Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (p. 171-175). / The inferior colliculus, the primary nucleus in the mammalian auditory midbrain, occupies a central position in the ascending auditory pathway. Nearly all ascending neural pathways converge and synapse in the central nucleus of the inferior colliculus (ICC). Further, the anatomical arrangement of axons and neurons in the ICC suggests the existence of functional regions which may play a role in organizing different types of physiological information. To investigate this organization, we characterized the response properties of neighboring neurons in the ICC. To record reliably from neighboring neurons, we adopted a relatively new electrophysiological technique, tetrode recordings. Tetrodes have four closely spaced recording sites (<20[mu]m) which record multi-unit activity from a small number of neighboring neurons. The recorded signals contain action potentials originating from more than one neuron. Based on action potential wave shape differences across the four channels, we can reconstruct the contributions of individual neurons. Applying tetrode recordings to the ICC of anesthetized cats, we successfully reconstructed individual spike trains for 190 neurons at 52 recording sites. / (cont.) To quantify the advantage of tetrodes, we compared our multi-channel recording results with waveform sorting from single-channel electrode recordings. At best, only 32% of the single-units from tetrode sorting were correctly identified using single-channel recordings. We used tetrode to characterize pure tone responses of neighboring neurons in the ICC in terms of frequency selectivity, level dependence, temporal discharge patterns, and sensitivity to interaural time differences. We find similarities in best frequency and pure-tone threshold among neighboring neurons; however, we find large disparities in bandwidth, level dependence, temporal discharge patterns, and sensitivity to interaural time differences. These results suggest that neighboring neurons in ICC can greatly differ in membrane properties and/or their patterns of synaptic input from different brainstem nuclei and tonotopic regions. Using tetrode recordings, we investigated how well multi-unit responses represent the response properties of the contributing single-unit responses. / (cont.) We find that multi-unit responses represent single-unit best frequency, pure-tone threshold and level dependence well, and they represent single-unit bandwidth and interaural phase sensitivity poorly. These results suggest caution must be used not to infer single-unit responses from multi-unit recordings. / by Chandran V. Seshagiri. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2004. / "June 2004." / Includes bibliographical references (leaves 152-156). / Current implementations of patient information review on Personal Digital Assistants (PDAs) are gaining traction in the in-patient hospital setting. There are tremendous patient safety and satisfaction, workflow improvement and physician satisfaction improvements possible if similar technology is optimized and used in the ambulatory care setting. We have performed a study of Partners HealthCare System (PHS) physicians to determine user requirements, implemented a formal method (not previously used within the PHS Information Systems division) to create a Software Requirements Specification (SRS), and developed a prototype user interface for a future LMR2go application (a mobile adjunct for the ambulatory care Longitudinal Medical Record system in use at PHS). The results of the study provided a core set of functions for the LMR2go application which physicians would like to use while on-call and substantiated the potential adoption of such an application. After an analysis of current software and hardware technologies, review of the study results and components of the actual SRS, a sample run through of a typical on-call physician workflow on the LMR2go User Interface is provided. / by Sameer A. Bade. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Includes bibliographical references (p. 173-178). / Over the past three decades, much research in motor neuroscience has focused on understanding how humans make coordinated reaching movements, yielding valuable insight into the planning and control of reaching movements, and establishing a foundation for robot-assisted rehabilitation. The goal of this doctoral research was to provide a quantitative characterization of humans' wrist rotations, paving the way for intelligent robot-assisted wrist rehabilitation. More specifically, we have characterized the kinematics, dynamics, and adaptation of wrist rotations, and discussed implications for planning and control. Kinematics: It is well known that humans make relatively straight reaching movements, suggesting that reaching movements are primarily under kinematic control of hand position. We used a motion capture system to test if wrist rotations are also under kinematic control. We found that wrist rotations exhibit a pattern with significantly more path curvature and variability than reaching movements (p = 0.001). While the increased path curvature could indicate that wrist rotations are not under kinematic control, this work provides evidence that the curvature is instead due to imperfect peripheral execution.Dynamics: In order to determine the exact cause of path curvature, an anatomically-accurate, mathematical model of the wrist was developed, including recent measurements of passive wrist stiffness. Combining experimentally-measured kinematics from human subjects with the wrist model revealed that moderately-sized wrist rotations can be approximated by a very simple model with virtually no loss in accuracy.Interaction torques, for which the nervous system compensates in reaching movements, are present but negligible in wrist rotations. / (cont) Rather, wrist rotation dynamics are dominated by stiffness, which was shown to be the likely cause of path curvature.Adaptation: When perturbed during reaching movements, humans adapt by straightening their paths, confirming that kinematics play a prominent role in planning reaching movements. We found that subjects consistently adapted to a conservative,velocity-dependent force field. Interestingly, this adaptation was more difficult to detect than in perturbation studies involving reaching movements. Taken together, these results suggest that wrist rotations are also primarily under kinematic control (albeit imperfect). / by Steven K. Charles. / Ph.D.

