Active movements are a key feature of human behavior. Even when we do not move our limbs we almost never stop guiding our eyes. As a minimal but omnipresent form of behavior, fast eye movements, called saccades, sample the visual world and determine to a large extent what we perceive. Despite being an integral part of visual perception, prevalent research practice treats the human subject as a passive observer who fixates a spot on the screen and is not allowed to move. Yet, learning sensorimotor interactions by active exploration in order to predict future changes and guide actions seems to be a fundamental principle of neural organization. This results in neural patterns of active behavior that can be fundamentally different from the neural processes revealed in movement-restricted laboratory settings questioning the transferability of results from experimental paradigms demanding fixation to real-world free viewing behavior. In this thesis, we aim at studying the neural mechanisms underlying free viewing behavior. In order to assess the fast, flexible and possibly distributed neural dynamics of active vision, we established a procedure for studying eye movements in magnetoencephalography (MEG) and investigated oscillatory signatures associated with sensorimotor processes of eye movements and saccade target selection, two fundamental processes of active vision. Electroencephalography (EEG) and MEG can non-invasively measure fast neural dynamics and hence seem ideally suited for studying active vision in humans. However, artifacts related to eye movements confound both EEG and MEG signals, and a thorough handling of these artifacts is crucial for investigating neural activities during active movements. Mostly, cleaning of ocular artifacts has been performed for occasional eye movements and blinks in fixation paradigms in EEG. Less is known about the impact of ocular artifacts and especially the saccadic spike on MEG. As a first step to enable active vision studies in MEG, we investigated ocular artifacts and possible ways of their separation from neural signals in MEG. We show that the saccadic spike seriously distorts the spatial and spectral characteristics of the MEG signal (Study 2). We further tested if electrooculogram (EOG) based regression is feasible for corneo-retinal artifact removal (Study 1). Due to an often-raised concern, we addressed if EOG regression eliminates neural activity when applied for MEG. Our results do not indicate such susceptibility and we conclude that EOG regression for removing the corneo-retinal artifact in MEG is suitable. Based on insights from both studies, we established an artifact handling procedure including EOG regression and independent component analysis (ICA) to assess the neural dynamics of active vision. In Study 3, we investigated spectral signatures of neuronal activity across cortex underlying saccade preparation, execution and re-fixation in a delayed saccade task. During preparation and execution, we found a dichotomic signature of gamma power increases and beta power decreases in widespread cortical areas related to saccadic control, including fronto-parietal structures. Saccade direction specific signatures resided in hemisphere lateralized changes in low gamma and alpha power in posterior parietal cortex during preparation extending to extrastriate areas during re-fixation. Real-world behavior implies the constant need to flexibly select actions between competing behavioral alternatives depending on both sensory input and internal states. In order to assess internally motivated viewing behavior, we compared neuronal activity of externally cued saccades with saccades to freely chosen, equally valuable targets. We found gamma band specific power increases in fronto-parietal areas that are likely to reflect a fast transient process of action guidance for sensory-guided saccades and a sustained process for internally selecting between competing behavioral alternatives. The sustained signature of internal action selection suggests that a decision between spatially oriented movements is mediated within sensorimotor structures by neural competition between assemblies encoding parallel evolving movement plans. Since our observations support the assumption that a decision emerges through the distributed consensus of neural activities within effector specific areas rather than in a distinct decision module, they argue for the importance of studying mental processes within their ecologically valid and active context. This thesis shows the feasibility of studying neural mechanisms of active vision in MEG and provides important steps for studying neurophysiological correlates of free viewing in the future. The observed spectrally specific, distributed signatures highlight the importance of assessing fast oscillatory dynamics across the cortex for understanding neural mechanisms mediating real-world active behavior.

The prefrontal cortices, in particular lateral prefrontal cortex (LPFC) and anterior cingulate cortex (ACC), have been implicated in top-down control of attention switching and behavioral flexibility. These cortices and their networks are disrupted in autism, a condition in which diverse behaviors such as social communication and attention control are dysregulated. However, little is known about the typical development of these cortical areas or the ways in which this process is altered in neurodevelopmental disorders. In order to identify changes that could affect the local processing of signals transmitted by the short-range pathways connecting the ACC and LPFC I assessed developmental changes in the distinct cortical layers, which send and receive different pathways and have unique inhibitory microenvironments that dictate excitatory-inhibitory balance. Normative developmental trends were compared with those seen in individuals with autism to identify changes that may contribute to symptoms of attention dysfunction. Unbiased quantitative methods were used to study overall neuron density, the density of inhibitory neurons labeled by the calcium-binding proteins calbindin (CB), calretinin (CR), and parvalbumin (PV), and the density, size, and trajectory of myelinated axons in the individual cortical layers in children and adults with and without a diagnosis of autism. There was a reduction in neuron density and an increase in the density of myelinated axons in both areas during neurotypical development. Axons in layers 1-3 of LPFC were disorganized in autism, with increased variability in the trajectory of axons in children and a decrease in the proportion of thin axons in adults. These findings were most significant in layer 1, the ultimate feedback-receiving layer in the cortex. While there were no differences in neuron populations between cohorts in children, in adults with autism there was a significant reduction in the density of CR-expressing neurons in LPFC layers 2-6 and a significant increase in the density of PV-expressing neurons in ACC layers 5-6. In autism, these findings suggest that dysregulation of the normal development of axonal networks, seen in children, may induce compensatory developmental changes in cell and axon populations in adults that could be connected to attention dysregulation. / 2021-10-07T00:00:00Z

