Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (p. 110-118). / Healthy ears generate sounds known as otoacoustic emissions that can be evoked and measured in the ear-canal using small, low-noise microphones. The ability to measure acoustic signals that originate within the cochlea provides noninvasive access to what in humans is an almost inaccessible organ. Although otoacoustic emissions (OAEs) are frequently used as noninvasive probes of cochlear function in both the clinic and the laboratory, their utility is limited by incomplete knowledge of their generating mechanisms. A recently proposed model suggests that most OAEs are mixtures of -emissions arising by two fundamentally different mechanisms: 1) nonlinear distortion induced by cochlear traveling: waves and 2) linear reflection 6f those waves from pre-existing micromechanical impedance perturbations. The model predicts that OAEs generated by wave-induced perturbations manifest a phase that is nearly-frequency invariant whereas OAEs generated by reflection from pre-existing perturbations manifest a phase that rotates rapidly with frequency. The model suggests that the relative contribution from each mechanism to any emission measurement depends on factors such as the type and intensity of the evoking stimulus. / (cont.) In this thesis we tested the relationships between common OAE measurements and the two proposed mechanisms of OAE generation. We tested the two-mechanism model by measuring and comparing OAEs evoked with single tones and broad-band clicks, as well as those evoked by two-tone complexes at frequencies not contained in the stimulus, so-called distortion-product emissions. Our results indicate that click-evoked and tone-evoked OAEs, previously regarded as different types of emission based on the characteristics of the stimuli used to evoke them, are really the same emission evoked in different ways. The phase characteristics of both emission types are consistent with those predicted for emissions originating by linear-reflection from pre-existing perturbations. In addition, we demonstrate that distortion-product OAEs are often mixtures of two components. By separating the two components we show that one component arises by linear reflection and the other component arises by induced distortion. Our results provide strong empirical support for the two-mechanism model of OAE generation. Since the two emission mechanisms depend on fundamentally different aspects of cochlear mechanics, measurements that isolate each emission type should improve the power and specificity of OAEs as non-invasive probes of cochlear function. / by Radha Kalluri. / Ph.D.

Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2002. / Includes bibliographical references. / A cell with extraordinary motile ability exists in our inner ear, the outer hair cell. Outer hair cell (OHC) motility can occur at acoustic frequencies and play a key role in mammalian cochlear frequency selectivity and hearing sensitivity. To date, the mechanism of cochlear amplification is not well understood and remains a matter of controversy. In order to understand the role of OHC motility in cochlear micromechanics we developed a technique to measure the mechanical responses within the organ of Corti (OC) due to OHC forces. We used an excised cochlea preparation because it provided a good view of the organ and allowed us to compare the resulting responses of hundreds of cells simultaneously. The tissue was stimulated electrically using sinusoidal current, and the resulting motion was captured at specific phases within the stimulus period using stroboscopic video microscopy. Animations of this motion were created, and the displacement magnitude and phase for each structure were calculated using two dimensional cross-correlation. With these techniques we were able to detect displacements as low as ten nanometers. The frequency responses of electrically-evoked vibrations from the apical and middle turn had low pass filtering characteristics with cutoff frequencies near or below the estimated characteristic frequency of the imaging location. Using a simple one dimensional electrical model of our excised cochlea preparation, we hypothesize that the electrical properties of the stria vascularis play an important role in shaping the frequency response of individual structures. / (cont.) The vibration pattern of the organ was complex and changed with frequency. These changes suggest that at least two OC vibration modes are excited by OHC motility. At all frequencies OHC motility induced oscillatory fluid flow in the tunnel of Corti. We modeled the tunnel of Corti as an elastic tube and showed that it can support a traveling wave. The tunnel of Corti wave could travel without significant attenuation for distances larger than the wavelength of the cochlear traveling wave at its peak. The classical view of cochlear partition vibration is that the structure simply bends in phase along the radial dimension, and that there is no coupling between adjacent sections other than that provided by the fluid above and below the OC. Our findings challenge the classical view of cochlear partition vibration, and support the existence of multiple vibration modes. In addition, the presence of fluid flow in the tunnel of Corti in response to OHC contractions suggests that a second traveling wave provides longitudinal coupling between adjacent sections. Such coupling may be critical for cochlear amplification. / Kiriaki Domenica Karavitaki. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2003. / Includes bibliographical references (leaves 164-169). / Hemodynamics has long been identified as a major factor in the determination and localization of atherosclerotic lesions. While the precise mechanism by which different hemodynamic factors act is not yet clear, the fact that they correlate highly with atherogenesis suggests that local disturbances in flow through blood vessels can promote arterial disease. These issues have become increasingly acute as physicians seek to alter the pathological arterial anatomy with bypass grafting or endovascular manipulations such as angioplasty or stenting. We proposed that local vascular interventions might cause previously unforeseen effects elsewhere in the arterial tree. As an example of these interactions, manipulation of one branch of a bifurcation might adversely affect the contralateral branch of the bifurcation. The goal of this work was to study the distant impact of local flow alterations, as well as to classify and evaluate the different parameters that determine their severity. Dynamic flow models of the arterial system were developed that allowed for the continuous alteration of model geometry in a controlled fashion to simulate the healthy and diseased states as well as the entire range in between. Moreover, these models permit simulation of different strategies of clinical intervention. Flow through the models was investigated using both qualitative and quantitative tools. Boundary layer separation and vascular resistance in one location of the arterial tree varied with geometrical alterations in another. In-vivo models were developed that allowed investigation of the effect of side branch occlusion or dilation on the acute and chronic outcome of main branch stenting in a bifurcation. Chronic side branch occlusions were protective of main branch stenting as reflected by a reduction in in-stent neo-intimal hyperplasia. / (cont.) This protective influence was mediated by an acute modulation of monocyte adhesion and accumulation on the lateral wall of the main branch, correlating with the location of flow disturbance demonstrated by the flow models. Chronic main branch vascular remodeling plays a major role in achieving this beneficial effect. The results of this study could have important implications for the diagnosis, treatment and long-term follow-up of the large number of patients who suffer from complex arterial diseases and undergo vascular interventions. In clinical manipulation of one arterial site one may well need to consider the hemodynamic impact on vascular segments at a distance. / by Yoram Richter. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Vita. / Includes bibliographical references (p. 52-56). / Post-marketing surveillance of medical pharmaceuticals and devices has received a great deal of media, legislative, and academic attention in the last decade. Among medical devices, these have largely been due to a small number of highly publicized adverse events, some of them in the domain of cardiac surgery and interventional cardiology. Phase three clinical trials for these devices are generally underpowered to detect rare adverse event rates, are performed in near-optimal environments, and regulators face significant pressure to deliver important medical devices to the public in a timely fashion. All of these factors emphasize the importance of systematic monitoring of these devices after being released to the public, and the FDA and other regulatory agencies continue to struggle to perform this duty using a variety of voluntary and mandatory adverse event rate reporting policies. Data quality and comprehensiveness have generally suffered in this environment, and delayed awareness of potential problems. However, a number of mandatory reporting policies combined with improved standardization of data collection and definitions in the field of interventional cardiology and other clinical domains have provided recent opportunities for nearly "real-time" safety monitoring of medical device data. / (cont.) Existing safety monitoring methodologies are non-medical in nature, and not well adapted to the relatively heterogeneous and noisy data common in medical applications. A web-based database-driven computer application was designed, and a number of experimental statistical methodologies were adapted from non-medical monitoring techniques as a proof of concept for the utility of an automated safety monitoring application. This application was successfully evaluated by comparing a local institution's drug-eluting stent in-hospital mortality rates to University of Michigan's bare-metal stent event rates. Sensitivity analyses of the experimental methodologies were performed, and a number of notable performance parameters were discovered. In addition, an evaluation of a number of well-validated external logistic regression models, and found that while population level estimation was well-preserved, individual estimation was compromised by application to external data. Subsequently, exploration of an alternative modeling technique, support vector machines, was performed in an effort to find a method with superior calibration performance for use in the safety monitoring application. / by Michael E. Matheny. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (p. 95-101). / This thesis describes results from two projects related to the efferent innervation of the cochlea. First, we investigated peripheral olivocochlear effects of sustained contralateral broadband noise in anesthetized guinea pig. We found evidence of medial olivocochlear (MOC) effects on two timescales: the classic MOC 'fast effect', followed by a gradually increasing suppression, which we call the MOC 'delayed effect'. Delayed suppression typically takes 2-3 minutes to build up, occurs at all frequencies of guinea pig hearing, and suppresses distortion product otoacoustic emissions (DPOAEs), compound action potentials (CAPs), and round window noise. In contrast to the MOC slow effect, which has been reported for sustained shockevoked MOC activity, MOC delayed suppression does not build up in the outer hair cells but is due to a central modulation (enhancement) of MOC responsiveness and can thus be viewed as a gradual increase in the strength of the MOC fast effect. We found that, on average, the magnitude of the delayed suppression is comparable to that of the MOC fast effect, but that there is an overall negative correlation between fast and delayed effect magnitudes. Thus, it may have significant implications for the functional roles of the MOC system, such as protection against