Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2007. / Vita. / Includes bibliographical references. / Most people have two ears, but we can hear with only one ear. The ability to use two ears can substantially improve performance in many circumstances. There are times, however, when the addition of a second ear results in poorer performance (i.e., contra-aural interference). Contra-aural interference is of interest because it is not explained by current auditory models, it has theoretical ramifications, and its understanding could lead to improvements in the quality of life of the hearing-impaired. More generally, the techniques and results can be applied to fields in which information is combined across an array of sensors (e.g., vision with two eyes and radar arrays). This thesis includes both psychophysical measurements and black-box modeling of level discrimination. Level discrimination was chosen to study contra-aural interference since it has traditionally been considered a monaural task (dependent on only a single ear) even though the loudness of a sound depends on both ears (i.e., binaural). This thesis demonstrates that the ability to discriminate small changes in the level of a low-frequency target stimulus presented at one ear can be adversely affected by a distractor stimulus presented simultaneously and contra-aurally to the target. / (cont.) The thesis focuses on conditions in which the target and distractor perceptually fuse; the dominant perception of the stimulus is a compact auditory image with a salient loudness and position and a secondary image referred to as the "time-image". Contra-aural interference was greatest when the introduction of the distractor decreased the reliability of both the perceived loudness and position of the dominant-image. Although the tasks used in this thesis are artificial, their simplicity allows for detailed computational modeling. The results are consistent with a model based on non-optimal integration of the information carried by the dominant-image and the time-image. The modeling separates the effects of internal coding noise and decision noise (criterion jitter). The techniques used to separate the internal coding noise from the criterion jitter can be applied to a broad range of psychology experiments. / by Daniel E. Shub. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 199-217). / In vivo multimodal, multiplexed microscopy allows real-time observation of hematopoietic cells, their stem and progenitor cells and metastatic cancer cells in their native bone marrow (BM) environment. Multiplexing has made possible detailed studies of the BM's microarchitecture, which helps define the niche of these cells; it has nonetheless been limited by the paucity of suitable probes fluorescent in the near-infrared spectrum that is favored by tissue optics. This project attempts to address this problem by developing cellular and vascular fluorescent imaging probes comprised of semiconductor nanocrystals, or quantum dots (QDs), with tunable fluorescence between 65o-8oonm and exhibiting photostability, robust quantum yield and narrow fluorescence profiles that are critical for such applications. The synthesis of alloyed CdTexSe1 x QDs will be detailed in the thesis. Reproducibility and workability in subsequent steps are emphasized in the methods. Special attention is also paid to the difference between working with alloyed versus single semiconductor QDs, especially the need to achieve physical and spectral uniformity when composition and its gradient are also variable. The steps for creating biological probes from these QD fluorophores are also described. They include overcoating, water solubilization and functionalization for cellular uptake and vascular retention. Finally, the thesis returns to its motivation and reports novel methods, developed using NIR QD vascular imaging probes, for visualizing in vivo 3-D imaging data of the murine BM and characterizing the tissue's architecture. Measuring the Euclidean distance between BM osteoblasts and blood vessels is presented to exemplify a potential platform for describing the geographic relationships between cells, molecules and structural components in any tissue. / by Juwell Wendy Wu. / Ph.D.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 1999. / Includes bibliographical references (leaves 115-128). / by Jagesh V. Shah. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 123-132). / The anterior thalamus and hippocampus are part of an extended network of brain structures underlying cognitive functions such as episodic memory and spatial navigation. Earlier work in rodents has demonstrated that hippocampal cell ensembles re-express firing profiles associated with previously experienced spatial behavior. Such recapitulation occurs during periods of awake immobility, slow wave sleep (SWS) and rapid eye movement sleep (REM). Despite its close functional and anatomical association with the hippocampus, whether or how activity in the anterior thalamus is related to activity in the hippocampus during behavioral states characterized by hippocampal replay remains unknown. Here, we monitor and compare thalamic and hippocampal activities during epochs in which rats execute a simple alternation task on a circular maze as well as during sleep periods before and after track running. We employ a neural decoding algorithm to interpret spiking activity in terms of spatial correlates during wake and REM. We analyze multi unit activity (MUA) to characterize the organization of thalamic and hippocampal populations during SWS. Consistent with their role in spatial navigation, we show that during active locomotion ensembles of thalamic and hippocampal neurons represent the spatial behavior of the rat in a coordinated fashion. However, during periods of hippocampal awake replay their spatial representations become decoupled. During REM, we demonstrate that thalamic activity replicates broad activity patterns associated with awake behavior and that both hippocampus and anterior thalamus concurrently represent similar ambulatory states. During SWS, we establish that the activities in these two areas alternate between frames of elevated firing and periods of little or no activity. We show that there is a tendency for thalamic depolarized states to start and end ahead of hippocampal activity frames. These results may shed light on how information encoded by thalamic circuits could bias or be incorporated into hippocampal replay phenomena. / Ph.D.

Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (p. 105-121). / The skin microcirculation performs a range of vital functions, such as maintaining nutritional perfusion to the tissues and overall thermoregulation. Not only does impairment to the skin blood supply lead to tissue necrosis and other disease complications, increasing evidence shows that dysfunctional vasoreactivity in the skin microcirculation is associated with multiple disease states, including hypertension, diabetes mellitus, hypercholesterolemia, peripheral vascular disease, and coronary artery disease, and it is one of the earliest indicators of systemic endothelial dysfunction, the precursor to atherosclerotic disease. Endothelial dysfunction is functionally characterized by abnormal vasomotor response to either a pharmacological or flow-mediated stimulus and can be demonstrated in the skin by measuring reperfusion following a period of ischemia, a phenomenon known as post-occlusive reactive hyperemia (PORH). In my research, I have reviewed the literature regarding endothelial dysfunction and its association with a wide range of cardiovascular risk factors. I have also described the mechanisms thought to link endothelial function in the central vascular beds (i.e. coronary) to that of peripheral conduit vessels and the microcirculation. The knowledge thus gathered confirmed that the microcirculation of the skin is an appropriate site for endothelial function assessment. The ultimate goal of my thesis is to design a noninvasive sensor that is capable of obtaining a quantitative measure of skin perfusion, continuously and in real-time, using the principle of thermal diffusion in perfused tissue. I performed preliminary noninvasive endothelial function testing with a modified Thermal Diffusion Probe (TDP), which has been previously validated for absolute perfusion measurement in an invasive setting. / (cont.) Based on an initial analysis, I have shown that thermal surface perfusion measurements are feasible and reflect the natural perfusion and temperature fluctuations intrinsic to skin tissue. I also established guidelines for determining quantitative parameters of reactivity from tests of PORH as well as temporal parameters of perfusion variations over time through a spectral analysis of resting blood flow. After establishing the necessary thermal boundary conditions for obtaining surface perfusion measurements, I embarked on a process of computer-assisted modeling and rapid prototyping of various design iterations on an insulated sensor housing, with subsequent fabrication of first generation noninvasive sensors. As a result of these initial sensor designs, specifications for the sensor housing were created to ensure that the appropriate thermal field would be established at the skin measurement site - an important step as it permits the most accurate determination of tissue thermal properties. Finally, I propose a candidate design for an ideal sensor capable of improving the reproducibility of noninvasive perfusion measurements on skin. The development of a noninvasive measure of endothelial dysfunction in the skin is of great value in the early identification of individuals at risk for atherosclerotic complications. Furthermore, the nature of such a technique would provide quantitative information on the presence of a disorder, the extent of dysfunction, and the effectiveness of treatment interventions. / by Vivian V. Li. / M.Eng.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (leaves 105-117). / Aphasia is an acquired impairment of language ability that occurs secondary to brain damage, and auditory comprehension deficits are a defining component of aphasia. At the single-word level, these deficits are thought to arise from impaired phonological processing, semantic representations, or both. The present study examined spreading lexical activation in people with aphasia by implementing thorough clinical evaluation, a series of listening tasks, and a time sensitive means of tracking cortical activation. Magnetoencephalography (MEG) was used to measure the cortical activity of 7 people with aphasia, 9 age-matched control participants, and 10 younger control participants as they completed an auditory lexical decision task and a passive listening task with phonemes. In the lexical decision task, target words were presented in three conditions of interest: semantically primed, where the target was preceded by a related word; identity primed, where the target was preceded by itself; and a control condition, where the target was preceded by an unrelated word. Behavioral reaction times and MEG data were collected in