Stroke is the leading cause of long-term disability costing the United States (US) health care system 34 billion dollars. However, stem cell based therapies have been shown to improve recovery after cortical injury by enhancing neural recovery and modulating immune responses (Lambertsen, Finsen, & Clausen, 2018; Orczykowski et al., 2018; Stonesifer et al., 2017). Specifically, reorganization of the motor circuit at the level of the spinal cord has been shown to improve functional recovery after injury (Christoph Wiessner; Weidner et al., 2001; Lee et al., 2004; Zai et al., 2009). In our study we used a non-human primate (NHP) model to study the neural recovery after cortical injury similar to damage from an ischemic stroke in the motor cortex with or without a systemic treatment of mesenchymal stem cell derived (MSCd) exosomes. We find a robust recovery in motor function within the first few weeks after injury including improved grasp patterns and faster retrieval times during behavioral tasks. Additionally, assessment of the cervical spinal cord (CSC) reveals decreased levels of sprouting axons from ipsilesional corticospinal tract (CST) and MAP2+ synapses in the contralesional ventral horn at 14 weeks post-injury, which correlates with improved retrieval latencies. We hypothesize that MSCd exosomes may encourage an earlier switch to anti-inflammatory and repair processes that reduces secondary damage in the cortex resulting in earlier pruning of axon collaterals and reducing the need for compensatory mechanisms of the spinal cord at 14 weeks post injury.

Although inhibitory cortical interneurons play a critical role in regulating brain excitability and function, the effects of stroke on these neurons is poorly understood. In particular, interneurons expressing vasoactive intestinal peptide (VIP) specialize in inhibiting other classes of inhibitory neurons, and thus serve to modulate cortical sensory processing. To understand how stroke affects this circuit, we imaged VIP neuron responses (using GCaMP6s) to low and high intensity forepaw stimulation, both before and after focal stroke in somatosensory cortex. Our data show that the fraction of forelimb responsive VIP interneurons and their response fidelity (defined as a cell’s number of responsive trials out of eight trials at a certain imaging week) was significantly reduced in the first week after stroke, especially when lower intensity forepaw stimulation was employed. The loss of responsiveness was most evident in highly active VIP neurons (defined by their level of responsiveness before stroke), whereas less active neurons were minimally affected. Of note, a small fraction of VIP neurons that were minimally active before stroke, became responsive afterwards suggesting that stroke may unmask sensory responses in some neurons. Although VIP responses to forepaw stimulation generally improved from 2-5 weeks recovery, the variance in response fidelity after stroke was comparatively high and therefore less predictable than that observed before stroke. Lastly, stroke related changes in response properties were restricted to within 400μm of the infarct border. These findings reveal the dynamic and resilient nature of VIP neurons and suggest that a sub-population of these cells are more apt to lose sensory responsiveness during the initial phase of stroke, whereas some minimally responsive cells are progressively recruited into the forelimb sensory circuit. Furthermore, stroke appears to disrupt the predictability of sensory-evoked responses in these cortical interneurons which could have important consequences for sensory perception. / Graduate / 2021-01-13

This study investigated memory in children with temporal lobe epilepsy and the ability to discern hippocampal dysfunction with conventional memory tests that are typically used to detect more global memory impairment. All data was obtained retrospectively from the epilepsy surgery program at a local children’s hospital. The research population consisted of 54 children with intractable epilepsy of temporal onset, balanced across pathology types (with and without hippocampal disease) and other demographics. Each was given a clinical battery prior to surgical intervention, which included the WRAML/WRAML2 Verbal Learning subtest from which the dependent variables for this study were extracted. The research hypothesis had predicted that memory retention between verbal learning and recall would be worse for participants with pathology that included hippocampal sclerosis than for those with non-hippocampal temporal lobe pathology. A two-way mixed-design ANOVA was used to test the hypothesis, which allowed incorporation of variables of interest related to memory factors, pathology type, and hemispheric laterality, as well as their various interactions. There was a significant main effect for change in the number of words retained from the final learning trial to the delayed recall. Although the interaction between memory retention and pathology type was not statistically significant, the average of the memory scores as it related to pathology by side did show significance. Thus, results did not support the hypothetical relationship between retention and hippocampal function. However, additional exploratory analyses revealed that the final learning trial by itself was associated with hippocampal pathology, which applied only to those participants with left-hemisphere lesions. Logistic regression with the final learning trial correctly classified 74 percent of participants into the appropriate pathology category, with 81 percent sensitivity to hippocampal dysfunction. Mean participant memory scores were nearly one standard deviation below the normative mean for both delayed recall and total learning scaled scores, regardless of pathology type or lesion hemisphericity. Thus, while the conventionally used indices of the WRAML Verbal Learning test are useful for determining overall memory status, they are not specific to pathological substrate. The within-subject main effect showed an expected loss of information across the time of the delay, but overall the recall score showed no association with hippocampal functioning. This study revealed the possibility of measuring hippocampal function at statistically significant group levels using learning scores from a widely used measure of verbal memory, even in participants with intact contralateral mesial temporal structures. It also indicated that hippocampal structures do not play a role during recall measures given after a standard time delay. Data further demonstrated a role of the hippocampus for encoding and transferring information beyond short term/working memory into long term. During the learning process, the hippocampus appears to work in concert with short-term memory systems, but does not take over the encoding process until enough repetitions have occurred to saturate the working memory buffer. This research represents a small, yet important step forward in our understanding of the hippocampus, with potentially important implications for the future study of memory constructs and mensuration.

