Thesis (Ph. D.)--Harvard University--MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (p. 141-148). / Pitch variations are used in different languages in a variety of communicative ways, from cueing lexical item identity to conveying meaning through phrasing and accentuation. Previously, linguistic theories of intonation and tone which have sought a unifying account for tonal phenomena have not defined a clear and systematic relation between phonological representations and phonetic output in terms of acoustically observable fundamental frequency (FO) variations. This is problematic, because meaningful pitch patterns cannot be related to underlying phonological primitives in any clear way, so that it is difficult to empirically verify or falsify the theory. This thesis addresses this problem by proposing a phonological description of intonation and tone for which there is a clear and systematic relationship between observed FO variations and underlying phonological primitives. The theory is based on a construct called the tone interval, which represents an abstraction of a ratio of two fundamental frequencies. A syntagmatic tone interval relates two sequentially-ordered tones, while a paradigmatic tone interval relates a tone and a speaker-specific referent level. Tone intervals define one of three relations: a tone may be higher, lower, or the same level as its referent. Additional language-specific categories may be formed which restrict the pitch distance between a tone and its referent. Tones in syntagmatic tone intervals are assumed to be arranged at the phrasal level with respect to a metrical grid, which represents the relative prominence and timing of syllables. / (cont.) This permits interactions between nonsequential tones occupying metrically prominent syllables, accounting for cross-linguistic observations involving control of relative height relations on nonadjacent syllables. Six experiments tested the predictions of tone interval theory and other phonological theories for English. Experiments 1 and 3 involved discrimination of pairs of stimuli in which the timing of an FO extremum had been varied along a continuum with respect to segments, while Experiments 2 and 4 involved imitation of these stimuli. Experiments 5 and 6 involved imitating stimuli in which absolute FO level had been varied along a continuum. Consistent with the tone interval theory, these results demonstrate the importance of relative pitch level for phonological representations. In particular, discrimination maxima and discreteness in production data were observed for positions in stimulus series in which either (i) the timing of an FO extremum was varied across a vowel onset, or (ii) the FO level of one syllable switched from higher than another syllable to lower than that syllable. / by Laura Christine Dilley. / Ph.D.

Thesis (M. Eng.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (leaves 92-95). / Breath analysis has potential to become a new medical diagnostic modality. In this thesis, a method for the analysis of human expired breath was developed using gas chromatography-mass spectroscopy. It was subsequently adopted for gas chromatography-differential mobility spectroscopy, a modality not previously applied to this problem. Tedlar bags and solid-phase microextraction were used for breath sampling and concentration prior to analysis. Four fiber coatings were evaluated with respect to selectivity and sensitivity; extraction time, gas chromatography temperature programming, and sample storage stability were explored for optimization. The method entails extraction and preconcentration with a polydimethylsiloxane-divinylbenzene coated fiber for 30 min at 37⁰C, and extraction profiles for several compounds demonstrate competitive adsorption. 120 compounds were identified in breath with response variability between 23 - 117% about mean values. Feasibility of differential mobility spectroscopy for breath analysis was established, and this method will be the basis for future investigations on the diagnostic potential of breath analysis. / by William Merrick. / M.Eng.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2003. / Includes bibliographical references (p. 167-171). / Advanced laryngeal cancer is often treated by surgical removal of the larynx (laryngectomy) thus rendering patients unable to produce normal voice and speech. Laryngectomy patients must rely on an alternative means of producing voice and speech, with the most common method being the use of an electrolarynx (EL). The EL is a small, hand-held, electromechanical device that acoustically excites the vocal tract when held against the neck or at the lips. While the EL provides a serviceable means of communication, the resulting speech has several shortcomings in terms of both intelligibility and speech quality. Previous studies have identified and tried to correct different single selected acoustic properties associated with the abnormal quality of EL speech, but with only limited success. There remains uncertainty about: 1) which components of the EL speech acoustic signal are contributing most to its abnormal quality and 2) what kinds of acoustic enhancements would be most effective in improving the quality of EL speech. Using a combination of listening experiments, acoustic analysis and acoustic modeling, this thesis investigated the perceptual and acoustic impacts of several aberrant properties of