Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2004. / Includes bibliographical references (p. 191-203). / The importance of the cochlear active mechanism in the reception of speech in different types of noise was explored. The perceptual effects of loudness recruitment, a consequence of loss of the active mechanism, were assessed in simulated-loss listeners using a multiband expansion algorithm that models abnormal cochlear linearity. While this algorithm, which derives the expansion characteristic from absolute hearing thresholds, can accurately simulate the mean speech intelligibility results of hearing-impaired listeners, its ability to simulate the performance of individual listeners is limited. Given the relationship between loudness perception and the active mechanism, deriving the expansion characteristic from estimates of cochlear compression should provide a more accurate model of an individual listener's impairment. Towards this aim, the reliability of two psychoacoustic methods used to estimate the magnitude of compression (growth of masking and temporal masking) was assessed. Results suggest that growth of masking is a more reliable measure of compression in listeners with both normal and impaired hearing. The relationship between the compressive characteristics of the auditory system and speech perception in complex acoustic backgrounds was also evaluated. The operational status of the active mechanism was assessed behaviorally using three independently derived measures: (1) slope ratio of off- and on-frequency growth of masking functions, (2) equivalent rectangular bandwidth of auditory filters, and (3) masker-phase masking differences. These measures were correlated with speech reception thresholds (SRTs) in backgrounds with and without spectral and/or temporal-modulations. The relationship between slope ratios, filter bandwidths, and the maximum / (cont.) SRT difference (SRT in steady noise minus SRT in temporally modulated, spectral gap noise) was significant. These results indicate that the ability to take advantage of momentary fluctuations in the amplitude or frequency spectrum of background noise requires an intact active mechanism. The speech reception performance of two hearing-impaired listeners was modeled using a customized version of the expansion algorithm. The algorithm was customized to an individual's impairment based on psychoacoustic measures used to evaluate the integrity of the active mechanism. The maximum SRT difference in the simulated-loss listeners more closely matched the results of their hearing-impaired counterparts, compared to SRTs measured using the original algorithm. These results provide further evidence of the importance of the active mechanism to the perception of speech in modulated noise. / by Peninah S. Rosengard. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (p. 155-174). / The bone marrow contains a multipotent stromal cell, commonly referred to as a mesenchymal stem cell (MSC). There has been recent interest in the clinical use of MSCs for cell-based therapy because: (1) bone marrow aspiration is a routine method used in medicine thereby allowing for easy accessibility to human MSCs; (2) MSCs are easily isolated and can expand to clinical scales in a relatively short period of time; (3) MSCs can be biopreserved without loss of potency and stored for point-of-care delivery; and (4) human trials of MSCs thus far have shown no adverse reactions to allogeneic versus autologous MSC transplants suggesting that therapy can cross histocompatibility barriers. This thesis describes the development of new modalities and indications for MSC-based treatments by leveraging the endogenous functions of these cells for therapeutic purposes. First, it is known that marrow stromal cells support hematopoiesis by secreting bioactive molecules that aid in the growth, differentiation, function and migration of hematopoietic cells within the marrow cavity. We show that these same secreted molecules derived from MSCs ex vivo can be formulated as an intravenous drug. In a D-galactosamine model of acute liver failure, a bolus injection of a concentrated form of MSC conditioned medium (MSC-CM) led to a significant survival benefit with a one week study endpoint. We employed in vitro and in vivo assays to demonstrate the effect of MSC-CM on leukocytes and resident liver cells. Traditional biochemical approaches were performed to identify active fractions within MSC-CM that were responsible for its therapeutic efficacy. As a corollary to an injectable drug, we developed MSCbased extracorporeal devices to serve as a dynamic source of MSC-CM in a dialysis-like setting. / (cont.) Liver injured rats supported by extracorporeal bioreactors seeded with MSCs had significant improvements in liver serologies and survival in the short-term, whereas a composite device containing both MSCs and hepatocytes was shown to have a long-term survival benefit after 30 days. The second natural function of MSCs that was exploited for therapy concerns recent evidence that stromal cells can present antigens in lymphoid organs. We discovered that MSCs can express peripheral tissue antigens similar to other specialized antigen presenting cells in the thymus and lymph nodes - a process known to induce tolerance to self-reactive T cells in vivo. We show that MSC transplantation can be an effective treatment of intestinal autoimmunity in a chemically-induced model of colitis and a mouse model deficient in regulatory T cells. In addition, we demonstrate that MSC grafts increase the endogenous population of suppressor cells in vivo, which can potentially amplify and sustain the immunosuppression of the original transplant. The proposed work is significant, as development of such therapies for acute liver failure and inflammatory bowel disease would potentially treat an estimated 100,000+ newly diagnosed patients or ones who are refractory or contraindicated to standard-of-care medical/surgical procedures. These studies may empower the future use of MSCs in other organ failure syndromes and autoimmune conditions. Finally, exploration of the therapeutic functions of MSCs is expected to enhance our understanding of the mechanisms involved in cell therapy and give further insight to the natural functions of MSCs during health and disease. / by Biju Parekkadan. / Ph.D.