December 2011. A thesis submitted to the College of Dental Medicine of Nova Southeastern University of the degree of Master of Science in Dentistry. Background: Temporary anchorage devices (TADs) provide a versatile means by which orthodontic anchorage can be established without the need for patient compliance and complex force systems. Their use is predicated on their ability to remain stable throughout the course of treatment in which they are needed. This has been shown to be the result of "primary stability" which is achieved through mechanical interlocking of the screw threads with the surrounding bone immediately upon placement. Therefore, evaluating the factors that can either enhance or detract from the primary stability of TADs can serve to improve the predictability of their success. Objectives: The objectives of this study were to describe how variations in synthetic cortical bone thickness and the angle of force applied in relation to the long axis of TADs affects their stability in terms of pull-out strength, and to ascertain the perspectives of practicing orthodontists in the state of Florida on their experiences with temporary anchorage devices with regards to success and failure. Methods: For the bench top study, 90 1.5x8mm long neck Orthotechnology Spider Screws were randomly allocated to 9 groups of 10 TADs each. The 9 groups were established based on both the thickness of synthetic cortical bone (1.0, 1.5, and 2.0mm) and the angle of force vector applied relative to the long axis of the TADs (45, 90, and 1800). Pull-out testing was carried out by applying a force to the TADs via a universal testing machine (Instron, Canton, MA) at a rate of 2.0mm/minute. Real-time graphical and digital readings were recorded, with the forces being recorded in Newtons (N). Each miniscrew was subjected to the pull force until peak force values were obtained. For the 450 and 1800 tests, the force registered at the time-point of pull-out, or screw head movement of 1.5mm within the synthetic bone blocks. The determination of 1.5mm of movement was made due the dramatically erratic deflection observed by the digital and graphical readouts at precisely this point. For the survey portion of this study, A customized survey was developed for this study. The survey was composed of 12 questions, some of which were obtained from a questionnaire that was created by Buschang et al.54 The additional questions were devised by the members of this research project, with the aim of answering questions regarding the clinical experiences that practicing orthodontists experienced with TADs. Results: For the bench top study: Implants placed in 2.0mm of synthetic cortical bone and pulled at an angle of 1800 had the highest pull-out strength among all groups (258.38N), while those placed in 1.0mm of synthetic cortical bone and pulled at an angle of 900 exhibited the lowest (67.11N). When evaluated separately, a cortical bone thickness of 2.0 mm displayed the highest pull-out forces for the three angles of force application, and 1800 angle of force displayed the highest-pull-out forces for the three cortical bone thicknesses. Conversely, 1.0mm of cortical bone thickness displayed the lowest pull-out forces for the three angles of force application, and 900 angle of force displayed the highest-pull-out forces for the three cortical bone thicknesses. For the survey: The most important factor associated with TAD failure was cited as placement location by 45.7% (n=16) of respondents, while root proximity was cited as the least important factor by 35.3% (n=12) of respondents. For the site from which practitioners indicated that they experience the greatest success, 81.8% cited the palate, while 51.9% responded that they experience the highest failure rates for the posterior maxilla (distal to the cuspids). Conclusions: A synthetic cortical bone thickness of 2mm and pull forces applied parallel to the long axis of TADs resulted in the greatest resistance to pull-out.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12817号 / 論医博第2079号 / 新制||医||1004(附属図書館) / 31304 / 京都大学大学院医学研究科脳統御医科学系専攻 / (主査)教授 河野 憲二, 教授 金子 武嗣, 教授 大森 治紀 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18874号 / 医博第3985号 / 新制||医||1008(附属図書館) / 31825 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邉 大, 教授 山田 亮, 教授 福山 秀直 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19230号 / 医博第4029号 / 新制||医||1011(附属図書館) / 32229 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邊 直樹, 教授 斎藤 通紀, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19366号 / 医博第4043号 / 新制||医||1011(附属図書館) / 32380 / 新制||医||1011 / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邉 大, 教授 福田 和彦, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM