Functional neuroimaging research on language recovery in patients with aphasia due to left hemisphere damage has generated some intriguing results. However, it is still not clear what role the right hemisphere plays in supporting language functions in chronic phase for patients with different site and size of lesion when different tasks are used. The present study was aimed at exploring the role of perilesional, ipsilesional and contralesional regions in neural recovery in participants with aphasia with different site and size of lesion using three different language tasks. All patients in the present study were in the chronic stage who had achieved high levels of recovery. Functional magnetic resonance imaging (fMRI) was used to characterize cortical activation in eight stroke patients and eight age/gender matched controls during lexical decision, semantic judgment and picture naming. An event related design using jittered interstimulus intervals (ISIs) was employed to present the stimuli. The fMRI scans revealed differences in activation patterns across the three tasks. Normal control participants and participants with aphasia mainly activated the left perisylvian region during the lexical decision task and the semantic judgment task. However, during the picture naming task, all participants activated bilateral posterior regions irrespective of the site or size of lesion. Subsequent regions of interest analysis and laterality index analysis revealed that patients with larger lesions produced greater right hemisphere activation than patients with smaller lesions during the picture naming task. The results of this study demonstrate that recovery is task, lesion site and lesion size specific. Further, the findings of the present study indicate a role for both homologous contralesional cortex and perilesional and ipsilesional regions as efficient mechanisms for supporting language functions in chronic stroke patients. / text

To date, research on cognitive aging has treated attention as a unitary resource that operates according to a single mechanism of top-down selection. However, contemporary theoretical models of attention propose that it is a distributed resource, embedded in distinct cortical subsystems, and operates in a manner that reflects the properties of those subsystems. For instance, perceptual attention is thought to originate in posterior sensory subsystems and filter competing unattended input prior to encoding, resulting in early selection of attended information. Executive attention, by contrast, is thought to originate in frontal control subsystems and filter unattended input after encoding, resulting in late selection of attended information. Guided by a distributed resource model, the work described here focuses on how healthy advanced aging influences early selection mechanisms embedded in posterior subsystems, perceptual encoding, and the relationship with frontal subsystems mediating late selection. To examine perceptual attention in isolation, object discrimination tasks were devised in which perceptual competition between repeated objects was manipulated while holding demand on executive control constant. Cortical mechanisms of early selection were probed using functional magnetic resonance imaging (fMRI) indices of neural response and adaptation. Evidence of an age-related impairment in early selection was detected across two fMRI experiments. Unlike young adults, unattended objects not only interfered with perceptual encoding in older adults, but were co-encoded along with the contents of attended input. Age impairments in early selection were also associated with greater reliance on frontally-mediated late selection resources, and, reduced functional connectivity with basal forebrain nuclei. In sum, the results indicate that with increasing age, frontal control subsystems become increasingly encumbered with compensatory redistribution of function from the perceptual cortices, possibly due to loss of central cholinergic integrity. Many well-described age-related deficits of executive attention may therefore represent a consequence of impaired early selection, rather than its cause.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by increased hyperactivity, impulsivity, and inattention. Some theories propose that ADHD is caused by a deficit in inhibitory control, interacting with other executive functions (e.g., emotional control) to lead to behavioural dysfunction. Furthermore, certain brain regions have been found to be involved in executive functions, and several studies have examined the neural correlates of ADHD at broad-based levels. Increased interest has been placed on the Anterior Cingulate Cortex (ACC), which is known to play a role in attention and other complex cognitive processes. Thus, to further clarify the nature of the behavioural and cognitive deficits observed in ADHD, and to elucidate potential relationships between these difficulties and their neural substrates with more specificity, volumetric analyses of the ACC were conducted. For this purpose, 10 children with ADHD and 10 matched controls underwent magnetic resonance imaging and neuropsychological assessment. Manual tracing of ACC subregions was conducted using ANALYZE 9.0 (Mayo Clinic), followed by between-group statistical comparisons. Correlation analyses were used to investigate whether ACC subregions were associated with performance on executive functions tasks. It was hypothesized that there would be significant volumetric groups differences between the two groups, and that subregions would have a differential relationship with executive function performance. Results indicated the ADHD group has marginally larger right dorsal ACC volumes relative to controls. Further, between the two groups, brain-behaviour relationships were different. These results provide support for the hypothesis of a delay in neuronal maturation of the ACC in children with ADHD from Spain. / Graduate

