Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2006. / Includes bibliographical references (p. 281-301). / This thesis will explore the use of Transcranial Magnetic Stimulation (TMS) and Transcranial DC Stimulation (tDCS) as modalities for neuropathology treatment by means of both experimental and modeling paradigms. The first and primary modality that will be analyzed is Transcranial Magnetic Stimulation (TMS). TMS is a technique that uses the principle of electromagnetic induction to focus induced currents in the brain and modulate cortical function. These currents can be of sufficient magnitude to depolarize neurons, and when these currents are applied repetitively (repetitive Transcranial Magnetic Stimulation (rTMS)) they can modulate cortical excitability, decreasing or increasing it, depending on the parameters of stimulation. This thesis will explore important facets of the electromagnetic field distributions and fundamental electromagnetic interactions to lay the foundation for future development of a more complete neural model and improved stimulation techniques. First, TMS will be analyzed as a technique used in normal healthy subjects. Finite element modeling (FEM) studies will be explored for realistic healthy human head models with a particular focus placed on the TMS induced cortical currents and their dependency on coil position, normal tissue anatomy, and the electromagnetic tissue properties. / (cont.) This component of the thesis will also include experimental work focused on exploring the in-vivo tissue conductivity and permittivity values used in TMS studies and their impact on stimulation (including a detailed literature review). The next component of the thesis will explore the use of TMS in subjects suffering from various pathologies. The first pathological condition that will be analyzed is cortical stroke. FEM studies will be evaluated and compared to the healthy head models to assess how the cortical modifications brought on at an infarction site can alter the TMS induced current densities. We will also include a laboratory study that assesses the efficacy of TMS in stroke treatment, where repetitive TMS (rTMS) was applied to the unaffected hemisphere to decrease inter-hemispheric inhibition of the lesioned hemisphere and improve motor function in stroke patients. Next, the use of TMS in conditions of brain atrophy will be assessed through modeling analyses. This component will also include an evaluation of the clinical work in the field and ways in which the current density alterations caused by the atrophy have led to clinical misconceptions. Transcranial DC Stimulation (tDCS) will be the second modality analyzed through modeling and experimental work. / (cont.) In tDCS, the cerebral cortex is stimulated through a weak dc current in a non-invasive and painless manner and can modulate cortical excitability like TMS. We will define finite element head models of tDCS for both normal and pathologic cases and evaluate the use of tDCS in the clinic in a stroke treatment experiment (analogous to the one completed with TMS). Finally, we will assess and compare these forms of brain stimulation to other forms of neurological treatment and conclude with proposed future improvements to the field of non-invasive brain stimulation. / by Tim Wagner. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 115-120). / Microfabricated transducers have enabled new approaches for detection of biomolecules and cells. Integration of electronics with these tools simplify systems and provide platforms for robust use outside of the laboratory setting. Suspended microchannel resonators (SMRs) are sensitive microfluidic platforms used to precisely measure the buoyant mass of single cells and monolayers of protein in fluid environments. Conventionally, micro cantilever deflection is measured by the optical-lever technique, wherein a laser beam is reflected off the cantilever onto a position sensitive photodiode. This thesis introduces microchannel resonators with electronic readout, eliminating the use of external optical components for resolving the sensor's resonant frequency. Piezo resistors have been fabricated on SMRs through ion implantation integrated with the existing SMR fabrication process. We fabricated two designs: one with a cantilever length of 210 pm and resonant frequency of -347 kHz, and the other with a cantilever length of 406 pm and resonant frequency of ~92 kHz. The work here builds upon knowledge of signal transduction from static and dynamic cantilever based sensors because the piezo resistors are implemented on vacuum encapsulated devices containing fluid. Electronic readout is shown to resolve the microchannel resonance frequency with an Allan variance of 5 x 10-18 (210 pm) and 2 x 1017 (406 pm) using a 100ms gate time, corresponding to a mass resolution of 0.1 and 0.4 fg respectively. This mass resolution calculated from piezoresistive readout frequency stability, is approximately 3X better than optical readout for the 210 pm device and 1.3X for the 406 pm device using the same gate time. Resolution is expected to improve with further optimization of the system. To demonstrate the readout, histograms of the buoyant masses of a mixture of size standard polystyrene beads (with nominal diameters 1.6, 1.8, and 2.0 pm) and budding yeast cells were made. / Ph.D.

Thesis (Ph. D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2001. / Vita. / Includes bibliographical references (p. 127-138). / The universality of many aspects of music, such as octave-based tuning systems and the use of dissonance and consonance to create harmonic tension and resolution, suggests that their perception may have fundamental neurophysiological bases. Thus, music provides a natural set of stimuli and associated percepts with which the auditory system can be studied. Here, we seek correlates of pitch, the essential element of melody, and roughness, a primary component of dissonance, in responses of single auditory neurons in anesthetized cats. Pitch, the perceived highness or lowness of sound, is generally thought to be based on a neurophysiological representation of frequency. Because neural responses (spikes) phaselock to low stimulus frequencies, interspike intervals (ISIs) reflect the stimulus period and can be used to estimate frequency. To rigorously test this potential code for pitch, we look for correlates of pitch under conditions where the percept deviates from a simple function of frequency. One such condition is the octave enlargement effect, listeners' preference for pure-tone octave ratios slightly greater than 2:1. Another is the pitch of a complex tone missing the fundamental frequency: the pitch matches that of the missing fundamental even when different harmonics are presented to opposite ears. We show that a correlate of the octave enlargement effect exists in ISIs of auditory nerve (AN) fibers and a correlate of the missing-fundamental pitch exists in ISIs of neurons in the inferior colliculus, the principal auditory nucleus of the midbrain. Results also reveal greater degradation of pitch representation at the midbrain compared to the periphery. / (cont.) Roughness, the sensation of temporal envelope fluctuations in the range of 20-200 Hz, is often equated with sensory dissonance. Here we examine IC neural responses for correlates of sensory dissonance. We show that sensory dissonance correlates with discharge rate fluctuations of all IC neurons and with average rates of a subset of IC neurons which only respond at the onset of pure-tones. Results indicate that IC neurons are specifically important for the coding of the temporal envelope. Our findings illustrate the complexity and specificity of auditory neural processing in the brainstem and midbrain and show that percepts generally considered to be high order, such as the dissonance of musical intervals, have direct correlates in neural responses in the midbrain. More generally they show that the auditory system performs processing important for music at multiple time scales. / by Martin Franciscus. / Ph.D.

Thesis: Ph. D. in Biomedical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 102-110). / When making daily decisions, people naturally ask two questions: how soon can I make a decision, and is it a good decision? In experimental setting, humans can subjectively yet quantitatively assess choice confidence (i.e. how good) based on their perceptual precision even when a decision is made without an immediate reward or feedback. Such choice confidence has been shown to have a non-monotonic relationship with decision time (i.e. how soon), such that choice confidence can be correlated either positively or negatively with decision time depending on how decision time is constrained. However, the neural mechanisms underlying the interaction between choice confidence and decision time during perceptual decision-making are still unclear. Hence, the goals of this research were to (1) develop dynamic computational models and to (2) find neural representations of choice confidence in human scalp potentials. The dynamic models of choice confidence were developed by merging two parallel conceptual frameworks of decision-making, signal detection theory and sequential analyses (i.e., drift diffusion model). Specifically, in order to capture the end-point statistics of binary choice and confidence, we built on a previous study that defined choice confidence in terms of psychophysics derived from signal detection theory. At the same time, we augmented this mathematical model to include accumulator dynamics of a drift-diffusion model to characterize the time-dependence of choice behaviors in a standard forced-choice paradigm. Twelve human subjects performed a subjective visual vertical task, simultaneously reporting binary orientation choice and probabilistic confidence. Both binary choice and confidence experimental data displayed statistics and dynamics consistent with both signal detection theory and evidence accumulation, respectively. Specifically, the computational simulations showed that the unbounded evidence accumulator model fits the confidence data better than the classical bounded model while bounded and unbounded models were indistinguishable for binary choice data. These results suggest that the brain can utilize mechanisms consistent with signal detection theory to assess confidence when observation duration is externally controlled. As a neural mechanism that binds choice action and confidence, a fronto-parietal network has been implicated. Such bi-local neural circuitry is consistent with dual-route model of metacognition, in which the prefrontal cortex supervises and evaluates objectlevel parietal cortex. However, the neural dynamics underlying the interaction between choice confidence and decision time in the fronto-parietal network during the perceptual decision-making have yet to be elucidated. Here we show in fifteen human subjects that choice confidence contributes to frontal event-related potential (ERP) during a predecisional stage when choice accuracy is emphasized over speed during a free response task. We found that the second positive peak, particularly the curvature, of the stimuluslocked frontal ERP at 400-600ms covaries with confidence while the amplitude of the centro-parietal ERP increases with faster decision response time during the same time interval. This finding provides evidence for a causal role of confidence in perceptual decision-making, complementing earlier ERP evidence supporting a retrospective role. Altogether, these results suggest that an internal representation of choice confidence evolves concurrently with choice action prior to reporting a decision. Furthermore, the non-monotonic dynamics of confidence arise from its dual roles that may be determined by the prior expectation of decision time constraint. In other words, the causal role of confidence may underlie the negative correlations between choice confidence and decision time behaviors while the retrospective role may underlie the positive correlations. / by Koeun Lim. / Ph. D. in Biomedical Engineering

