Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2002. / Includes bibliographical references (p. 219-235). / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / The sensitivity and frequency selectivity of the hearing sense are determined primarily by mechanical properties of the cochlea. These mechanical properties are poorly understood in any species. This thesis contributes to our understanding of cochlear mechanics by presenting measurements of sound-induced motion of the alligator lizard cochlea. Novel methods were developed to maintain the cochlea in vitro for the time required to measure three-dimensional motions. Three-dimensional images of cochlear motion were taken by illuminating the cochlea with a light-emitting diode stroboscopically at predetermined phases of the acoustic stimulus. The resulting images were analyzed using computer vision algorithms to extract three-dimensional motions of all visible structures with nanometer precision. The sound-induced motion of the entire basilar papilla and of individual hair bundles of hair cells were simultaneously measured. The basilar papilla, in which the hair cells reside, moved as a rigid body, exhibiting simultaneous translational and rotational modes of motion. Both modes apply shearing forces to hair bundles. A simple mechanical model of the basilar papilla, based on these measurements, provides a physical basis for a mechanical low-pass filter hypothesized in previous models. In the tectorial region of the cochlea, motion of the tips of hair bundles and of the tectorial membrane (TM) were in phase with motion of the basilar papilla. None of the motions had significant frequency dependence, suggesting that this region does not exhibit appreciable mechanical frequency selectivity. In the free-standing region, which has no TM, hair bundle deflection depended on stimulus frequency and hair bundle height. / (cont.) At high frequencies, hair bundle deflection was proportional to basilar papilla displacement. At low frequencies, hair bundle deflection was proportional to a linear combination of basilar papilla velocity and acceleration. Measured hair bundle deflections were well fit by a simple hydrodynamic model (Freeman and Weiss, 1990) of this region of the cochlea. The measurements in this study provide the first characterization of the three-dimensional motion of all structures in a vertebrate cochlea. / by Alexander James Aranyosi. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references. / Drug-eluting stents have emerged as the most effective method for treating restenosis following percutaneous coronary interventions. This thesis investigates how drugs with similar physiochemical properties but different specific binding targets yield drastically different tissue transport, retention and ultimately efficacy independent of their putative biological effects. Our central hypothesis is that both specific and general binding of drugs to tissue proteins, as mediated by drug-specific physiochemical properties, plays a central role in arterial transport and distribution. We define and compare the kinetic and transport properties of clinically implemented compounds with different binding modes. While hydrophilic compounds are rapidly cleared, hydrophobic ones are retained with an arterial transmural distribution dependent upon the distribution of specific and general binding sites. Common systemically administered cardiac drugs compete with locally delivered agents through displacement of general binding sites. Exploration of drug binding in thrombus indicates significant specific and general binding capacity. Stent-to- arterial wall drug transfer is acutely sensitive to stent strut position in clot relative to the wall due to thrombus binding capacity. A poorly controlled microthrombotic environment around a stent strut can drastically enhance systemic washout while reducing delivery to the tissue. Together this body of work implies that specific and general binding plays a critical role in the clinical efficacy of locally delivered drugs, and must be a consideration in the rational design of stent-based delivery devices. / by Andrew D. Levin. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2010. / "September 2009." Cataloged from PDF version of thesis. / Includes bibliographical references (p. 160-175). / This project is an experimental study of perceptual interactions between auditory and tactile stimuli. These experiments present vibrotactile stimuli to the fingertip and auditory tones diotically in broadband noise. Our hypothesis states that if the auditory and tactile systems integrate, the performance of the two sensory stimuli presented simultaneously will be different from the performance of the individual sensory stimuli. The research consists of work in two major areas: (1) Studies of the detection of auditory and tactile sinusoidal stimuli at levels near the threshold of perception (masked thresholds for auditory stimuli and absolute thresholds for tactile stimuli); and (2) Studies of loudness matching employing various combinations of auditory and tactile stimuli presented at supra-threshold levels. Results were compared to