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Aeronautics and Astronautics, 1998. / At head of title: MIT/Draper Technology Development Partnership Program. / Includes bibliographical references (p. 103-105). / by Garrett W. Shook. / M.Eng.

Thesis (Ph. D. in Health Sciences and Technology)--Harvard-MIT Program in Health Sciences and Technology, 2012. / Cataloged from PDF version of thesis. In title on title page, double underscored "v̳" appears as subscript. / Includes bibliographical references (p. 73-83). / Voltage-gated sodium (Nav) channels are diverse, comprising nine known mammalian subunits, which are classified pharmacologically into tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-insensitive (TTX-1) categories. The pattern of Nav channel expression shapes response properties of neurons, while changes in these expression patterns are related to many pathological conditions. Previous RT-PCR results indicated the expression of a variety of Nav channel subunits in the vestibular ganglion, the sensory ganglion that conveys information about motion and orientation. The expressed subunits included several TTX-1 subunits with unique biophysical properties that have been extensively characterized in somatosensory neurons and the heart, but never reported in published electrophysiological studies of the vestibular ganglion. Using whole-cell patch clamp, we show the presence of two types of TTX-l Nav currents in acutely dissociated rat vestibular ganglion neurons (VGNs) from the first postnatal week: a fast and negatively-inactivating current (midpoint of inactivation: ~-100 mV) that resembled current previously described for the Nav1.5 subunit, and a slower current with a depolarized voltage range of inactivation (midpoint ~-30 mV) which had properties consistent with Nav1.8 channels. All neurons also expressed TTX-S Nav currents with similar properties to those previously described in VGN (midpoint of inactivation: ~-75 mV). The Nav1.5-like current contributed about 10% of the total Nav current, was expressed in most VGNs on the first postnatal day (P1), and gradually decreased in prevalence throughout the first week. The Nav1.8-like current was present in ~25% of cells and was correlated with broader action potentials, higher voltage thresholds, and minimal spike height accommodation. We confirmed the expression of Nav1.8 using a reporter mouse in which fluorescence is restricted to Nav1.8- expressing cells; intense fluorescent signal was seen in many VGN cell bodies and peripheral processes. These results suggest that Nav1.8 may be expressed in non-somatosensory peripheral neurons. Nav channel expression in immature VGNs may contribute to development, while differential expression in adulthood may underlie diversity of mature response properties. / by Xiao-Ping Liu. / Ph.D.in Health Sciences and Technology

Thesis: Ph. D. in Medical Engineering and Bioastronautics, Harvard-MIT Program in Health Sciences and Technology, 2014. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 126-139). / Bone adapts its mass and architecture in response to its mechanical environment. Yet control of this process by mechanical cues is poorly understood, particularly for unloading. Defining the fundamental mechano-regulation of bone adaptation is critical for the better understanding and mitigation of bone loss in astronauts as well as clinical conditions such as spinal cord injury, stroke, muscular dystrophy, and bed rest. The overall goal of this work was to study skeletal adaptation to varying amounts of reduced loading to help delineate the relationship between mechanical stimuli and skeletal adaptation. We first examined the relative contribution of muscle and gravitational forces to the maintenance of skeletal health in mice, using botulinum toxin (BTX) to induce muscle paralysis and hindlimb unloading to eliminate external loading on the hindlimbs, alone and in combination. BTX led to greater bone loss than hindlimb unloading, while the combination of interventions led to the most detrimental effects overall, suggesting that both muscle and gravitational forces play a role in skeletal maintenance, with greater contributions from muscle forces. We then characterized skeletal adaptation to controlled reductions in mechanical loading of varying degrees employing a novel model that enables long-term exposure of mice to partial weightbearing (PWB). We found that declines in bone mass and architecture were linearly related to the degree of unloading. Even mice bearing 70% of their body weight exhibited significant bone loss, suggesting that the gravity of the moon (0.16 G) and Mars (0.38 G) will not be sufficient to prevent bone loss on future exploration missions. Finally, since bone remodeling is highly site-specific, we used gait analysis and inverse dynamics to determine the mechanical environment during PWB, and then developed a finite element model of the tibia to resolve the local strain-related stimulus proposed to drive changes in bone mass. We found modest correlations between cortical bone architecture at different PWB levels and strain energy density. Altogether this work provides a critical foundation and rationale for future studies that incorporate detailed quantification of the mechanical stimuli and longitudinal changes in bone architecture to further advance our understanding of the skeletal response to reduced loading. / by Rachel Ellman. / Ph. D. in Medical Engineering and Bioastronautics