To date, research on cognitive aging has treated attention as a unitary resource that operates according to a single mechanism of top-down selection. However, contemporary theoretical models of attention propose that it is a distributed resource, embedded in distinct cortical subsystems, and operates in a manner that reflects the properties of those subsystems. For instance, perceptual attention is thought to originate in posterior sensory subsystems and filter competing unattended input prior to encoding, resulting in early selection of attended information. Executive attention, by contrast, is thought to originate in frontal control subsystems and filter unattended input after encoding, resulting in late selection of attended information. Guided by a distributed resource model, the work described here focuses on how healthy advanced aging influences early selection mechanisms embedded in posterior subsystems, perceptual encoding, and the relationship with frontal subsystems mediating late selection. To examine perceptual attention in isolation, object discrimination tasks were devised in which perceptual competition between repeated objects was manipulated while holding demand on executive control constant. Cortical mechanisms of early selection were probed using functional magnetic resonance imaging (fMRI) indices of neural response and adaptation. Evidence of an age-related impairment in early selection was detected across two fMRI experiments. Unlike young adults, unattended objects not only interfered with perceptual encoding in older adults, but were co-encoded along with the contents of attended input. Age impairments in early selection were also associated with greater reliance on frontally-mediated late selection resources, and, reduced functional connectivity with basal forebrain nuclei. In sum, the results indicate that with increasing age, frontal control subsystems become increasingly encumbered with compensatory redistribution of function from the perceptual cortices, possibly due to loss of central cholinergic integrity. Many well-described age-related deficits of executive attention may therefore represent a consequence of impaired early selection, rather than its cause.

Background: Healthy cognitive ageing entails a number of neurobiological processes which may contribute to optimal functioning and quality of life in ageing. While the full extent of the underlying mechanisms of healthy ageing are yet to be described, there is an important interplay between brain structure, function, and genetic makeup that determines ageing trajectories. Notably, the Apolipoprotein E (APOE) gene has been established in the Alzheimer’s disease (AD) literature to impact brain structure and function, and may also show congruent effects in healthy older adults, although findings in this population are much less consistent. Structural Magnetic Resonance Imaging (MRI), Diffusion Tensor Imaging (DTI), and neuropsychological measures present as useful, non-invasive tools to investigate the impact of APOE allele status on grey matter structure, white matter integrity, and cognitive functioning, respectively. Few studies have used these measures together to describe healthy ageing, and findings are mixed (e.g., no differences seen, different suggested regions of difference, etc.). The current study aims to describe the impact of APOE genotype on brain structure and function in healthy older adults using multimodal methods. Method: Data were obtained from the Alzheimer’s Disease Initiative phase 3 (ADNI3) database. Baseline MRI, DTI and cognitive composite scores for memory (ADNI-Mem) and EF (ADNI-EF) were acquired from 116 healthy controls. Participants were grouped according to APOE allele presence (APOE-ε2+ N= 17, APOE-ε3ε3 N= 64, APOE-ε4+ N=35). Voxel-based morphometry (VBM) and tract based spatial statistics (TBSS) were used to compare grey matter volume (GMV) and white matter integrity respectively between APOE-ε2+ and APOE-ε3ε3 controls, and again between APOE-ε4+ and APOE-ε3ε3 controls. Multivariate analysis of covariance (MANCOVA) was used to examine the effects of APOE polymorphism on memory and EF across all APOE groups with covariates of age, sex, and education, and cognitive scores were correlated (Pearson r) with imaging metrics within groups. Results: No significant differences were seen across groups or within-groups in MRI metrics or cognitive performance (p>0.05, corrected for multiple comparisons). Non-significant trend-level results suggested 1) Increased fractional anisotropy (FA) and GMV was present in APOE-ε2+ compared to APOE-ε3ε3. 2) Increased mean diffusivity (MD) and decreased GMV was present in APOE-ε4+ compared to APOE-ε3ε3 (p<0.2, corrected for multiple comparisons). Non-significant moderate effect sizes were seen for a positive trend between GMV and EF (r= 0.36, p= 0.18) in APOE-ε2+ and a negative trend between MD and EF in APOE-ε4+ (r= -0.33, p= 0.05). Conclusions: APOE polymorphisms do not appear to impact brain structure and function differently in healthy ageing. Trend-level findings align with reports from previous research, although results remain mixed. Overall, this study suggests neurostructural and functional differences across APOE genotype are not present in cognitively healthy older adults, and future studies should aim to clarify APOE mechanisms in healthy ageing with the addition of other variables (e.g., imaging, cognitive, & lifestyle factors), longitudinal design, and in a larger sample. / Graduate / 2022-08-17

