Damage to motor areas of the brain, caused by stroke, can produce devastating motor deficits, including aberrant control of force. After stroke, reorganization of the brain’s motor system has been identified as one of the fundamental mechanisms involved in recovery of motor control after stroke. Yet, few studies have investigated how force production and modulation are encoded in the brain after stroke and how this relates to motor outcome. Thus, the purpose of this study was to (1) understand how past neuroimaging literature has contributed to establishing common patterns of brain reorganization during both relative and absolute force production after stroke, (2) examine how brain function is reorganized during force production and modulation in individuals with stroke, and (3) relate this task-related reorganization of brain function to the amount of paretic arm use after stroke. In the second chapter, we systematically reviewed all relevant literature examining brain activation during force production after stroke. The following chapters (chapters 3 and 4) applied functional magnetic resonance imaging (fMRI) to examine the neural correlates of force production and modulation after stroke. Chapter 2 supports differences in task-related brain activation dependent on features of stroke, such as severity and chronicity, as well as influence of rehabilitation. In addition, results suggest that activation of common motor areas of the brain during force production can be identified in relation to functional outcome after stroke. Results from the subsequent two chapters (3 and 4), demonstrate that brain function reorganizes in terms of absolute, and not relative force production after stroke. Specifically, stroke participants exhibit greater activation of motor areas than healthy controls when matched for absolute force production. Moreover, there is a relationship between paretic arm usage and brain activation, where stroke participants having less paretic arm use, as measured using wrist accelerometers, exhibit higher brain activation. Results of this thesis suggest that during absolute force production, brain activation may approach near maximal levels in stroke participants at lower forces than healthy controls. Furthermore, this effect may be amplified even further in subjects with less paretic arm usage, as increased activation in motor areas occurs in participants with less arm use after stroke. Ultimately, the results from this thesis will contribute to research relevant to brain reorganization in individuals with stroke and may lead to the development of new, beneficial therapeutic interventions that optimize brain reorganization and improve functional recovery after stroke.

Judgments of spatial relationships are often made when the object or observer are moving. Behaviourally, there is evidence that these ‘dynamic’ judgments of spatial extent differ from static judgments. Here I used three separate techniques for exploring dynamic judgments: first, a line bisection paradigm was employed to study ocular and pointing judgments of spatial extent while manipulating line length, position, speed, acceleration, and direction of scanning (Experiments 1-4); second, functional MRI (fMRI) was used to examine whether distinct brain regions were involved in dynamic versus static judgments of spatial extent (Exp 5); and finally, a mathematical and computational model of dynamic judgments was developed to provide a framework for interpreting the experimental results. In the behavioural experiments, substantial differences were seen between static and dynamic bisection, suggesting the two invoke different neural processes for computing spatial extent. Surprisingly, ocular and pointing judgments produced distinct bisection patterns that were uncorrelated, with pointing somewhat more impervious to manipulations such as scan direction and position than ocular bisections. However, a new experimental task for probing dynamic judgments (the ‘no line’ Experiment 4) found that scan direction can influence both hand behaviour. Functional MRI demonstrated that dynamic relative to static judgments produced activations in the cuneus and precuneus bilaterally, left cerebellum, and medial frontal gyrus, with reduced activation relative to static judgments observed in the supramarginal gyrus bilaterally. Dynamic bisections relative to a control condition produced activations in the right precuneus and left cerebellum, as well as in left superior parietal lobule, left middle temporal gyrus, and right precentral gyrus. It may be the case that velocity processing and temporal estimates are integrated primarily in the cuneus and precuneus bilaterally to produce estimates of spatial extent under dynamic scanning conditions. These results highlight the fact that dynamic judgments of spatial extent engage brain regions distinct from those employed to make static judgments, supporting the behavioural results that these are separate and distinct. Finally, a mathematical model was proposed for dynamic judgments of spatial extent, based on the idea that, rather than using an ‘all-or-none’ approach, spatial working memory actually takes about 100 ms to reach full representational strength for any given point in space. The model successfully explains many of the effects seen in the behavioural experiments including the effects of scan direction, velocity, line length, and position. In conjunction with the neuroimaging data, it also suggests why neglect patients may fail to show rightward bisection biases when making dynamic judgments of spatial extent. Overall, this work provides novel insights into how the brain executes dynamic judgments of spatial extent.