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Includes bibliographical references (leaves 21-22). / Clinical documentation by physicians and nurses has struggled to evolve with advancing technology and societal requirements. Originally designed as a physician's personal notes for a patient, the modern medical record functions as a patient record, communication tool between providers, and instrument for financial reimbursement. Technology has played a pivotal part in advancing the role of the medical record. Advantages and disadvantages inherent in the introduction of each new technology have prompted much debate, but none more than the introduction of electronic documentation systems within electronic medical records. Electronic systems provide clear advantages of information exchange as well as decision and diagnostic support. They have also proven quite controversial, particularly in the initial implementation stages. One aspect of electronic documentation, electronic copying and pasting, provides a tool for the clinician that is not clearly beneficial or detrimental, with proponents on each side. In this paper we explore the social, economic, and legal issues surrounding electronic copying and pasting in clinical documentation, review the literature on this subject, and propose a model for future research in this topic to help shape how clinicians use and process patient information from multiple sources. / by Michael Jernigan. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2003. / Includes bibliographical references (leaves 146-166). / Lymph node metastases have a negative impact on cancer survival, but the mechanisms for lymphatic metastasis are not well understood. The universal finding in solid tumors of an absence of functional lymphatic vessels seems paradoxical, as cancer cells do travel through lymphatics in order to disseminate. In order to address some of these issues, this thesis proposes two etiologies for the absence of functional lymphatic vessels in solid tumors. The first hypothesis addresses whether Vascular Endothelial Growth Factor-C (VEGF-C), a lymphangiogenic factor, was sufficient to induce lymphatic function in tumors. The overexpression of VEGF-C in tumors leads to an increase in lymph node metastasis as well as structures that positively stain for lymphatic markers, but does not induce functional lymphatics within the tumor. Thus VEGF-C is not sufficient to grow functional lymphatic vessels in tumors. The second hypothesis addresses whether mechanical forces generated by the proliferation of cancer cells in a confined space compress lymphatic vessels in tumors. The mechanical forces inside of the tumor were reduced by the selective killing of human cancer cells grown in mice by Diphtheria Toxin. Tumor cell death leads to an increase in the fraction of lymphatics with open lumen. In addition, lymphatic vessels with open lumen are surrounded by a lower cellular density than collapsed vessels. Thus, relieving solid stress allows lymphatic vessels to open. However, function was not restored in these vessels. This is presumably due to the inability of the lymphatic vessels to completely open along its entire length, leaving focal areas of lymphatic collapse. Compressive forces are common to all growing tumors, giving credence to the mechanical etiology of the absence of functional lymphatic vessels in tumors, regardless of tumor type or organ site. / (cont.) These findings lead to an interesting question: Does cancer treatment in humans relieve the mechanical compression allowing lymphatic and blood vessels to open? Furthermore, would the resumption of function of compressed blood and lymphatic vessels lead to a paradoxical increase in metastasis? These questions require further investigation. / by Timothy P. Padera. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (p. 295-303). / Normal human listeners have a remarkable ability to focus on a single sound or speaker of interest and to block out competing sound sources. Individuals with hearing impairments, on the other hand, often experience great difficulty in noisy environments. The goal of our research is to develop novel signal processing methods inspired by neural auditory processing that can improve current speech separation systems. These could potentially be of use as assistive devices for the hearing impaired, and in many other communications applications. Our focus is the monaural case where spatial information is not available. Much perceptual evidence indicates that detecting common amplitude and frequency variation in acoustic signals plays an important role in the separation process. The physical mechanisms of sound generation in many sources cause common onsets/offsets and correlated increases/decreases in both amplitude and frequency among the spectral components of an individual source, which can potentially serve as a distinct signature. However, harnessing these common modulation patterns is difficult because when spectral components of competing sources overlap within the bandwidth of a single auditory filter, the modulation envelope of the resultant waveform resembles that of neither source. To