acoustic trauma, anti-masking, and dynamic range extension. Second, we investigated the LOC bilateral balancing model, which proposes that the LOC system acts to balance long-term average neural output from both cochleae, which would be important for binaural processing of sounds. For this, we tested various cohorts of mice by repeatedly measuring bilateral auditory brainstem responses (ABR) and "DPOAE growth functions across a wide range of frequencies and levels for periods of about 1-2 months. About halfway through the period, a unilateral reduction in neural output was created, either by acoustic overexposure or conductive impairment. Although the LOC balancing model predicts that the unilateral reduction in neural output should be matched contralaterally, we found no evidence for short-term or long-term efferent-induced contralateral response changes in any of the cohorts, either for DPOAE or ABR metrics. / (cont.) In view of these results, a revision of the LOC bilateral balancing model is called for. / by Erik Larson. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Cataloged from student submitted PDF version of thesis. / Includes bibliographical references. / The human genome sequence can be thought of as an instruction manual for our species, written and rewritten over more than a billion of years of evolution. Taking a complete inventory of our genome, dissecting its genes and their functional components, and elucidating how these genes are selectively used to establish and maintain cell types with markedly different behaviors, are key challenges of modern biology. In this thesis we present contributions to our understanding of the structure, function and evolution of the human genome. We rely on two complementary approaches. First, we study signatures of evolutionary processes that have acted on the genome using comparative sequence analysis. We generate high quality draft genome sequences of the chimpanzee, the dog and the opossum. These species share a last common ancestor with humans approximately 6 million, 80 million and 140 million years ago, respectively, and therefore provide distinct perspectives on our evolutionary history. We apply computational methods to explore the functional organization of the genome and to identify genes that contribute to shared and species-specific traits. Second, we study how the genome is bound by proteins and packaged into chromatin in distinct cell types. We develop new methods to map protein-DNA interactions and DNA methylation using single-molecule based sequencing technology. We apply these methods to identify new functional sequence elements based on characteristic chromatin signatures, and to explore the relationship between DNA sequence, chromatin and cellular state. / by Tarjei Sigurd Mikkelsen. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Pages 185-186 blank. Cataloged from PDF version of thesis. / Includes bibliographical references (p. 171-184). / This thesis focuses on the use of ultrathin therapeutic protein delivery films to control host tissue/medical device implant interactions, thereby reducing complications that lead to implant failure. The Layer by Layer (LbL) deposition platform was used to fabricate conformal, tunable, micron scale reservoirs for the controlled release of a wide variety of proteins including enzymes, growth factors, and antibodies that were shown to be capable of directing cells in vitro to desired outcomes including proliferation, differentiation, and quiescence. Film release profiles were controlled through rational polymer design, tuning film composition, and varying film architecture. In studies with a model protein lysozyme, 100% retention of protein function was observed, underscoring gentle process conditions. In vitro experiments with Fibroblast Growth Factor-2 (FGF-2) and Bone Morphogenetic Protein -2 (BMP-2) showed that released growth factors are more active than growth factors supplemented in medium, suggesting a surface concentration mechanism and/or specific growth factor interactions with LbL film components. Anti-VEGF releasing LbL films afforded new opportunities to modify cancer therapy nanoparticles for multi therapeutic release, and provided an important switch to turn off the cellular response to growth factors. Using an orthopedic hip implant model as a test case, the first LbL film with enough growth factor load to direct in vivo host cell response was demonstrated. BMP-2 releasing LbL films were used to direct MC3T3 pre-osteoblast differentiation in vitro, and the differentiation of host mesenchymal stem cells in a rat quadriceps model in vivo to form bone tissue in a first generation model for remediating orthopedic hip implant complications. Preliminary data on second generation, multifunctional drug delivery films are promising. These studies contribute to the mechanistic design of protein LbL films and show promise for a wide variety of clinical applications, opening avenues for multifunctional drug delivery from LbL films. / by Mara Lee Macdonald. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 105-109). / Few empirically-derived guidelines exist for optimizing the assessment of vocal function in children with voice disorders. The goal of this investigation was to identify a minimal set of speech tasks and associated acoustic analysis methods that are most salient in characterizing the impact of vocal nodules on vocal function in children. Hence, a pediatric assessment protocol was developed based on the standardized Consensus Auditory Perceptual Evaluation of Voice (CAPE-V) used to evaluate adult voices. Adult and pediatric versions of the CAPE-V protocols were used to gather recordings of vowels and sentences from adult females and children (4-6 and 8-10 year olds) with normal voices and vocal nodules, and these recordings were subjected to perceptual and acoustic analyses. Results showed that perceptual ratings for breathiness best characterized the presence of nodules in children's voices, and ratings for the production of sentences best differentiated normal voices and