Memory is a complex and multifaceted entity. Cognitive psychology has adopted terminology to help simplify the study of memory. For example, one can consider the cognitive process the brain is engaged in, such as encoding versus retrieval. Similarly, one can consider the content of information, such as words, faces, or scenes. Content and process can also interact such as with instructions to view a face that happens to be situated next to a house (item memory) versus instructions to evaluate whether the face 'belongs' in the house (relational memory). Although neuropsychology, animal lesion studies, and cognitive neuroscience have identified brain structures that are consistently associated with memory performance, such as the medial temporal lobes (MTL) and prefrontal cortex (PFC), the specifics of when and why such regions participate in memory is still largely unexplored. Theoretical standpoints are often at odds about whether regions such as the MTL operate as a functional unit, supporting memory in general, or whether subregions within the MTL support specific types of memory (e.g. item versus relational memory). To investigate how memory processes might recruit unique and common brain regions, three functional magnetic resonance imaging (fMRI) studies were conducted. Each study involved comparisons of successful encoding (trials later remembered versus forgotten) and successful retrieval (hits versus misses). Experiment 1, using semantic and perceptual word pairs, found unique contributions for subregions in the MTL and PFC, dependent on memory phase and stimulus class. One region in the left hippocampus was associated with memory success, regardless of either memory phase or stimulus class. Experiment 2, using faces and scenes, found unique contributions for 'stimulus sensitive' subregions of the fusiform gyrus and parahippocampal gyrus, as well as for the PFC, and MTL that were dependent on content-process interactions, or independent of content and process. Experiment 3, using faces, scenes, and face-scene pairings, found unique contributions for subregions of the MTL and PFC based on item versus relational processing and memory phase. Together, the results of the three experiments provide support for dichotomies in brain structures based on specific processes, specific content, or process-content interactions. / Dissertation

The judgment of prior stimulus occurrence, generally referred to as item recognition, is perhaps the most heavily studied of all memory skills. A skilled recognition observer not only recovers high fidelity memory evidence, he or she is also able to flexibly modify how much evidence is required for affirmative responding (the decision criterion) depending upon whether the context calls for a cautious or liberal task approach. The ability to adaptively adjust the decision criterion is a relatively understudied recognition skill, and the goal of this thesis is to examine reinforcement learning mechanisms contributing to recognition criterion adaptability. In Chapter 1, I review a measurement model whose theoretical framework has been successfully applied to recognition memory research (i.e., Signal Detection Theory). I also review major findings in the recognition literature examining the adaptive flexibility of criteria. Chapter 2 reports behavioral experiments that examine the sensitivity of decision criteria to trial-by-trial feedback by manipulating feedback validity in a potentially covert manner. Chapter 3 presents another series of behavioral experiments that used even subtler feedback manipulations based on predictions from reinforcement learning and category learning literatures. The findings suggested that feedback induced criterion shifts may rely upon procedural learning mechanisms that are largely implicit. The data also revealed that the magnitudes of induced criterion shifts were significantly correlated with personality measures linked to reward seeking outside the laboratory. In Chapter 4 functional magnetic resonance imaging (fMRI) was used to explore possible neurobiological links between brain regions traditionally linked to reinforcement processing, and recognition decisions. Prominent activations in striatum tracked the intrinsic goals of the subjects with greater activation for correct responding to old items compared to correct responding to new items during standard recognition testing. Furthermore, the pattern was amplified and reversed by the addition of extrinsic rewards. Finally, activation in ventral striatum tracked individual differences in personality reward seeking measures. Together, the findings further support the idea that a reinforcement learning system contributes to recognition decision-making. In the final chapter, I review the main implications arising from the research and suggest future research that could bolster the current results and implications. / Dissertation

For children with intractable epilepsy, surgery provides significant reduction in seizure frequency, with no significant declines in intellectual or behavioral functioning (Datta, et al., 2011). Prior to surgery, children must undergo a thorough assessment to determine the location of the seizure-focus and to evaluate risks of post-operative impairment (Lee, 2010). Currently, fMRI offers one of the most reliable and least invasive means of localizing language prior to surgery (McDonald, Saykin, William & Assaf, 2006). Dichotic listening, a behavioral task in which subjects are asked to listen to two competing stimuli simultaneously, offers a possible alternative for children who cannot complete fMRI studies. Previous studies have relied on research-based listening tasks and the type of quantitative analysis of the fMRI rarely available in the clinical setting. Instead, this study examined how well dichotic listening results predict language lateralization from fMRI within a clinical setting. Data were gathered through a records review of 13 children with intractable epilepsy referred to Austin Neuropsychology through the epilepsy treatment team at Dell Children’s Medical Center. Overall, children classified as atypical language dominance on the fMRI studies showed lower levels of right ear advantage on the dichotic listening measure. Despite this trend, a discriminant analysis using the dichotic listening results to predict fMRI classification showed no significant improvement over chance classification. A secondary analysis examined factors related to a child’s ability to complete an fMRI language study, comparing 12 children from the original sample with 6 children referred through the same process and over the same time period who could not obtain a successful fMRI determination of language lateralization. Overall, children who successfully completed the fMRI language studies showed a trend of lower levels of difficulty with behavioral regulation and higher levels of intelligence. Although the non-significant results highlight the limitations of dichotic listening as a clinical tool, the failure rate within the total sample, along with the information about the roles of intelligence and behavioral regulation, may help spur the development of alternative methods of language lateralization. / text