EL speech, with the overall goal of using the results to direct future EL speech improvement efforts. Perceptual experiments conducted by having 10 listeners judge the naturalness of differently enhanced versions of EL speech demonstrated that adding pitch information would produce the most benefit. Removing the EL self-noise and correcting for a lack of low frequency energy would also improve EL speech, but to a lesser extent. However, / (cont.) this study also demonstrated that monotonous, normal speech was found to be more natural than any version of EL speech, indicating that there are other abnormal properties of EL speech contributing to its unnatural quality. An acoustic analysis of a corpus of pre- and post-laryngectomy speech revealed that changes in vocal tract anatomy produce narrower formant bandwidths and spectral zeros that alter the spectral properties of EL speech. Vocal tract modeling confirmed that these spectral zeros are a function of EL placement and thus their effects will vary from user to user. Even though the addition of pitch information was associated with the greatest improvement in EL speech quality, its implementation is not currently possible because it would require access to underlying linguistic and/or neural processes. Based on these findings it was concluded that an enhancement algorithm that corrects for the low frequency deficit, the interference of the EL self-noise, the narrower formant bandwidths, and the effect of the source location, should produce EL speech whose quality surpasses what is currently available. / by Geoffrey Seth Meltzner. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (leaves 43-49). / Electronic prescription software is replacing traditional handwritten medication orders. This development however doesn't come without a cost and speed has been one of the most complained about issues. It is important to address this problem and develop methods to reduce the time spent entering medication orders into computerized prescription software. The objective of this study was to understand the structure of prescription patterns and explore the possibility of designing a method that will predict prescription patterns with only the knowledge of past prescription history. Various machine-learning methods were used and their performance measured by the accuracy of prediction as well as their ability to produce desirable results, within practical time limits. This paper presents a method to transform prescription data into a stochastic time series for prediction. The paper also presents a new nonlinear local algorithm based on nearest neighbor search. In analyzing the database the drug patterns were found to be diverse and over 30% of the patients were unique, in the sense that no other patient had been prescribed the same set of active ingredients. In spite of this diversity, it was possible to create a list of 20 drugs that contained the drug to be prescribed next for 70.2% of patients. This suggests that probabilistically created pick lists, tailored specifically for one patient at the time of prescription, might be used to ease the prescription process. However, further research is needed to evaluate the impact of such lists on prescription habits. / by Ívar S. Helgason. / S.M.

Thesis (S.M.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 1999. / Includes bibliographical references (leaves 42-44). / The functionality of prosthetic limbs is restricted by the limited availability of sensory feedback. This research aims to develop a technology to allow the presentation of sensory information directly to the sensory afferent neurons of the transected peripheral nerve in the stump of the amputee. lntraneural implants of several designs were developed and implanted in rabbit animal models and monitored for chronic functionality evaluated using both neurophysiological and behavioral tests. Animal studies have demonstrated single channel implant functionality of up to 129 days. The relative merit of the designs is assessed, and future directions for implant design and behavioral testing are suggested. / by Daniel DiLorenzo. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (leaves 91-100). / Advances in microarray technology facilitate the study of biological systems at a genome-wide level. Meaningful analysis of these transcriptional profiling studies, however, demands the concomitant development of novel computational techniques that take into account the size and complexity of the data. We have devised statistical algorithms that use replicate microarrays to define a genome-wide expression profile of a given cell type and to determine a list of genes that are significantly differentially expressed between experimental conditions. Applying these algorithms to the study of cultured human umbilical vein endothelial cells (HUVEC), we have found approximately 54% of all genes to be expressed at a detectable level in HUVEC under basal conditions. The set of highest expressed genes is enriched in nucleic acid binding proteins, cytoskeletal proteins and isomerases as well as certain known markers of endothelium, and the complete list of genes can be found at ... We have also studied the effect of a 4-hour exposure of HUVEC to 10 U/mL of IL-1, and detected 491 upregulated and 259 downregulated statistically significant genes, including several chemokines and cytokines, as well as members of the TNFAIP3 family, the KLFfamily and the Notch pathway. Applying these rigorous statistical techniques to genome-wide expression datasets underscores known patterns of endothelial inflammatory gene regulation and unveils new pathways as well. / (cont.) Finally, we performed a direct comparison of direct-labeled microarrays with amplified RNA microarrays for an initial assessment of the effect of the additional noise of amplification on the outputs of the statistical algorithms. These techniques can be applied to additional genome-wide profiling studies of endothelium and other cell types to refine our understanding of transcriptomes and the gene regulatory network governing cellular function and pathophysiology. / by Sripriya Natarajan. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (p. 193-201). / It is now widely accepted that cells are capable of processing both mechanical and chemical signals from the extracellular environment. Exactly how these two factors affect the cell biology in the context of physiological circumstances is an area of intense interest that has given rise to an entire field of study called cell mechanotransduction. The unambiguous decoupling of mechanical and chemical properties that stimulate cell development and phenotypic change is challenging from an experimental standpoint. This thesis describes some of the first studies of chemomechanical coupling arising from anchorage-dependent forces between cells and a versatile class of chemically and mechanically tunable polymer thin films, termed polyelectrolyte multilayers. Specifically, investigation of the effects of extracellular chemomechanical stimulation on cell morphology and adhesion in the eukaryotic cells such as vascular endothelial cells and fibroblasts; and the adhesion of prokaryotic cells S. epidermidis and E. coli are presented. Endothelial cells (EC) comprise a major portion of the cell population in the human body. Because of the extensive distribution of endothelial cells in various tissues, they function across a broad range of mechanical and chemical environments. Furthermore, a general understanding of how mechanical forces contribute to the development of cellular function is an important aspect in the development of therapeutic techniques and materials capable of addressing a wide spectrum of human diseases and injuries. Cell adhesion to extracellular matrices and tissues can be indicative of underlying molecular processes in both healthy and disease states. / (cont.) Through the use of a mechanically tunable class of polymer thin films called polyelectrolyte multilayers (PEMs) developed by Rubner et al., we have demonstrated that the adhesion and morphology of human microvascular endothelial cells depend directly on the mechanical stiffness of these synthetic substrates, as quantified by the nominal elastic modulus E. Characterization of the mechanical properties and surface features of PEMs is attained via scanning probe microscopy (SPM) and SPM-enabled nanoindentation. Typical cellular response to increased substrata stiffness includes increased number of cells adhered per unit substratum area. We have further demonstrated that the chemical and mechanical signals imposed at the cell-substrata interface can be decoupled, thereby providing two independent parameters capable of controlling cell behavior. This capacity of the cell to sense and/or exert chemical and mechanical forces, in addition to initiating a sustained molecular response, is termed the chemomechanical response element. Finally, adhesion dependent mechanosensation in bacteria is explored, with respect to the chemomechanical response elements common to eukaryotic and prokaryotic cells. Potential applications towards the development of therapeutic materials and compounds for treatment of various disease states are discussed, with particular attention to limiting hospital acquired infections. / by Michael Todd Thompson. / Ph.D.

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2002. / Vita. / Includes bibliographical references. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / The temporal envelope of sound strongly influences the intelligibility of speech, pattern analysis, and the grouping of sequential stimuli. This thesis examined the coding of sound temporal envelope in the time-patterns of population neural activity of the human auditory pathway. Traditional microelectrode recordings capture the fine time-pattern of neural spiking in individual neurons, but do not necessarily provide a good assay of temporal coding in neural populations. In contrast, functional magnetic resonance imaging (fMRI), the technique chosen for the present study, provides an indicator of population activity over a time-scale of seconds, with the added advantage that it can be used routinely in human listeners. In a first study, it was established that the time-pattern of cortical activity is heavily influenced by sound repetition rate, whereas the time-pattern of subcortical activity is not. In the inferior colliculus, activity to prolonged noise burst trains (30 s) increased with increasing rate (2/s - 35/s), but was always sustained throughout the train. In contrast, the most striking sound rate dependence of auditory cortex was seen in the time-pattern of activity. Low rates elicited sustained activity, whereas high rates elicited "phasic" activity, characterized by strong adaptation early in the train and a robust response to