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 252-256). / Embryonic Stem Cells (ESCs) are pluripotent and thus are considered the "cell type of choice". ESCs exhibit several phenotypic traits (e.g., proliferation, differentiation, apoptosis, necrosis, etc.) and when differentiated into a particular lineage they can perform an array of functions (e.g., protein secretion, detoxification, energy production). Typically, these cellular objectives compete against each other because of thermodynamic, stoichiometric and mass balance constraints. Analysis of transcriptional regulatory networks and metabolic networks in ESCs thus requires both a nonequilibrium thermodynamic and mass balance framework for designing and understanding complex ESC network approach as well as an optimality approach which can take cellular objectives into account simultaneously. The primary goal of this thesis was to develop an integrated energy and mass balance-based multi objective framework for a transcriptional regulatory network model for ESCs. The secondary goal was to utilize the developed framework for large-scale metabolic flux profiling of hepatic and ESC metabolic networks. Towards the first aim we first developed a complete dynamic pluripotent network model for ESCs which integrates several different master regulators of pluripotency such as transcription factors Oct4, Sox2, Nanog, Klf4, Nacl, Rexl, Daxl, cMyc, and Zfp281, and obtained the dynamic connectivity matrix between various pluripotency related gene promoters and transcription factors. The developed model fully describes the self-renewal state of embryonic stem cells. / (cont.) Next, we developed a transcriptional network model framework for ESCs that incorporates multiobjective optimality-based energy balance analysis. This framework predicts cofactor occupancy, network architecture and feedback memory of ESCs based on energetic cost. The integrated nonequilibrium thermodynamics and multiobjective-optimality network analysis-based approach was further utilized to explain the significance of transcriptional motifs defined as small regulatory interaction patterns that regulate biological functions in highly interacting cellular networks. Our results yield evidence that dissipative energetics is the underlying criteria used during evolution for motif selection and that biological systems during transcription tend towards evolutionary selection of subgraphs which produces minimum specific heat dissipation, thereby explaining the frequency of some motifs. Significantly, the proposed energetic hypothesis uncovers a mechanism for environmental selection of motifs, provides explanation for topological generalization of subgraphs into complex networks and enables identification of new functionalities for rarely occurring motifs. Towards the secondary goal, we have developed a multiobjecive optimization-based approach that couples the normalized constraint with both energy and flux balance-based metabolic flux analysis to explain certain features of metabolic control of hepatocytes, which is relevant to the response of hepatocytes and liver to various physiological stimuli and disease states. We also utilized this approach to obtain an optimal regimen for ESC differentiation into hepatocytes. / (cont.) The presented framework may establish multiobjective optimality-based thermodynamic analysis as a backbone in designing and understanding complex network systems, such as transcriptional, metabolic and protein interaction networks. / by Marco A. Avila. / Ph.D.

Thesis: S.M., Harvard-MIT Program in Health Sciences and Technology, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 73-77). / The health of the human respiratory system depends critically on airway clearance via motile hair-like structures (cilia), which transport and eliminate unwanted particles trapped within mucus. Impairment of mucociliary clearance (MCC) can lead to life-threatening airway narrowing and lung infections, and is a major cause of morbidity and mortality in patients with cystic fibrosis, primary ciliary dyskinesia and chronic obstructive lung disease. However, no tool for microscopic in-vivo visualization of ciliary function is currently available, limiting studies of disease pathogenesis, refined diagnosis and phenotyping, and the development of novel therapeutics. In this thesis, a novel, 1-pm resolution, optical interferometric imaging technique termed Micro-OCT was incorporated into miniaturized common-path endoscopes and mucociliary transport was visualized in vivo for the first time. The first-generation Micro-OCT probe had a rigid design with outer diameter of 4 mm and a two-prism configuration providing beam splitting and sample beam shaping into an annular profile. Image quality of the probe allowed visualization of the periodic pattern of ciliary beating, measurement of airway surface liquid depth (ASL) and visualization of mucociliary transport. Unaltered ciliary function was demonstrated in a living, spontaneously breathing swine model. Newer generation common-path endoscope designs were demonstrated that improve, among other limitations, the stability of the reference reflector position and provide greater potential for miniaturization. The presented work opens unprecedented avenues for studying MCC and the effect of novel therapeutics within the complexity of a living organism. Further, it lays the groundwork for the development of a human probe with the potential to revolutionize diagnosis, phenotyping, and therapy management for all patients with respiratory disease involving the mucociliary escalator. / by Carolin Isabella Unglert. / S.M.