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Concussion management is changing. Recent years have marked a sea change, with the former rest-is-best approach being supplanted by an exercise-is-medicine mindset. Despite this, important questions remain unanswered in the pediatric exercise-concussion literature. The overarching aim of this thesis was to examine the effects of exercise on outcomes beyond concussion symptoms, and build our understanding of the relationship between pediatric concussion and physical activity. Four studies were performed to this end. First, per a systematic review, we found that randomized trials on the effects of exercise on neuroimaging and cognitive outcomes remain limited. Studies suggest that exercise may improve brain structure and function post-concussion, while data with respect to cognitive outcome were mixed. Second, we provided the first evidence that the functional neuropathology of pediatric concussion differs by sex at 1 month post-injury, with females demonstrating impairment not observed in males. Namely, only females with concussion showed patterns of both hyper-connectivity (between the lateral pre-frontal cortex & inferior frontal gyrus, lateral pre-frontal cortex & lateral occipital cortex, and the posterior cingulate cortex & cerebellum; all p-corrected <0.05) and hypo-connectivity (between the anterior cingulate cortex & precuneus, anterior cingulate cortex & cingulate gyrus, and posterior cingulate cortex & paracingulate gyrus; all p-corrected <0.05). Third, we provided the first accelerometer-based characterization of physical activity and sedentary time in children with concussion in comparison to 1:1 matched healthy controls. Relative to healthy controls, children with concussion were more sedentary, with a mean difference [MD] of 38.3 minutes/day (95% confidence interval [CI] 11.2 to 65.4, p<0.01), and they also performed less light (MD -19.5 minutes/day, CI -5.3 to -33.7, p<0.01), moderate (MD -9.8 minutes/day, CI -5.7 to -13.8, p<0.001) and vigorous physical activity (MD -12.0, CI -6.9 to -17.2, p<0.001); greater physical activity deficits were observed in females with concussion. Fourth, per the first study to employ both accelerometry and functional neuroimaging in pediatric concussion, we found that intra-network connectivity of the default mode network was associated with subsequent accelerometer-measured light (F(2, 11) = 7.053, p = 0.011, Ra2 = 0.562; β = 0.469), moderate (F(2, 11) = 6.159, p = 0.016, Ra2 = 0.528; β = 0.725), and vigorous (F(2, 11) = 10.855, p = 0.002, Ra2 = 0.664; β = 0.792) physical activity. This study provides the insight into a potential link between brain activity and physical activity in pediatric concussion. The next wave of exercise and physical activity research in concussion needs to move beyond symptom studies, employ sex-specific analyses, understand the impact of exercise on brain function, and consider interventions that increase habitual physical activity. Doing so is necessary for exercise to become medicine for concussion patients. / Thesis / Doctor of Philosophy (PhD) / Until a few years ago, the advice children received after a concussion (or mild brain injury) was to rest until they no longer had symptoms. But the way concussions are being treated is changing. Scientists have found that exercising soon after a concussion can lessen symptoms. It is no longer thought that rest-is-best. Instead, it is now believed that exercise-is-medicine. But there are still important questions about the role of exercise after a concussion that have not been answered. The four studies in this thesis had the goal of answering some of those questions. In the first study, we found that while exercise improves symptoms after a concussion, we know less about how it impacts the brain and our ability to think. From the second study, we learned that a concussion impacts the brains of boys and girls in different ways, and that girls may have longer lasting brain changes after a concussion than boys. Our third study showed that after a concussion, girls take part in less physical activity than boys throughout the day. The fourth study suggests that there may be a link between brain activity and physical activity in children with a concussion. This thesis adds to our knowledge of the role of exercise in concussion. It also raises some important questions that should be answered by new studies in the near future.