three models of auditory-tactile integration. The objective detection studies explore the effects of three major variables on perceptual integration: (a) the starting phase of the auditory relative to the tactile stimulus; (b) the temporal synchrony of stimulation within each of the two modalities; and (c) the frequency of stimulation within each modality. Detection performance for combined auditory-tactile (A+T) presentations was measured using stimulus levels that yielded 63%-77%-correct unimodal performance in a 2-Interval, 2-Alternative Forced- Choice procedure. Results for combined vibrotactile and auditory detection indicated: (1) For synchronous presentation of 500-msec, 250 Hz sinusoidal stimuli, percent-correct scores in the combined A+T conditions were significantly higher than scores within each single modality; / (cont.) (2) Scores in the A+T conditions were not affected by the relative phase of the 250 Hz auditory and tactile stimuli; (3) For asynchronous presentation of auditory and tactile 250 Hz stimuli, scores on the A+T conditions improved only when the tactile stimulus preceded the auditory stimulus (and not vice versa); and (4) The highest rates of detection in the combined-modality stimulus were obtained when stimulating frequencies in the two modalities were equal or closely spaced (and within the Pacinian range). The lack of phase effect suggests that integration operates on the envelopes rather than on temporal fine structure. The effects of asynchronous presentation imply a shorter time constant in the auditory compared to the tactile modality and are consistent with time constants deduced from single-modality masking experiments. The effects of frequency depend both on absolute frequency and on relative frequency of stimulation within each modality. In general, we found that an additive sensitivity model best explained detection performance when tones were presented synchronously and of the same frequency. In the second area of research, loudness matching was employed in a subjective study of the effects of frequency on auditory-tactile integration for stimuli presented at supra-threshold levels. These experiments, which were derived from previous auditory studies demonstrating the dependence of loudness on critical-band spacing of tonal signals, employed various combinations of auditory and tactile stimuli that were presented at equally loud levels in isolation. / (cont.) Loudness matches were obtained for auditory-only (A+A) and auditory-tactile (A+T) stimuli that were both close as well as farther apart in frequency. The results show that the matched loudness of an auditory pure tone is greater when the frequencies of combined stimuli (both A+A and A+T) are farther apart in frequency than when they are close in frequency. These results are consistent with the results found in the previous experiment exploring the frequency relationships at near-threshold levels, as well as with results in the psychoacoustic literature, and suggest that the auditory and tactile systems are interacting in a frequency-specific manner similar to the interactions of purely auditory stimuli. The research conducted here demonstrates objective and subjective perceptual effects that support the mounting anatomical and physiological evidence for interactions between the auditory and tactual sensory systems. / by E. Courtenay Wilson. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (leaves 35-36). / In normal-hearing ears, sound waves are amplified within the cochlea and a small fraction of the sound energy travels backward out into the ear canal, producing sounds known as "otoacoustic emissions" (OAE) that can be measured with a sensitive microphone. One class of OAE, called "stimulus-frequency-otoacoustic-emissions" (SFOAEs), has been hypothesized to be produced by a process known as "coherent reflection filtering" (CRF). The CRF theory provides a prediction between the SFOAE group delay and the group delays of tone responses on the basilar membrane within the cochlea. Using single and multiple-tone stimuli, we collected data from the firing patterns of single auditory-nerve-fibers (ANFs) from which basilar-membrane tone-response group delays can be calculated for both high and low best-frequency (BF) positions along the basilar membrane. These calculated basilar-membrane group delays were compared to published SFOAE group delays. Our results suggest that group delays calculated from the tip, the lower-frequency tail, or the above-BF region of ANF tuning curves do not match the CRF theory prediction. In obtaining the data to the test the CRF theory, we used two methods for obtaining ANF group delays at frequencies above BF: a previously published method and a simpler new method based on the same principle. / (cont.) Surprisingly, the two methods produced different results. Control measurements suggest that the previously published method does not do what it was expected to do. / by Holden Cheng. / S.M.