train offset. These results for auditory cortex suggested that certain sound temporal envelope characteristics are encoded over multiple seconds in the time-patterns of cortical population activity. A second study tested this idea more fully by using a wider variety of sounds (e.g., speech, music, clicks, tones) and by systematically varying different sound features. / (cont.) Important for this test was the development of a new set of basis functions for use in a general linear model that enabled the detection and quantification of the full range of cortical activity patterns. This study established that the time-pattern of cortical activity is strongly dependent on sound temporal envelope, but not sound level or bandwidth. Namely, as either rate or sound-time fraction increases, the time-pattern shifts from sustained to phasic. Thus, shifts in the time-pattern of cortical activity from sustained to phasic signal subsecond differences in sound temporal envelope. These shifts may be fundamental to the perception of successive acoustic transients as either distinct or grouped acoustic events. / by Michael Patrick Harms. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 83-90). / Tinnitus, the ongoing perception of sound in the absence of a physical stimulus, and hyperacusis, the intolerance of sound intensities considered comfortable by most people, are two often co-occurring clinical conditions lacking effective treatments. This thesis identified neural correlates of these poorly understood disorders using functional magnetic resonance imaging (fMRI) and auditory brainstem responses (ABRs) to measure sound-evoked activity in the auditory pathway. Subjects with clinically normal hearing thresholds, with and without tinnitus, underwent fMRI or ABR testing and behavioral assessment of sound-level tolerance (SLT). The auditory midbrain, thalamus, and primary auditory cortex (PAC) showed elevated fMRI activation related to reduced SLT (i.e. hyperacusis). PAC, but not midbrain or thalamus, showed elevated fMRI activation related to tinnitus, perhaps reflecting undue attention to the auditory domain. In contrast to fMRI activation, ABRs showed relationships only to tinnitus, not SLT. Wave I of the ABR, which reflects auditory nerve activity, was reduced in tinnitus subjects, while wave V, reflecting input activity to the midbrain, was elevated. Wave I reduction in tinnitus subjects suggests that auditory nerve dysfunction apparent only above threshold is a factor in tinnitus. Because ABRs reflect activity in only one of multiple pathways from cochlear nucleus to midbrain, the wave V elevation implicates this particular pathway in tinnitus. The results directly link tinnitus and hyperacusis to hyperactivity within the central auditory system. Because fMRI and ABRs reflect different aspects of neural activity, the dependence of fMRI activation on SLT and ABR activity on tinnitus in the midbrain raises the possibility that tinnitus and hyperacusis arise in parallel from abnormal activity in separate brainstem pathways. / by Jianwen Wendy Gu. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (p. 101-110). / Sound-evoked vibrations transmitted into the mammalian cochlea produce traveling waves that provide the mechanical tuning necessary for spectral decomposition of sound. These traveling waves of motion propagate along the basilar membrane (BM) and ultimately stimulate the mechano-sensory receptors. The tectorial membrane (TM) plays a key role in this stimulation process, but its mechanical function remains unclear. Here we show that the TM supports traveling waves that are an intrinsic feature of its visco-elastic structure. Radial forces applied at audio frequencies (1-20 kHz) to isolated TM segments generate longitudinally propagating waves on the TM with velocities similar to those of the BM traveling wave near its best frequency (BF) place. We compute the dynamic shear storage modulus and shear viscosity of the TM from the propagation velocity of the waves and show that segments of the TM from the basal turn are stiffer than apical segments are. Analysis of loading effects of hair bundle stiffness, the limbal attachment of the TM, and viscous damping in the subtectorial space suggests that TM traveling waves can occur in vivo. To test how TM waves may participate in cochlear function, we investigated waves in genetically modified mice lacking beta-tectorin, a glycoprotein found exclusively in the TM. Tectb-/- mutant mice were previously shown to exhibit significant loss of cochlear sensitivity at low frequencies and sharpened frequency tuning compared to wild types. We show that the spatial extent and propagation velocity of TM traveling waves are significantly reduced in Tectb-/- mice compared to wild types, consistent with the concept that there is a reduction in the spread of excitation via TM waves and less TM wave interaction with the BM traveling wave in Tectb-/- mice. / (cont.) The differences in TM wave properties between mutants and wild types arise from changes to the mechanical properties of the TM; mutant TMs are significantly less stiff than wild type TMs are. Our results show the presence of a traveling wave mechanism through the TM that can functionally couple a significant longitudinal extent of the cochlea and may interact with the BM wave, suggesting that TM waves are crucial for cochlear sensitivity and tuning. / by Roozbeh Ghaffari. / Ph.D.