voices with nodules for both children and adults. Selected voice quality-related acoustic algorithms designed to quantitatively evaluate acoustic measures of vowels and sentences, were modified to be pitch-independent for use in analyzing children's voices. Synthesized vowels for children and adults were used to validate the modified algorithms by systematically assessing the effects of manipulating the periodicity and spectral characteristics of the synthesizer's voicing source. / (cont.) In applying the validated algorithms to the recordings of subjects with normal voices and vocal nodules, the acoustic measure tended to differentiate normal voices and voices with nodules in children and adults, and some displayed significant correlations with the perceptual attributes of overall severity of dysphonia, roughness, and/or breathiness. None of the acoustic measures correlated significantly with the perceptual attribute of strain. Limitations in the strength of the correlations between acoustic measures and perceptual attributes were attributed to factors that can be addressed in future investigations, which can now utilize the algorithms that were developed in this investigation for children's voices. Preliminary recommendations are made for the clinical assessment of pediatric voice disorders. / by Asako Masaki. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 169-175). / This thesis is motivated by the gaps between speech science and technology in analyzing dialects. In speech science, investigating phonetic rules is usually manually laborious and time consuming, limiting the amount of data analyzed. Without sufficient data, the analysis could potentially overlook or over-specify certain phonetic rules. On the other hand, in speech technology such as automatic dialect recognition, phonetic rules are rarely modeled explicitly. While many applications do not require such knowledge to obtain good performance, it is beneficial to specifically model pronunciation patterns in certain applications. For example, users of language learning software can benefit from explicit and intuitive feedback from the computer to alter their pronunciation; in forensic phonetics, it is important that results of automated systems are justifiable on phonetic grounds. In this work, we propose a mathematical framework to analyze dialects in terms of (1) phonetic transformations and (2) acoustic differences. The proposed Phonetic based Pronunciation Model (PPM) uses a hidden Markov model to characterize when and how often substitutions, insertions, and deletions occur. In particular, clustering methods are compared to better model deletion transformations. In addition, an acoustic counterpart of PPM, Acoustic-based Pronunciation Model (APM), is proposed to characterize and locate fine-grained acoustic differences such as formant transitions and nasalization across dialects. We used three data sets to empirically compare the proposed models in Arabic and English dialects. Results in automatic dialect recognition demonstrate that the proposed models complement standard baseline systems. Results in pronunciation generation and rule retrieval experiments indicate that the proposed models learn underlying phonetic rules across dialects. Our proposed system postulates pronunciation rules to a phonetician who interprets and refines them to discover new rules or quantify known rules. This can be done on large corpora to develop rules of greater statistical significance than has previously been possible. Potential applications of this work include speaker characterization and recognition, automatic dialect recognition, automatic speech recognition and synthesis, forensic phonetics, language learning or accent training education, and assistive diagnosis tools for speech and voice disorders. / by Nancy Fang-Yih Chen. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 157-162). / Epilepsy is a chronic disorder of the central nervous system that predisposes individuals to experiencing recurrent seizures. It affects 3 million Americans and 50 million people world-wide. A seizure is a transient aberration in the brain's electrical activity that produces disruptive physical symptoms such as a lapse in attention and memory, a sensory hallucination, or a whole-body convulsion. Approximately 1 out of every 3 individuals with epilepsy continues to experience frequent seizures despite treatment with multiple anti-epileptic drugs. These intractable seizures pose a serious risk of injury, limit the independence and mobility of an individual, and result in both social isolation and economic hardship. This thesis presents novel technology intended to ease the burden of intractable seizures. At its heart is a method for computerized detection of seizure onset. The method uses machine learning to construct patient-specific classifiers that are capable of rapid, sensitive, and specific detection of seizure onset. The algorithm detects the onset of a seizure through analysis of the brain's electrical activity alone or in concert with other physiologic signals. When trained on 2 or more seizures and tested on 844 hours of continuous scalp EEG from 23 pediatric epilepsy patients, our algorithm detected 96% of 163 test seizures with a median detection delay of 3 seconds and a median false detection rate of 2 false detections per 24 hour period. / (cont.) In this thesis we also discuss how our detector can be embedded within a low power, implantable medical device to enable the delivery of just-in-time therapy that has the potential to either eliminate or attenuate the clinical symptoms associated with seizures. Finally, we report on the in-hospital use of our detector to enable delay-sensitive therapeutic and diagnostic applications. We demonstrate the feasibility of using the algorithm to control the Vagus Nerve Stimulator (an implantable neuro stimulator for the treatment of intractable seizures), and to initiate ictal SPECT (a functional neuroimaging modality useful for localizing the cerebral site of origin of a seizure). / by Ali Hossam Shoeb. / Ph.D.