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 72). / Alzheimer's disease (AD) is a field with huge unmet need and only a few symptomatic treatments with limited efficacy have been made available to patients. With the testing of disease-modifying drugs in recent years, the length of AD clinical trials has tripled and the enrollment has gone up drastically. These investigational disease-modifying drugs address new targets including the amyloid beta and tau protein aggregation pathways in the brain. They have opened up a whole research field on biomarkers specific to these pathways. These biomarkers have however never been used to select a subpopulation that would enroll in clinical trials. This thesis defines a framework for assessing any AD biomarker's quality as a selection tool for enrolling a subpopulation into an AD clinical trial. Carefully selecting the patient population with appropriate biomarkers can lead to a reduction in required enrollment in a study to show statistical significance. In turn, the decreased patient enrollment helps sponsors reduce costs and allows them to test several drugs with the same budget. In order to test our framework in an applied and relevant setting, we established from www.clinicaltrials.gov that for disease-modifying drugs the primary endpoint is change in ADAS-cog points at 18 months and that the trials enrolled on average 337 patients per treatment group. These disease-modifying AD trials use the inference on means statistical model. / (cont.) The standard deviation and the treatment effect of the primary endpoint variable (the change in ADAS-cog points at 18 months) are the main leverage factors that will influence the required enrollment (or sample size) in the trial. In a first step, we defined the baseline values for those main variables from published information on past or ongoing trials. Using that information, we conducted a theoretical exercise showing how much you needed to affect these variables in order to reduce enrollment by a factor of 5x, an important reduction in enrollment that could potentially realistically be achieved. In a second step, we looked in an applied setting at how well a selection of biomarkers in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database reduces the sample size by only selecting a sub population of the patients. Even with the limited data sample available on a preliminary basis from ADNI, we found that the biomarkers ABeta 1-42, ratio of Tau/ABeta 1-42, Apoe4 carriers on both genes, and average hippocampal volume show predictive power to identify change in ADAS-cog scores. When using criteria for these biomarkers to select a subpopulation we show that you can reduce the enrolled population by up to a factor 5.0x while decreasing your trial cost by up to 73% (corresponding to a $92M reduction out of $133M, the current Phase 3 costs of an 18 months diseases-modifying drug). Under the best scenario of these cost savings the sponsor can conduct pivotal trials for three drugs instead of only one. / (cont.) In a last step, the biomarker and combination of biomarkers associated with the enrollment benefit and the cost savings were assessed with additional criteria such as effect on restricted labeling, necessity for longitudinal screening or additional enrollment difficulties. Even after that analysis, several of the biomarkers stood out as very strong candidates to select for subpopulations in future disease-modifying trials and save costs. ADNI is an industry and NIH-sponsored initiative monitoring 800 normal, Mild Cognitive Impairment (MCI) and AD patients for up to three years with regular cognitive assessments and biomarker measurements. / by Hampus Hillerstrom. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references. / This thesis explores two aspects of small regulatory RNAs in mammals: (1) the genomic origin of mammalian piwi-interacting RNAs (piRNAs), (2) the evolutionary and functional implication of the seed-based target recognition mechanism of microRNAs (miRNAs). First, we participated in the discovery of mammalian piRNAs from adult rat testes. Our initial characterization of mammalian piRNAs by high-throughput sequencing revealed the peculiar features of their genomic origin: they predominantly derive from long singlestranded RNA precursors that are encoded at ~100 loci with no preferential association to repeat elements. Second, we measured the efficacy of polymorphic miRNA target sites in mammals. A large part of the miRNA-target recognition is determined by the 7-8-nt match between the seed region of miRNAs and the 3'UTR of mRNAs. Because of the small informational complexity of the specificity, spontaneous point mutations in 3'UTRs often create or disrupt miRNA target sites. The resulting polymorphisms in the target sites may contribute to gene expression diversity. By experimentally measuring the efficacy of such polymorphic target sites, we were able to conclude that between two unrelated mammalian individuals of the same species more than 100 genes are likely differentially regulated due to the target-site polymorphisms. Some of the expression diversity might translate into phenotypic diversity, providing substrates for the natural selection to act upon. We also constructed a miRNA library covering nearly all ~-16,000 theoretically possible seed sequences. Under the assumption that the functionality of a miRNA is approximately defined by the identity of the seed, the library is a resource that may enable the systematic exploration of the phenotypic consequences of nearly all possible functionally distinct miRNA species. / by Jinkuk Kim. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 50-51). / The National Institutes of Health (NIH) has been the stalwart of research funding at universities and academic teaching hospitals. However, since the start of the last decade NIH funding has contracted in real terms. Anticipating future Federal Government fiscal austerity, the situation appears unlikely to improve and most likely will become worse. Local area teaching hospitals have explored other funding to support their large research infrastructure such as industry-sponsored research. This thesis qualitatively assessed whether the Federal Government and local area academic hospital fiscal data over the last six years support the hypothesis: Yes, industry funding has been received to support research at local area teaching hospitals to substitute for decreased availability of NIH funds. To test the hypothesis, Federal and local hospital fiscal data were extracted and statistical analysis was performed in three key areas to challenge the hypothesis and eliminate confounding data. First, is National Institutes of Health funding decreasing in real terms? Second, have local area teaching hospitals compensated by soliciting and receiving greater levels of industry sponsored research dollars? Third, has industry increased support in light of decreased NIH funding or are industry research commitments uncorrelated? The test questions were evaluated across two different hospitals and against various economic benchmarks. The hypothesis was rejected. Decreased NIH research funding granted to local academic hospitals has not caused a corresponding increase in industry sponsored research funding. Given the structural difficulties of industry and academic hospital collaboration, this likely impacts the level of industry sponsored research funding. Unfortunately, upcoming long-term Federal fiscal austerity may severely curtail NIH budgets. Academic hospitals will either need to consider greater industry collaboration or reduce the size and scope of their research activities. / by John A. Truesdell, Jr. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (p. 139-145). / Since the voicing source is located between the lower and upper airways and has a high impedance, the resonances of the lower airway appear as pole-zero pairs in vowel spectra. These pole-zero pairs interact non-linearly with the vocal tract formants, producing narrow frequency bands within which formant structure is unstable. The broader frequency bands between lower airway resonances are thus potentially optimal for the reliable production and accurate perception of specific formant patterns. This possibility is explored from three directions. First, models of the lower airway are built and analyzed, and their effects on vowel spectra are characterized. Second, evidence for the non-linear interactions between formants and lower airway resonances is presented from a speech production study, and the relations between these non-linearities and certain distinctive feature contrasts are explored. Third, a speech perception experiment is carried out in which the identification of a vowel (which could be either [+back] or [-back]) is dependent upon the interaction of the second lower airway resonance (represented as a zero without an accompanying nearby pole) with the second formant. The results of these studies indicate that lower airway resonances do play a role in speech production and perception, and that further study is warranted. In addition, some potential applications to respiratory and vocal medicine are suggested. / by Steven Michael Lulich. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2007. / Includes bibliographical references (leaves 136-138). / Increasing competition and specialization of firms in the life sciences industry has led to recognition of the need for collaboration. Bioclusters, the co-location of life sciences entities in a specific geographic area, have therefore emerged as a global trend. While it is assumed that such clusters allow stakeholders to realize synergies through participation and presence in the local area, the collaborative behavior within these clusters has yet to be explored. The goal of this study was to characterize the barriers and enablers of effective collaboration within bioclusters, and amongst their key stakeholder groups. This study directly compared the bioclusters of San Diego and Singapore to gain an understanding of their relative collaborative environments. San Diego, with cluster longevity of over 40 years, provided an example of organic growth, given its roots in entrepreneurial activities. The Singapore cluster, still in an embryonic state, has a history of organized growth due to the leadership, support, and funding of the Singaporean government. The study of clusters that differ in history of formation and longevity of presence provided the breadth of information needed for an effective