Thesis: Ph. D. in Biomedical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Magnetic resonance imaging (MRI) is a remarkably flexible diagnostic platform due to the variety of clinically relevant physical, chemical, and biological phenomena it can detect. In addition to the host of endogenous contrast mechanisms available, MRI functionality can be further extended by incorporating exogenous factors to attain sensitivity to new classes of indicators. Molecular imaging with targeted injectable contrast agents and MR elastography with externally delivered acoustic vibrations are two such advancements with increasing clinical significance. Conventionally employed separately, this work explores how exogenous components can interact cooperatively in imaging disease and may be combined to more accurately stage disease progression and generate novel mechanisms of MR contrast, using contrast agents and acoustic stimulation as model systems. We imaged hepatic fibrosis in a rat model and found that collagen-binding paramagnetic contrast agents and shear wave MR elastography had partially uncorrelated staging abilities, due to the disease condition's differential timing of collagen production and its stiff cross-linking. This complementary feature enabled us to form a composite multivariate model incorporating both methods which exhibited superior diagnostic staging over all stages of fibrosis progression. We then integrated acoustics and molecular-targeting agents at a deeper level in the form of a novel contrast mechanism, Acoustically Induced Rotary Saturation (AIRS), which switches "on" and "off" the image contrast due to the agents by adjusting the resonance of the spin-lock condition. This contrast modulation ability provides unprecedented clarity in identifying contrast agent presence as well as sensitive and quantitative statistical measurements via rapidly modulated block design experiments. Finally, we extend the AIRS method and show preliminary results for Saturation Harmonic Induced Rotary Saturation (SHIRS), which detects the second harmonic time-oscillation of iron oxide nanoparticles' magnetization in response to an oscillating applied field around B0. We also illustrate an exploratory method of selectively imaging iron oxide agents by diffusion kurtosis measures of freely diffusing water in solutions of magnetic nanoparticles. / by Bo Zhu. / Ph. D. in Biomedical Engineering

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 64-66). / The purpose of the research was to identify the clinical and commercial benefits of switching from intravenous (IV) to buccal delivery of antibiotics. then, the research continued to select 3-5 antibiotics that best met the buccal delivery and market requirements. Methods: The research began with the hypothesis that some injectable antibiotics are good candidates for buccal delivery even with the limitations imposed by the buccal tissue. The thesis captures a two-year research period encompassing three critical fronts - the clinical viability of switching from IV to buccal delivery for antibiotics, the market's desire and readiness to switch, and the antibiotic brands available for commercialization. Then the research moved to drug identification and selection in order to assess the antibiotics that would best function in the buccal delivery model. Results: Intravenous (IV) antibiotics are usually reserved for severe infections that require faster treatment. Less aggressive bacterial growths are treated with oral antibiotics, which has fewer side effects and complications. In the past two decades, the understanding of drug transport across different tissues has increased resulting in improved patient adherence to the therapeutic regimen and pharmacologic response. The administration of drugs by transdermal or transmucosal routes are relatively painless, offers patients more choices, and reduces the need to establish intravenous access, which is a particular benefit for children and elderly. These alternative methods also provide clinical care providers with more choices to better manage their patient's course of treatment. In the past, clinicians administered sedatives, narcotics, and a variety of other medications by transdermal, sublingual, nasal, rectal, and even tracheal-mucosal routes. These delivery options have provided flexible practice settings and this paper intends to show that antibiotics could be the next set of drugs to be administered in variety of ways to provide patients and clinicians the best array of choices. Conclusion: A few years ago, the buccal delivery method was fairly unknown. However, advances in nano encapsulation, physiology, toxicity, and the availability of certain drugs make the timing ideal for introducing antibiotics that have undergone a highly selective process for delivering through the buccal tissue. / by Manijeh Nazari Goldberg. / S.M.