overcome this, for the coherent, constant-frequency AM case, we derive a set of matrix equations which describes the mixture, and we prove that there exists a unique factorization under certain constraints. These constraints provide insight into the importance of onset cues in source separation. We develop algorithms for solving the system in those cases in which a unique solution exists. This work has direct bearing on the general theory of non-negative matrix factorization which has recently been applied to various problems in biology and learning. For the general, incoherent, AM and FM case, the situation is far more complex because constructive and destructive interference between sources causes amplitude fluctuations within channels that obscures the modulation patterns of individual sources. / (cont.) Motivated by the importance of temporal processing in the auditory system, and specifically, the use of extrema, we explore novel methods for estimating instantaneous amplitude, frequency, and phase of mixtures of sinusoids by comparing the location of local maxima of waveforms from various frequency channels. By using an overlapping exponential filter bank model with properties resembling the cochlea, and combining information from multiple frequency bands, we are able to achieve extremely high frequency and time resolution. This allows us to isolate and track the behavior of individual spectral components which can be compared and grouped with others of like type. Our work includes both computational and analytic approaches to the general problem. Two suites of tests were performed. The first were comparative evaluations of three filter-bank-based algorithms on sets of harmonic-like signals with constant frequencies. One of these algorithms was selected for further performance tests on more complex waveforms, including AM and FM signals of various types, harmonic sets in noise, and actual recordings of male and female speakers, both individual and mixed. For the frequency-varying case, initial results of signal analysis with our methods appear to resolve individual sidebands of single harmonics on short time scales, and raise interesting conceptual questions on how to define, use and interpret the concept of instantaneous frequency. Based on our results, we revisit a number of questions in current auditory research, including the need for both rate and place coding, the asymmetrical shapes of auditory filters, and a possible explanation for the deficit of the hearing impaired in noise. / by Barry David Jacobson. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2004. / Includes bibliographical references (p. 67-70). / Introduction. Models that represent mathematical relationships between clinical outcomes and their predictors are useful to the decision making process in patient care. Many models, such as the score of neonatal physiology (SNAP II) that predicts in-hospital mortality, have been well validated on several large populations. However, the performance profile of such models in the midst of changing predictor-outcome relationships or newly appearing outcome predictors have not been well studied. We address this problem using statistical process control (SPC) techniques in a novel way. Although widely used in the manufacturing industry to maintain high quality in critical processes, SPC's value to healthcare has begun only recently to gain attention from decision makers. It has been used to construct risk-adjusted charts to track outcomes in the intensive care unit and the surgical arena, and to monitor hospital acquired infections. However, there are no reports of using SPC techniques to scrutinize the performance quality of a clinical model over time. The series of experiments in this manuscript show that the deterioration of a model's performance can be a useful indicator of unexpected changes in the environment that it represents; therefore, defining when a model is statistically not performing according to expectations is the first step towards determining the causes of clinical variations that might impact patient healthcare. Methods. We obtained a database of 3437 newborns admitted to 7 Neonatal Intensive Care Units in the New England area from October 1994 to January 1996. We chronologically arranged the patients by birthday and grouped them into 14 sequential periods; thereby establishing a time-sequenced database to be used in our SPC experiments. / (cont.) Each of the first thirteen periods contained 250 cases, while the last period had the remaining 187 cases. Several versions of the database were constructed by altering patient data in order to simulate various clinical scenarios--we either introduced graded changes in predictor values and mortality outcomes, or added new predictors. We analyzed the prediction performance pattern of the SNAP II model as applied to periods 1 to 14 in the original and modified versions of our database. The quality parameter tracked by our SPC charts is the C-index, which has been shown to be equivalent to the area under the Receiver Operating Characteristic curve and a well accepted indicator of a model's predictive performance. We introduced the 'deterioration index' as a quantitative measure of performance degradation that permitted us to compare results among experiments. Results. Applying the SNAP II model to the unaltered database, we showed that the c-indices remained well within statistically acceptable boundaries over time. This supported the generalizability of the SNAPII model as well as allowed us to use the mean and standard deviation of the c-indices as control values for our later experiments. In chapter 5, we showed that the model's performance can be degraded beyond acceptable limits by variations in the database (high deterioration index). The index depends on how much the changes in the database affect the existing predictor-outcome relationships. We also showed how the deterioration index can be used to assess and rank contributions of predictors to the model over time. In chapter 6, we showed that model performance ... / by John Chuo. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Page 146 blank. / Includes bibliographical references. / The cellular microenvironment is remarkably complex. In the small space near each cell, growth factors are liberated from extracellular matrix, cytokines are secreted from neighboring cells, and hormones arrive from distant organs. These spatially and temporally diverse cues are integrated by signal transduction cascades to modulate the activity of transcription factors, the principle regulators of gene expression. To date, experimental investigation of spatial and temporal transcription factor activation patterns has been limited by the use of destructive measurement techniques that require averaging responses over large cell populations. Similarly, control of complex microenvironments has been limited by the use of static tissue culture platforms. This thesis describes development of a high-throughput experimental platform called the microfluidic living cell array (mLCA) that combines fluidically-addressable cell arrays with a library of GFP reporter cells to enable nondestructive spatiotemporal gene expression profiling in living cells. The first section describes construction of the GFP reporter library and the development of methodologies for performing routine seeding and culture of cells in microfluidic channels. Microfluidic circuits are then designed to achieve parallel control of soluble stimulus concentration and timing for delivery to downstream cells. A novel "Flow-encoded Switching" (FES) design strategy is introduced to control simultaneous delivery of temporally distinct stimulus patterns using a single input. These circuits are demonstrated by profiling dynamic transcriptional responses to cytokine stimulation, and in each case, cell responses are found to depend quantitatively and qualitatively on the timing of the stimulus. / (cont.) The second section describes development of a two-dimensional valve-controlled mLCA for simultaneously profiling the entire transcriptional reporter library in response to a panel of stimuli. Integrated microvalve arrays control row-seeding and column-stimulation of 256 nanoliter-scale bioreactors, creating a high density matrix of stimulus-response experiments. The platform is demonstrated in the context of the hepatocyte stress response by collecting -5000 single-time-point measurements in each automated and unattended experiment. Results from these studies revealed a novel relationship between TNF-alpha and heat shock response activation, and more generally, illustrated that a single cytokine can activate multiple transcription factors with distinct dynamics. The third section transitions from temporal to spatial profiling and describes discovery and exploration of a spatially heterogeneous gene expression pattern in the innate immune system. Using a stable monoclonal ISRE-GFP reporter, double-stranded DNA (dsDNA) stimulation is found to result in 'colonylike' patterns of reporter activity in an otherwise confluent monolayer. Cell sorting and expression profiling reveal that activated reporter colonies are functionally distinct from their non-activated neighbors, and that colonies are responsible for the majority of cytokine and chemokine expression, including the potent antiviral interferon-beta. Using a novel transplant co-culture experiment, colonies are shown to form by contact-dependent intercellular communication and furthermore, this communication is found to depend on gap junctions. In summary, this thesis introduces promising new tools for conducting high-throughput investigations of spatiotemporal gene expression patterns in living cells, and it provides evidence for a novel dsDNA-induced intercellular communication mechanism that amplifies innate immune responses. / by Kevin R. King. / Ph.D.

Thesis: Ph. D. in Bioinformatics and Integrative Genomics, Harvard-MIT Program in Health Sciences and Technology, 2018. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Cataloged student-submitted from PDF version of thesis. / Includes bibliographical references (pages 141-156). / Comparative genomics is a powerful method for identifying functional genetic elements by their evolutionary patterns across species. However, current studies largely focus on analysis of genome sequences. The recent development of RNA-sequencing reveals dimensions of regulatory information previously inaccessible to us by sequence alone. The comparison of RNA-sequencing data across mammals has great potential for addressing two open problems in biology: identifying the regulatory mechanisms crucial to mammalian physiology, and deciphering how gene regulation contributes to the diversity of mammalian phenotypes. For my thesis, I developed two methodologies for interrogating comparative transcriptomic data for biological inference. First, I developed a framework for quantifying the evolutionary forces acting on gene expression and inferring evolutionarily optimal expression levels. I demonstrate how to use this framework to identify expression pathways underlying conserved, adaptive, and disease states of mammalian biology. Second, I developed novel metrics of transcriptional evolution to evaluate the conservation of long noncoding RNAs. These metrics further reveal that long noncoding RNAs harbor distinct evolutionary signatures, suggesting that they are not a homogenous class of molecules but rather a mixture of multiple functional classes with distinct biological roles. My thesis work provides fundamental quantitative tools for asking biological questions about transcriptome evolution. These tools provide a pivotal framework for interpreting transcriptional data across species and pave the way for deciphering the regulatory changes that lead to mammalian phenotypic variation. / by Jenny Chen. / Ph. D. in Bioinformatics and Integrative Genomics