Thesis (Ph. D. in Speech and Hearing Bioscience and Technology)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 165-180). / Speakers use auditory feedback to monitor their own speech, ensuring that the intended output matches the observed output. By altering the acoustic feedback signal before it reaches the speaker's ear, we can induce auditory errors: differences between what is expected and what is heard. This dissertation investigates the neural mechanisms responsible for the detection and consequent correction of these auditory errors. Linguistic influences on feedback control were assessed in two experiments employing auditory perturbation. In a behavioral experiment, subjects spoke four-word sentences while the fundamental frequency (FO) of the stressed word was perturbed either upwards or downwards, causing the word to sound more or less stressed. Subjects adapted by altering both the FO and the intensity contrast between stressed and unstressed words, even though intensity remained unperturbed. An integrated model of prosodic control is proposed in which FO and intensity are modulated together to achieve a stress target. In a second experiment, functional magnetic resonance imaging was used to measure neural responses to speech with and without auditory perturbation. Subjects were found to compensate more for formant shifts that resulted in a phonetic category change than for formant shifts that did not, despite the identical magnitudes of the shifts. Furthermore, the extent of neural activation in superior temporal and inferior frontal regions was greater for cross-category than for within-category shifts, evidence that a stronger cortical error signal accompanies a linguistically-relevant acoustic change. Taken together, these results demonstrate that auditory feedback control is sensitive to linguistic contrasts learned through auditory experience. / by Caroline A. Niziolek. / Ph.D.in Speech and Hearing Bioscience and Technology

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (leaves 152-160). / Imaging speed in conventional magnetic resonance imaging (MRI) is limited by the performance of magnetic field gradients and the rate of power deposition in tissue. Parallel MRI techniques overcome these constraints by exploiting information stored within the spatial sensitivity patterns of radiofrequency detector arrays to substitute for some of the spatial information that would normally be obtained using magnetic field gradients. Parallel MRI strategies have been applied clinically to increase patient comfort, enhance spatial resolution, expand anatomical coverage, and reduce image artifacts. The effectiveness of parallel MRI techniques is largely determined by the amount of spatial information that is stored in the detector coil sensitivities. This dissertation investigates the spatial encoding properties of coil arrays from three practical and fundamental perspectives. First, a novel array design is presented that enables spatial encoding in multiple directions simultaneously. Second, the impact of inductive coupling between array elements in parallel MRI is investigated theoretically and experimentally. Finally, electromagnetic calculations are described that permit computation of the ultimate intrinsic signal-to-noise ratio available to any physically realizable coil array for parallel MR. These calculations help to establish fundamental limits to the image accelerations that may be achieved using parallel MRI techniques. These limits are intrinsically related to the wavelengths of the electromagnetic fields at MR imaging frequencies. The sensitivity patterns that correspond to the ultimate intrinsic SNR also represent potential starting points for new coil designs. / by Michael A. Ohliger. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (p. 119-133). / High-resolution ex vivo magnetic resonance microscopy (MRM) can be used to delineate prominent architectonic features in the human brain, but increased contrast is required to visualize more subtle distinctions. The goal of this thesis is to employ target-specific MR contrast agents to regionally alter relaxation rates, resulting in increased contrast in ex vivo MRM of the human brain, with the aim of providing richer information about cyto- and/or myelo-architechtonics than is currently achievable. To accomplish this goal, a traditional optical myelin stain, luxol fast blue (LFB) MBSN with a paramagnetic copper core, has been introduced as a white-matter-selective MR contrast agent in ex vivo brain tissue. The solution relaxivity of LFB was measured at high (4.7 Tesla) and ultra-high (14 Tesla) field strengths. A methodology was developed for staining large tissue samples, enabling MR imaging. Longitudinal (R1) and transverse (R.2) relaxation rates in LFB-stained tissue increased proportionally with myelination at both field strengths. Ri changes produced larger contrast-to-noise ratios (CNR), per unit time, on Ti-weighted images between the deeper, more myelinated cortical layers (IV-VI) and adjacent, superficial layers (I-III) at both field strengths. Specifically, CNR for LFB-treated samples increased by 229± 13 per cent at 4.7T and 269± 25 per cent at 14T when compared to controls. Also, additional cortical layers (IVca, IVd, and Va) became resolvable in 14TMR images after en bloc staining with LFB. After imaging was completed, the LFB-stained sample was prepared for light microscopy. / (cont.) Both macroscopic and microscopic distributions of LFB were found to mimic those of traditional histological preparations. Next, the LFB-MR method was employed to investigate microstructure in X-linked adrenoleukodystrophy (ALD), a confluent demyelinating disorder characterized by accumulation of abnormal lipids. LFB-MR revealed an additional zone, unseen in formualin preparations and best visualized in T2*-weighted images, which produced four-fold increases in contrast-to-noise ratio. Immunohistological analysis identified a corresponding area of perivascular macrophages, and ultrastructural examination suggested LFB particulates bound to lipids within these macrophages. We thus conclude that LFB-MR is able to detect the actively demyelinating edge in cerebral ALD. The results presented in this thesis suggest target-specific contrast agents will 1) enable more detailed MR images, permitting the construction of better MR atlases and advancing the field of MR histopathology, and 2) guide the design of future in vivo contrast agents. / by Megan Leticia Hepler Blackwell. