Browsing by Subject "Thalamus"
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Item Experimental and Model-based Approaches to Directional Thalamic Deep Brain Stimulation(2016-09) Xiao, JoeDeep brain stimulation (DBS) is an effective surgical procedure for the treatment of several brain disorders. However, the clinical successes of DBS hinges on several factors. Here, we describe the development of tools and methodologies in the context of thalamic DBS for essential tremor (ET) to address three key challenges: 1) accurate localization of nuclei and fiber pathways for stimulation, 2) model-based programming of high-density DBS electrode arrays (DBSA) and 3) in vivo assessment of computational DBS model predictions. We approached the first challenge through a multimodal imaging approach, utilizing high-field (7T) susceptibility-weighted imaging and diffusion-weighted imaging data. A nonlinear image deformation algorithm was used in conjunction with probabilistic fiber tractography to segment individual thalamic sub-nuclei and reconstruct their afferent fiber pathways. We addressed the second challenge by developing subject-specific computational model-based algorithms built on maximizing population activating function values within a target region using convex optimization principles. The algorithms converged within seconds and only required as many finite-element simulations as the number of electrodes on the DBSA being modeled. For the third challenge, we recorded (in two non-human primates) unit-spike data from neurons in the vicinity of chronically implanted thalamic DBSAs before, during and after high-frequency stimulation. A novel entropy-based method was developed to quantify the degree and significance of stimulation-induced changes in neuronal firing pattern. Results indicated that neurons modulated by thalamic DBS were distributed and not confined to the immediate proximity of the active electrode. For those that were modulated by DBS, their responses increasingly shifted from firing rate modulation to firing pattern modulation with increased stimulation amplitude. Additionally, strong low-pass filtering effect was observed where <4% of DBS pulses produced phase-locked spikes in cells exhibiting significant excitatory firing pattern modulation. Finally, we quantified the spatial distribution of neurons modulated by DBS by developing a novel spherical statistical framework for analysis. Together, these tools and methodologies are poised to improve our understanding of DBS mechanisms and improve the efficacy and efficiency of DBS therapy.Item Investigating neurogenesis and cell type specification in the mammalian thalamus.(2012-06) Bluske, Krista K.The thalamus mediates a variety of important brain functions that are critical for behavior and survival. A key feature that enables the thalamus to perform such diverse functions is its parcellation into anatomically and functionally distinct groups of neurons called nuclei. The purpose of this project was to identify the origin of neuronal diversity within the thalamus by investigating the process of neurogenesis. During neurogenesis, proliferating progenitor cells begin to divide asymmetrically to generate neurons. The central hypothesis of the research presented herein is that thalamic organization requires the appropriate number and types of neurons to be generated and that these critical processes are regulated during neurogenesis. This work has characterized the different types of progenitor cells present during thalamic neurogenesis. We confirmed the existence of a special population of thalamic progenitor cells, intermediate (or basal) progenitor cells, and identified transcription factors that regulate their formation and/or maintenance. We also addressed the origin of distinct subtypes of neurons. The spatial organization of thalamic progenitor cells into two distinct progenitor domains during neurogenesis is thought to drive the formation of different subtypes of thalamic neurons. Signaling molecules have been proposed to induce the formation of distinct progenitor domains in numerous brain areas, including the thalamus. We provided a detailed characterization of components of the Wnt/β-catenin-mediated transcriptional pathway during thalamic neurogenesis. Based on the pattern of signaling activity, we hypothesized that Wnt/β-catenin-mediated transcription has a function in forming the two progenitor domains during thalamic neurogenesis. Using conditional genetic manipulations of β-catenin, we found that β-catenin-mediated transcription is required for the specification of thalamic progenitor domains. Furthermore, we found that the Wnt/β-catenin signaling pathway functions in parallel with the sonic hedgehog (Shh) signaling pathway, which had been previously shown to specify thalamic progenitor identity in an opposing manner, by independently regulating transcriptional networks in thalamic progenitor cells. Collectively, the process of neurogenesis involves the generation of the correct number of neurons by regulating asymmetric progenitor divisions and generation of appropriate neuronal subtypes through the functions of signaling pathways and transcriptional networks. These mechanisms provide a broad map for the generation and positioning of appropriate types of neurons in the correct locations within the thalamus.Item On the formation and functions of the neurons in the spinal cord that project axons to the thalamus, in rodent and primate.(2009-07) Davidson, SteveMammals and other advanced vertebrates possess a population of neurons located in the spinal cord that put forth axons to the thalamus. These cells are responsive to somatosensory stimuli and in humans are required for the normal perception of mechanical, thermal, and chemical stimuli. The studies contained in this thesis examine both the development of this pathway, called the spinothalamic tract (STT), and its physiological responses to stimuli that evoke somatosensory experiences. Experiments in adult mice show that the whole STT is made up of about 7000 cells and these are located in a pattern homologous to the STT in rat, cat and monkey. Experiments in neonatal and embryonic mice show that the axons of the STT reach the thalamus before birth. A study of the physiological characteristics of STT neurons located in the marginal zone of the spinal cord dorsal horn in the adult rat suggests that STT axons are topographically organized within the ventrobasal complex of the thalamus according to their responses to thermal stimuli. Studies in primates show that axons from the STT that project to the nuclei of the posterior thalamus are responsive to multiple modalities of somatosensory stimuli but differ from neurons projecting to VPL in some functional properties. A special focus of this thesis explores the poorly understood sensation of itch. Evidence is provided for at least two pathways for itch; one that is activated by cutaneous administered histamine and another that is activated by the protease contained within the spicules of the tropical legume cowhage. Despite this specificity for types of itch, each of these pathways is also responsive to noxious and/or innocuous mechanical, thermal and/or chemical stimuli. The population of cells that is responsive to histamine is transiently inhibited by scratching the skin during the histamine response, suggesting a mechanism for the well known relief from itch that is produced by scratching. The main conclusions from the studies in this thesis are that the STT is extant before the time of birth; that, in adults, it is a complex pathway that can contribute to the encoding of specific somatosensory sensations from cells that are responsive to multimodal stimuli.