response to each target, and the M350, a MEG signal associated with lexical processing, was evaluated. MEG data collected during the passive listening task were used to evaluate the mismatch field (MMF), a response associated with the formation of an auditory memory trace. Analysis was conducted at both the group and single-subject levels. / (cont.) All groups showed identity priming of the M350 response, although this was seen in the amplitude dimension for the control groups but in the latency dimension for the group with aphasia. The older control group showed semantic priming of the M350 and the younger group showed a marginally significant priming effect, while the group with aphasia failed to show this effect. There was evidence that some people with aphasia may have a delayed or absent M350 response. Finally, the behavioral results indicated that the younger and older control participants were using different strategies to complete the lexical decision task. These findings highlight the potential importance of latency differences when analyzing electrophysiological responses in aphasic populations. Furthermore, they indicate that some cognitive-linguistic tasks may induce different types of processing in older and younger groups. / by Lauryn Rose Zipse. / Ph.D.

Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2002. / Includes bibliographical references (p. 82-91). / This dissertation describes a novel mechanism for the entry of organic cations, including the styryl pyridinium dyes and the notoriously ototo.xic aminoglycoside antibiotic drugs, into sensory hair cells: permeation through the transduction channels. Both gentamicin, an aminoglycoside, and FM1-43, a styryl pyridinium dye, rapidly and selectively enter hair cells. The hair cell transduction channel passes monovalent cations, but is selective for the divalent calcium. FM1-43 and gentamicin are larger than calcium, and FM1-43 is quite lipophilic. These experiments localize the rapid entry to the tips of the stereocilia, and show that perturbations of channel behavior also modulate the dye and drug entry, and that entry requires mechanical gating of the transduction channel. Channel expression in cultured cells also allows dye entry when those channels are opened. Less rapid routes also fill both hair cells and neighboring cells. Two lines of evidence extend these conclusions. First, voltage clamp recording confirmed gentamicin entry via the transduction channel: current was diminished but not blocked by the drug, and the block was not enhanced at more negative potentials. Second, injection of FM1-43 into mice labeled many sensory end organs and neurons. Limiting access-to the sensory endings diminished labeling. These results provide a powerful tool for visualizing the transduction process in living cells, for testing transduction and channel permeation, and perhaps for developing less toxic antibiotic drugs. / by Richard B. MacDonald. / Ph.D.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2000. / "August 1999." / Includes bibliographical references. / A human exploration mission to Mars could take place within 10 years. During the 6 to 12 month journey astronauts would likely lose bone mineral density (BMD) at a mean rate of 1-2 percent per month in weight-bearing areas, approximately 10 times the rate associated with normal ageing. There exists an important need to quantify the fracture risk associated with this loss. Methods: Using computational modeling, the factor of risk for hip fracture (applied load divided by failure load) was assessed following 0, 6, and 12 months of weightlessness for: 1) the mid-stance phase of gait, and 2) a fall to the side impacting the greater trochanter. Peak applied loading was calculated for Earth and Mars gravity levels using the equations of motion for three-segment models representing locomotion and falls. Mars simulations included extravehicular activity (EVA, with spacesuit) and intravehicular activity (IVA). The structural properties of the femur were analyzed using a three-dimensional finite element model derived from quantitative computed tomography scans of a representative cadaveric femur. Space flight associated changes in density, geometry, and muscle strength were incorporated. Results: Peak applied joint contact force ranges for mid-stance were: 1.2- 2.5 kN (Earth), 0.9-1.8 kN (Mars IVA), and 1.5-2.4 kN (Mars EVA). Peak applied joint contact forces for fall impact were: 4.2-8.0 kN (Earth), 2.7-5.1 kN (Mars IVA), and 3.1-5.0 kN (Mars EVA). Femoral strength in mid-stance decreased from 5.9-6.1 kN (0 months) to 5.1- 5.4 kN (12 months), while femoral strength in fall impact decreased from 4.2-4.4 kN (0 months) to 3.8-4.0 kN (12 months). Typically, the factor of risk for hip fracture was highest for falls in Earth gravity following 12 months of weightlessness (1.12-2.08), and lowest for IVA locomotion in Mars gravity (0.26-0.49). All fall conditions yielded a high likelihood of fracture. Astronauts are advised to take precautions against falling following long duration space flight and could benefit from the temporary use of hip pads. / by Grant Schaffner. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Cancer is a leading cause of death worldwide, accounting for at least 10% of all deaths globally. Current therapies for cancer include surgical excision, chemotherapy and immunotherapy. CD8[+] T cells are adaptive immune cells responsible for eradicating tumor cells. However, these T cells can be rendered ineffective through tolerance. Yet in various mouse models and human patients, tolerant T cells persist. The aim of this project is to identify factors that support T cell persistence in a tolerizing tumor environment. Using a spontaneous prostate cancer model, we study antigen-specific T cells that have been shown to be locally tolerant in the prostate tumor environment. In this thesis, I compare the immune response in normal, antigen bearing, tumor transgenic and tumor-antigen transgenic mouse models. Results show that T cell infiltration and persistence in the tolerizing prostate environment is dependent on the presence of antigen and tumorigenic/tumor-related factors. Although antigen-specific T cells are locally tolerant in the prostate of tumor-antigen transgenic mice, they generally persist in the prostates of tumor transgenic mice regardless of whether antigen is present or not. Further analyses revealed that T cells infiltrate the prostate and can proliferate extensively in the tolerizing tumor environment due to the presence of antigen. Interestingly, antigen-specific T cells are depleted from the spleens of mice that express antigen in their prostates. / (cont.) This depletion from the spleen is correlated with low levels of IL-7R[alpha] expression and the presence of antigen in the prostate. Tumorigenic or tumor-related factors in the prostate also appear to be supporting CD8[+] T cell persistence. This thesis shows that persistence of antigen-specific T cells in the tumor environment is not dependent on IL-15 and IL-7; cytokines known to support proliferation and maintenance of persisting functional CD8[+] T cells. Some potential candidates are also discussed. More investigative work needs to be done to identify the role of these factors on T cell infiltration and persistence. In combination with tolerance-breaking strategies, persisting T cells may be excellent vehicles for delivering site-specific cancer immunotherapy. / by Mobolaji 0. Olurinde. / Ph.D.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2015. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 221-235). / Visual perception of objects is a computationally challenging problem and fundamental to human well-being. Extensive previous research has revealed that the inferior temporal cortex (IT), a high-level visual area, is involved in various aspects of visual perception. Yet, little is known about: how IT neural responses to objects support human perception of the objects; and how IT responses are produced from retinal images of objects. The goal of this research is to tackle these two related questions and find out explicit, quantitative mechanisms that describe human core visual perception of objects, a remarkable ability achieved with brief (<200ms) image viewing duration. We first operationally define the core visual perception by measuring behavioral reports of human subjects in hundreds of visual tasks. These tasks are designed to systematically assess subjects' ability to estimate key visual parameters of an object in an image, such as the object's category, identity, position, size, and viewpoint angles. Combined with a rich dataset of monkey visual neural responses to the same task images, we systematically explore a large number of explicit hypotheses that might explain the human behavioral reports. Here, we demonstrate that weighted linear sums of IT responses robustly predict the human pattern of behavior. Moreover, we show that performance-optimized hierarchical neural networks explain a large portion of neural responses of high-level visual areas including IT. These results establish a working mechanistic model of core visual perception by providing an end-to-end understanding of the human visual system from images to neural responses to behavior. / by Ha Hong. / Ph. D.