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. "Pages 65-70 contain illegible text. This is the best copy available"--P. after t.p. / Includes bibliographical references (p. 63-64). / Investors have difficulty funding the life sciences because of the high risks involved in research and development and commercialization of new products. Risk in the biopharmaceutical industry is the result of scientific, regulatory and economic uncertainty. The nature of the biopharmaceutical industry introduces many challenges. Each of these challenges incorporates a measure of risk into drug development. The level of understanding of technical success interdependencies has not been fully investigated. These interdependencies (correlations) could lead to an overall greater risk to the company's portfolio than previously expected. A better understanding of the risks that lead to success or failure in drug development might encourage more investment in the life sciences and specifically in the biopharmaceutical industry, and a greater awareness of the correlations between risks and products might lead to more informed decision making on a biopharmaceutical portfolio leading increased productivity. A dataset was collected from Thomson Reuters. The dataset is the oncology portfolio from a biopharmaceutical company, Genentech Inc. Logistic regression was used to determine if any of the defined variables contributed to the success or failure of the oncology products. The chi-square value was 7.738 with the degrees of freedom equal to 5 and with a p-value of 0.17. Therefore, none of the variables significantly contributed to the outcome. More research should be performed in this area in order to better understand the risk in a biopharmaceutical portfolio. / by Alice Elizabeth Wagner. / S.M.

Thesis (Ph. D.)--Harvard University--MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references. / Breast cancer is the most commonly diagnosed cancer among women in the United States. It is the most common cause of death in women ages 45-55. Optical techniques can potentially play a diagnostic role in several aspects of breast cancer evaluation and treatment. This thesis outlines progress on the use of Raman spectroscopy to diagnose breast cancer. Laboratory studies on fresh-frozen tissues are used to demonstrate that the detailed information provided by Raman spectroscopy yields accurate breast disease diagnosis. A Raman spectroscopic-based diagnostic algorithm was developed which classifies samples into four categories according to specific pathological diagnoses: normal, fibrocystic change, fibroadenoma, and infiltrating carcinoma. Cancerous lesions were separated from non- cancerous tissues with a sensitivity of 94% and a specificity of 95%. Further, use of a spectral model based on the morphological structures that comprise breast tissue allows increased understanding of the relationship between a Raman spectrum and tissue disease state. Based on the excellent results of our laboratory work, two clinical studies were undertaken. These studies translate Raman spectroscopy from a laboratory technique into a clinically useful tool. The first study tests the diagnostic algorithm in a prospective manner on freshly excised tissue. Preliminary results are promising. The second study is the first demonstration of in vivo data acquisition of Raman spectra of breast tissue. The culmination of this research is the demonstration of accurate intra-operative margin status assessment during partial mastectomy surgeries. / (cont.) Application of our previously developed diagnostic algorithm resulted in perfect sensitivity and specificity in this small in vivo data set. These preliminary findings indicate that Raman spectroscopy has the potential to lessen the need for re-excision surgeries resulting from positive margins and thereby reduce the recurrence rate of breast cancer following partial mastectomy surgeries. The experiments and theory presented throughout this thesis demonstrate that Raman spectroscopy is a viable clinical tool that can be used to accurately diagnosis breast cancer and breast disease. / by Abigail Susan Haka. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2006. / Includes bibliographical references (leaves 73-85). / Proteomics has been revolutionized in the last couple of years through integration of new mass spectrometry technologies such as -Enhanced Laser Desorption/Ionization (SELDI) mass spectrometry. As data is generated in an increasingly rapid and automated manner, novel and application-specific computational methods will be needed to deal with all of this information. This work seeks to develop a Bayesian framework in mass-based proteomics for protein identification. Using the Bayesian framework in a statistical signal processing manner, mass spectrometry data is filtered and analyzed in order to estimate protein identity. This is done by a multi-stage process which compares probabilistic networks generated from mass spectrometry-based data with a mass-based network of protein interactions. In addition, such models can provide insight on features of existing models by identifying relevant proteins. This work finds that the search space of potential proteins can be reduced such that simple antibody-based tests can be used to validate protein identity. This is done with real proteins as a proof of concept. Regarding protein interaction networks, the largest human protein interaction meta-database was created as part of this project, containing over 162,000 interactions. A further contribution is the implementation of the massome network database of mass-based interactions- which is used in the protein identification process. / (cont.) This network is explored in terms potential usefulness for protein identification. The framework provides an approach to a number of core issues in proteomics. Besides providing these tools, it yields a novel way to approach statistical signal processing problems in this domain in a way that can be adapted as proteomics-based technologies mature. / by Gil Alterovitz. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (leaves 80-88). / Neutrophils traversing the pulmonary microcirculation are subjected to mechanical stimulation during their deformation into narrow capillaries. To better understand the time- dependant changes caused by this mechanical stimulus, in the first part of the thesis, neutrophils were caused to flow into a microchannel, which allowed simultaneous visualization of cell morphology, and passive rheological measurement by tracking the Brownian motion of endogenous granules. Above a threshold stimulus, mechanical deformation resulted in neutrophil activation with pseudopod projection. The activation time was inversely correlated to the rate of mechanical deformation experienced by the neutrophils. A reduction in shear moduli was observed within seconds after the onset of the mechanical stimulus, suggesting a sudden disruption of the neutrophil cytoskeleton when subjected to mechanical deformation. However, the magnitude of the reduction in moduli was independent of the degree of deformation. Recovery to nearly the initial values of viscoelastic moduli occurred within one minute. These observations confirm that mechanical deformation of neutrophils, similar to conditions encountered in the pulmonary capillaries is not a passive event; rather, it is capable of activating the neutrophils and enhancing their migratory tendencies. The second part of the thesis seeks to understand the changes in the cytoskeletal structure and the extent of biological activation as a result of this deformation process. Neutrophils were passed through narrow polycarbonate filter pores under physiological driving pressures, fixed and stained downstream in order to visualize the F-actin content and distribution. / (cont.) Below a threshold capillary size, the cell remodeled its cytoskeleton through initial F-actin depolymerization, followed by recovery and increase in F-actin content associated with formation of pseudopods. 'This rapid depolymerization and subsequent recovery of F-actin was consistent with our previous observation of an immediate reduction in moduli with eventual recovery when the cells were subjected to deformation. Results also show that neutrophils must be retained in their elongated shape for an extended period of time for pseudopod formation, suggesting that a combination of low driving pressures and small capillary diameters promotes cellular activation. These observations show that mechanical deformation of neutrophils into narrow pulmonary capillaries have the ability to influence cytoskeletal structure, the degree of cellular activation and migrational capabilities of the cells. / by Belinda Yap. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (leaves 158-172). / The overall goal of this research is to acquire a more complete picture of the neurological processes of visual influences on speech perception and to investigate effects of hearing status on AV speech perception. More specifically, functional magnetic resonance imaging (fMRI) was used to investigate the brain activity underlying audio-visual speech perception in three groups of subjects: (1) normally hearing, (2) congenitally deafened signers (American Sign Language) who do not use hearing aids, and (3) congenitally hearing impaired individuals with hearing aids. FMRI data were collected while subjects experienced three different types of speech stimuli: video of a speaking face with audio input, audio speech without visual input, and video of a speaking face without audio input. The cortical areas found to be active for speechreading included: visual cortex, auditory cortex (but not primary auditory cortex), speech motor network areas, supramarginal gyrus, thalamus, superior parietal cortex and fusiform gyrus. For hearing impaired subjects, in addition to the areas listed above, Heschl's gyrus, right angular gyrus (AG), cerebellum and regions around right inferior frontal sulcus (IFS) in the frontal lobe were also found to be active. / (cont.) Results from our study added to existing evidence of the engagement of motor-articulatory strategies in visual speech perception. We also found that an individual's speechreading ability is related to the amount of activity in superior temporal cortical areas, including primary auditory cortex, pre-SMA, IFS and right AG during visual speech perception. Results from effective connectivity analyses suggest that posterior superior temporal sulcus may be a potential AV speech integration site; and that AG serves a critical role in visual speech perception when auditory information is absent for hearing subjects, and when auditory information is available for hearing impaired subjects. Also, strong excitatory projections from STS to inferior frontal gyrus (IFG) and premotor/motor areas, and a strong inhibitory projection from IFG to STS seem to play an important role in visual speech perception in all subject groups. Finally, correlation analyses revealed that in hearing aid users, the amount of acoustic and speech signal gained by using hearing aids were significantly correlated with activity in IFG. / by Julie J. Yoo. / Ph.D.