The objective of this thesis is to examine the validity of functional near-infrared spectroscopy (fNIR) to examine brain regions involved in rule based (RB) and information integration (II) category learning. We predicted similar patterns of activation found by past studies that used fMRI scans. Our goal was to test if fNIR would be able to detect changes in blood oxygenation levels of participants who learned to categorize (learners) vs. those that did not (non learners). The stimulus set comprised of lines that differed in length and orientation. Participants had to learn to categorize by trial and error based on the feedback provided. Behavioral and neuroimaging data was recorded for both RB and II conditions. Results showed an upward trend in response accuracy over trials for participants identified as learners. Furthermore, blood oxygenation levels reported by fNIR indicated a systematic increase in oxygen consumption for learners as compared to non learners. These areas of increased prefrontal cortex activity recorded by fNIR correspond to the same areas found to be involved in categorization by fMRI. This paper reviews the background of category learning, explores various neuroimaging techniques in categorization research, and investigates the efficacy of fNIR as a relatively new neuroimaging modality by comparing it to fMRI.

Dyspnoea (breathlessness) is a debilitating, often poorly controlled, symptom of cardiopulmonary, neurovascular and psychological disorders. This thesis develops the necessary methodology to dissociate aspects of the acute dyspnoea experience using functional magnetic resonance imaging (FMRI) in healthy volunteers. The neuronal mechanisms underlying dyspnoea anticipation, its perceived intensity and unpleasantness and the modulation of these mechanisms by the opioid remifentanil were explored. We investigated the subjective perception of respiratory loading, a commonly used dyspnoea stimulus, and its potential systematic confounds on FMRI due to cerebral blood flow changes. Investigation of the perception of respiratory loading at different levels of hypercapnia (increased end-tidal CO₂) showed that hypercapnia should be kept to a minimum to avoid increased baseline respiratory unpleasantness whilst maintaining the stable arterial CO₂ (isocapnia) beneficial for FMRI analysis. Investigation of the effects of respiratory loading (± 9 cmH₂O) on cerebral blood flow showed that systematic confounds of respiratory loading on perfusion-based neuroimaging data were small (~5%) and did not significantly alter neural activation in response to visual stimulation. Isocapnic respiratory loading during a classical fear-conditioning paradigm during FMRI was used to investigate dyspnoea anticipation, and dissociate the intensity and unpleasantness of acute dyspnoea by modulating unpleasantness with remifentanil. Differential neural networks were found to be involved in perceived intensity (thalamus, insula, somatosensory cortex) and unpleasantness (hippocampus, medial prefrontal cortex). Remifentanil reduced respiratory unpleasantness without affecting the perceived intensity and differentially reduced brain activity during both dyspnoea anticipation and perception. This thesis showed the potential of isocapnic respiratory loading for the study of dyspnoea with FMRI. This stimulus revealed, for the first time, brain activation for dyspnoea anticipation, perceived intensity and unpleasantness. The opioid-sensitive nature of the anticipation and unpleasantness of dyspnoea provides brain targets for future research and might facilitate more effective dyspnoea palliation.

This study investigated the hypothesis that severity of depressive symptoms following acute ischemic stroke is associated with degree of tissue infarction and severity of white matter changes (WMCs). It employed a novel quantitative region-based approach considering both infarction and WMCs. Of 54 ischemic stroke patients recruited, 50 (72.3 ± 12.8 years, 52.0% male) had useable CT scans. The typical patient was recruited within 3 weeks of their stroke (19.7 ± 31.0 days), exhibited minor cognitive impairment (MMSE score 25.8 ± 4.6), and had mild to moderate stroke severity (NIHSS score 6.5 ± 5.4). 28.0% of patients screened positive for clinical depression with a CES-D score ≥16. While neither degree of infarction nor severity of WMCs (ARWMC score) in the 12 brain regions correlated with depressive symptoms (CES-D score), stroke severity was a significant predictor of depressive symptoms. This stressor, related to physical disability, was a predominant predictor over lesion characteristics.