent to move. Feature extraction and classification are two important components of a BCI in which discriminant features are extracted from the brain signals and then decoded to interpret the user’s intent. Using the fNIRS data in the first part of this thesis, different features were extracted (mean, peak, minimum, skewness, and kurtosis) and classification algorithms (linear (LDA) and quadratic discriminant analysis (QDA), support vector machine (SVM), Logistic Regression, and Naïve Bayes) were compared to find the set of features and classifiers with the highest accuracy. The mean, peak, and minimum of HbO, as well as the mean of HbR and mean of difference between HbO and HbR produced the highest accuracies among features, whereas skewness and kurtosis of HbO resulted in the lowest accuracies. Furthermore, QDA and SVM with polynomial and Gaussian kernel functions resulted in the highest accuracies compared to other classifiers. Using QDA and SVM, this study assessed a channel selection algorithm to reduce the number of sensors in the BCI examining a strategy to use fNIRS results to target the placement of EEG electrodes. Lastly, the feasibility of hybrid EEG and fNIRS system was investigated by comparing corresponding classification accuracies to EEG and fNIRS alone. The combined EEG and fNIRS system resulted in significant improvements in classification accuracies compared to EEG or fNIRS alone.

Background: Obsessive-compulsive disorder (OCD) is a debilitating mental health disorder with current psychotherapeutic treatments, while somewhat effective, yielding low accessibility and scalability. A lack of knowledge regarding the neural pathology of OCD may be hindering the development of innovative treatments. Previous research has observed baseline brain activation patterns in OCD patients, elucidating some understanding of the implications. However, by using neuroimaging to observe the effects of treatment on brain activation, a more complete picture of OCD can be drawn. Currently, the gold standard treatment is cognitive behavioural therapy (CBT). However, CBT is often inaccessible, time-consuming, and costly. Fortunately, it can be effectively delivered electronically (e-CBT). Objectives: This pilot study implemented an e-CBT program for OCD and observed its effects on cortical activation levels during a symptom provocation task. It was hypothesized that abnormal activations could be attenuated following treatment. Methods: OCD patients completed a 16-week e-CBT program administered through an online platform, mirroring in-person content. Treatment efficacy was evaluated using behavioural questionnaires and neuroimaging. Activation levels were assessed at resting state and during the symptom provocation task. Results: Significant improvements (p < 0.05) were observed between baseline and post-treatment for symptom severity and levels of functioning. No statistically significant (p = 0.07) improvement was observed in quality-of-life. Participants had mostly positive qualitative feedback, citing accessibility benefits, comprehensive formatting, and relatable content. No significant changes in cortical activation were observed between baseline and post-treatment. Decreases in activation were seen in the orbitofrontal cortex, thalamus, precuneus, fusiform gyrus, and lingual gyrus. Increases in activation in the cingulate were observed. Conclusion: This project sheds light on the application e-CBT as a tool to evaluate the effects of treatment on cortical activation, setting the stage for a larger-scale study. The program showed great promise in feasibility and effectiveness. While there were no significant findings regarding changes in cortical activation, the trends were in agreeance with previous literature, suggesting future work could provide insight into whether e-CBT offers comparable cortical effects to in-person psychotherapy. Applying a greater knowledge of the neural mechanisms of action in OCD can help develop novel treatment plans in the future.

Opioid receptors are the sites of action for morphine and most other clinically-used opioid drugs. Abundant evidence now demonstrates that different opioid receptor types can physically associate to form heteromers. Owing to their constituent monomers’ involvement in analgesia, mu/delta opioid receptor (M/DOR) heteromers have been a particular focus of attention. Understandings of the physiological relevance of M/DOR formation remain limited in large part due to the reliance of existing M/DOR findings upon contrived heterologous systems. This thesis investigated the physiological relevance of M/DOR generation following prolonged MOR activation. To address M/DOR in endogenous tissues, suitable model systems and experimental tools were established. This included a viable dorsal root ganglion (DRG) neuron primary culture model, antisera specifically directed against M/DOR, a quantitative immunofluorescence colocalizational analysis method, and a floxed-Stop, FLAG-tagged DOR conditional knock-in mouse model. The development and implementation of such techniques make it possible to conduct experiments addressing the nature of M/DOR heteromers in systems with compelling physiological relevance. Seeking to both reinforce and extend existing findings from heterologous systems, it was first necessary to demonstrate the existence of M/DOR heteromers. Using antibodies directed against M/DOR itself as well as constituent monomers, M/DOR heteromers were identified in endogenous tissues and demonstrated to increase in abundance following prolonged mu opioid receptor (MOR) activation by morphine. The next experiments addressed an aspect of the functional consequences of M/DOR formation in endogenous tissues by investigating the post-internalization trafficking of delta opioid receptor (DOR) in conditions of augmented M/DOR formation. These experiments identified perturbations to DOR trafficking consistent with incorporation into a M/DOR species with probabilistic post-internalisation trafficking behaviour intermediate to that of either constituent and responsive to both MOR and DOR agonists in a manner subject to blockade by DOR antagonist. These studies provide concurrent evidence of the existence and functionality of physiologically-relevant M/DOR heteromers in endogenous tissues.

To date, most studies investigating the neural signature of pain in humans have focused on the brain, and those studies concerned with more caudal areas (such as the spinal cord (SC) or brainstem) have used only experimental models of pain. The objectives of this study were 1) to determine the neural activity in the human brainstem and SC that is caused by a noxious mechanical stimulus and 2) to compare the neural response to noxious stimuli in healthy controls and a patient population diagnosed with peripheral neuropathic pain. The SC and brainstem contain important synaptic points in several major pain pathways, and comparing the neural response between a control and patient population in these areas provides a more complete picture of healthy and pathological pain processing. Functional MRI studies of the SC and brainstem were carried out in healthy control subjects and patients diagnosed with carpal tunnel syndrome (CTS) in a 3T Siemens Magnetom Trio. Subjects reported the point at which the pressure (in mmHg, applied to the wrist at the location of the median nerve) corresponded to a pain level of 2, 4, and 6 on a numerical 11 point pain scale. Spatially normalized group results superimposed on anatomical templates in the axial orientation were visually identified using several stereotaxic atlases. We observed consistent signal intensity change in areas implicated in the transmission and modulation of pain in both control and CTS groups. Both groups showed a similar decrease in signal change with increasing pain, as results at pain level 2 are predominantly positive signal change and at pain level 6 are typically negative. This may indicate a reduction in the tonic inhibition of painful sensations. Differences between groups were readily visible in regions anatomically consistent with the dorsal horn (DH) of the cervical SC, rostral ventromedial medulla (RVM), dorsolateral pontine tegmentum (DLPT), and midbrain periaqudectal gray (PAG). The anatomical variation in signal change between groups may represent, for the first time, a visualization of the functional difference between healthy and pathological pain processing in the SC and brainstem using spinal fMRI.