Emotion regulation plays an important role in emotional well-being, as well as in the protection against and recovery from mood and anxiety disorders. Previous studies of the functional neuroanatomy of emotion regulation have reported greater activity in prefrontal control-related regions during active regulation. These activations are accompanied by decreases in activity in emotion-responsive regions such as the amygdala and insula. These findings are widely interpreted as consistent with models of cognitive control that implicate top-down, negative influences from prefrontal cortex upon emotion-related processing in other regions. However, no studies to date have used measures of effective connectivity to investigate the likely influence of prefrontal control regions upon emotion-responsive regions in the context of effortful emotion regulation. In the present study, participants alternated between responding naturally to negative emotional stimuli and reinterpreting the negative stimuli with the goal of reducing their experienced negative affect. Functional magnetic resonance imaging (fMRI) was used to measure whole-brain blood-oxygen level dependent signal throughout the task. fMRI data were analyzed using partial least squares (PLS) and structural equations modeling (SEM) to test for differences in effective connectivity between natural and regulated emotional responding. Results indicate that three paths significantly distinguish between regulation and non-regulation negative conditions. The path from inferior frontal gyrus (IFG) to anterior cingulate cortex (ACC) was significantly less positive during regulation than natural responding. In addition, the reciprocal paths between ACC and insula were more negative during regulation than natural responding. Taken as a whole, these changes in effective connectivity are consistent with assumptions of top-down modulation during effortful emotion regulation. In addition, these changes suggest a pivotal role for the influence of IFG upon ACC and the ACC-insula loop in emotion regulation. The processes represented by these changes and implications for future research are discussed.

Damage to motor areas of the brain, caused by stroke, can produce devastating motor deficits, including aberrant control of force. After stroke, reorganization of the brain’s motor system has been identified as one of the fundamental mechanisms involved in recovery of motor control after stroke. Yet, few studies have investigated how force production and modulation are encoded in the brain after stroke and how this relates to motor outcome. Thus, the purpose of this study was to (1) understand how past neuroimaging literature has contributed to establishing common patterns of brain reorganization during both relative and absolute force production after stroke, (2) examine how brain function is reorganized during force production and modulation in individuals with stroke, and (3) relate this task-related reorganization of brain function to the amount of paretic arm use after stroke. In the second chapter, we systematically reviewed all relevant literature examining brain activation during force production after stroke. The following chapters (chapters 3 and 4) applied functional magnetic resonance imaging (fMRI) to examine the neural correlates of force production and modulation after stroke. Chapter 2 supports differences in task-related brain activation dependent on features of stroke, such as severity and chronicity, as well as influence of rehabilitation. In addition, results suggest that activation of common motor areas of the brain during force production can be identified in relation to functional outcome after stroke. Results from the subsequent two chapters (3 and 4), demonstrate that brain function reorganizes in terms of absolute, and not relative force production after stroke. Specifically, stroke participants exhibit greater activation of motor areas than healthy controls when matched for absolute force production. Moreover, there is a relationship between paretic arm usage and brain activation, where stroke participants having less paretic arm use, as measured using wrist accelerometers, exhibit higher brain activation. Results of this thesis suggest that during absolute force production, brain activation may approach near maximal levels in stroke participants at lower forces than healthy controls. Furthermore, this effect may be amplified even further in subjects with less paretic arm usage, as increased activation in motor areas occurs in participants with less arm use after stroke. Ultimately, the results from this thesis will contribute to research relevant to brain reorganization in individuals with stroke and may lead to the development of new, beneficial therapeutic interventions that optimize brain reorganization and improve functional recovery after stroke.