comparison of their collaborative environments and approach to collaborative endeavors. / (cont.) Key stakeholder groups, namely academia, industry, finance, and government, were identified and interviews within each cluster were targeted accordingly. Eighteen interviews were conducted in San Diego and sixteen in Singapore. Through literature review, design of a detailed questionnaire, completion of 34 interviews, and analysis of the resulting data, an empirical assessment of the environment for collaboration within each biocluster was performed. Use of two scoring models provided an objective relative comparison of the clusters, serving as tools to view aggregated interview results. The first model measured the environment for and level of local collaboration and resulted in a Collaboration Score. The second model compared the process of engagement in collaborative endeavors, and resulted in a Formality of Approach Score. The scoring models were also used to compare the collaborative behavior of key stakeholder groups. Results from relative scoring models indicated a higher Collaboration Score for Singapore as compared to San Diego (p-value=0.0421), and a higher Formality of Approach Score for San Diego, trending toward significance. Aggregate analysis of key stakeholder groups found finance as the most collaborative, with a higher Collaboration Score when compared to industry, the least collaborative group (p-value=0.0189). / (cont.) A higher Formality of Approach Score was also seen for finance when compared to academia (p-value=0.0479). Other notable results include a greater degree of local competition within San Diego (p-value=0.0266) and a particularly low percentage of local industry collaborations in both bioclusters, when compared to academia (p-value=0.0002). The enablers of collaboration in the San Diego biocluster were identified as the entrepreneurial culture and the existence of top research institutes, and barriers were found to be the high level of competition amongst cluster members and the lack of local venture capital presence. The enablers in the Singapore biocluster were identified as the physical co-location of public and private entities in the Biopolis and the leadership and financial support provided by the Singaporean government, and barriers were the culture of risk aversion that exists in the cluster and the relatively few entrepreneurs, who often serve as a backbone for the creation of informal networks. A model for the development of a biocluster was also identified through a comparison of the cluster formation history of San Diego and Singapore. This model needs to be refined and further tested for general applicability, but does suggest a promising start. / (cont.) Collaborations are important for the continued cycle of innovation in the field of life sciences. Bioclusters provide a forum for these collaborations to occur. Promoting the enablers and removing the barriers increases the effectiveness of collaborations, enhancing the success of a biocluster and its member firms. / by Rupa Bahri. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2004. / Includes bibliographical references (leaves 134-151). / Focused ultrasound is currently being developed as a non-invasive thermal ablation technique for benign and cancerous tumors in several organ systems. Although these therapies are designed to ablate tissue purely by thermal means, cavitation, the formation and collapse of gas bubbles, can occur. These bubbles can be unpredictable in their timing and location and often interfere with thermal therapies. Therefore, focused ultrasound techniques have tried to avoid bubbles and their effects. However, gas bubbles in vivo have some potential useful features for therapy. They greatly enhance local ultrasound absorption, and can on their own induce mechanical damage to the tissue. In addition, bubble clouds can block ultrasound wave propagation, providing a means to protect vital tissues during ablation of nearby pathology. If induced and controlled properly, cavitation in focused ultrasound therapy could potentially be very beneficial. The first aim of this research is to design and test in vivo ultrasound exposures that induce cavitation at appropriate times and take advantage of their absorption enhancing properties. In addition, methods to monitor and control cavitation induction and the associated therapy will be investigated. Second, a theoretical bubble model and acoustic field simulations will be used to design optimal pressure fields which very tightly control the cavitation location. These models will also be used to investigate methods for reducing the acoustic powers needed to induce cavitation while preventing off focus cavitation. For the final phase of the research a multi-channel, multi-frequency ultrasound amplifier system capable of delivering optimal exposures via large scale phased array systems will be developed and tested. In / (cont.) total, the thesis research will justify applications for cavitation in ultrasound therapy, and develop the technology and methodology to optimally use cavitation and monitor its effects in vivo. / by Shunmugavelu D. Sokka. / Ph.D.