Judgments of spatial relationships are often made when the object or observer are moving. Behaviourally, there is evidence that these ‘dynamic’ judgments of spatial extent differ from static judgments. Here I used three separate techniques for exploring dynamic judgments: first, a line bisection paradigm was employed to study ocular and pointing judgments of spatial extent while manipulating line length, position, speed, acceleration, and direction of scanning (Experiments 1-4); second, functional MRI (fMRI) was used to examine whether distinct brain regions were involved in dynamic versus static judgments of spatial extent (Exp 5); and finally, a mathematical and computational model of dynamic judgments was developed to provide a framework for interpreting the experimental results. In the behavioural experiments, substantial differences were seen between static and dynamic bisection, suggesting the two invoke different neural processes for computing spatial extent. Surprisingly, ocular and pointing judgments produced distinct bisection patterns that were uncorrelated, with pointing somewhat more impervious to manipulations such as scan direction and position than ocular bisections. However, a new experimental task for probing dynamic judgments (the ‘no line’ Experiment 4) found that scan direction can influence both hand behaviour. Functional MRI demonstrated that dynamic relative to static judgments produced activations in the cuneus and precuneus bilaterally, left cerebellum, and medial frontal gyrus, with reduced activation relative to static judgments observed in the supramarginal gyrus bilaterally. Dynamic bisections relative to a control condition produced activations in the right precuneus and left cerebellum, as well as in left superior parietal lobule, left middle temporal gyrus, and right precentral gyrus. It may be the case that velocity processing and temporal estimates are integrated primarily in the cuneus and precuneus bilaterally to produce estimates of spatial extent under dynamic scanning conditions. These results highlight the fact that dynamic judgments of spatial extent engage brain regions distinct from those employed to make static judgments, supporting the behavioural results that these are separate and distinct. Finally, a mathematical model was proposed for dynamic judgments of spatial extent, based on the idea that, rather than using an ‘all-or-none’ approach, spatial working memory actually takes about 100 ms to reach full representational strength for any given point in space. The model successfully explains many of the effects seen in the behavioural experiments including the effects of scan direction, velocity, line length, and position. In conjunction with the neuroimaging data, it also suggests why neglect patients may fail to show rightward bisection biases when making dynamic judgments of spatial extent. Overall, this work provides novel insights into how the brain executes dynamic judgments of spatial extent.

Traumatic brain injury (TBI) is a leading cause of disability globally. Cognitive deficits represent the primary source of on-going disability in this population, yet the mechanisms of these deficits remain poorly understood. Here functional and diffusion-weighted imaging techniques were employed to characterize the mechanisms of neurofunctional change following TBI and their relationship to cognitive function. TBI subjects who had sustained moderate to severe brain injury, demonstrated good functional and neuropsychological recovery, and screened positive for diffuse axonal injury but negative for focal brain lesions were recruited for the project. TBI subjects and matched controls underwent structural, diffusion-weighted and functional MRI. The functional scanning paradigm consisted of a complex working memory task with both load and executive control manipulations. Study one demonstrated augmented functional engagement for TBI subjects relative to healthy controls associated with executive control processing but not maintenance operations within working memory. In study two, multivariate neuroimaging analyses demonstrated that activity within a network of bilateral prefrontal cortex (PFC) and posterior parietal regions was compensatory for task performance in the TBI sample. Functional connectivity analyses revealed that a common network of bilateral PFC regions was active in both groups during working memory performance, although this activity was behaviourally relevant at lower levels of task demand in TBI subjects relative to healthy controls. In study three, diffusion-imaging was used to characterize the impact of diffuse white matter pathology on these neurofunctional changes. Unexpectedly, decreased white matter integrity was not correlated with working memory performance following TBI. However, markers of white matter pathology did inversely correlate with the compensatory functional changes observed previously. These results implicate diffuse white matter pathology as a primary mechanism of functional brain change following TBI. Moreover, reactive neurofunctional changes appear to mediate the impact of diffuse injury following brain trauma, suggesting new avenues for neurorehabilitation in this population.

Traumatic brain injury (TBI) is a leading cause of disability globally. Cognitive deficits represent the primary source of on-going disability in this population, yet the mechanisms of these deficits remain poorly understood. Here functional and diffusion-weighted imaging techniques were employed to characterize the mechanisms of neurofunctional change following TBI and their relationship to cognitive function. TBI subjects who had sustained moderate to severe brain injury, demonstrated good functional and neuropsychological recovery, and screened positive for diffuse axonal injury but negative for focal brain lesions were recruited for the project. TBI subjects and matched controls underwent structural, diffusion-weighted and functional MRI. The functional scanning paradigm consisted of a complex working memory task with both load and executive control manipulations. Study one demonstrated augmented functional engagement for TBI subjects relative to healthy controls associated with executive control processing but not maintenance operations within working memory. In study two, multivariate neuroimaging analyses demonstrated that activity within a network of bilateral prefrontal cortex (PFC) and posterior parietal regions was compensatory for task performance in the TBI sample. Functional connectivity analyses revealed that a common network of bilateral PFC regions was active in both groups during working memory performance, although this activity was behaviourally relevant at lower levels of task demand in TBI subjects relative to healthy controls. In study three, diffusion-imaging was used to characterize the impact of diffuse white matter pathology on these neurofunctional changes. Unexpectedly, decreased white matter integrity was not correlated with working memory performance following TBI. However, markers of white matter pathology did inversely correlate with the compensatory functional changes observed previously. These results implicate diffuse white matter pathology as a primary mechanism of functional brain change following TBI. Moreover, reactive neurofunctional changes appear to mediate the impact of diffuse injury following brain trauma, suggesting new avenues for neurorehabilitation in this population.