Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2017. / 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 (pages 147-155). / Recent advances have allowed the hardware integration of positron emission tomography (PET) and magnetic resonance imaging (MRI). The spatiotemporally correlated data acquisition opened up opportunities for numerous applications. Furthermore, the MRI data can be utilized to improve the PET scanner performance. While PET has many advantages, including the fact that it could provide a quantitative means to assess in vivo biological processes, its accuracy is confounded by several factors. For example, attenuation correction is required to account for the interactions of the annihilation photons in the subject; motion correction is needed to minimize image degradation due to subject movements; partial volume effects correction is required due to the relatively limited spatial resolution. Although many applications could benefit from these methodological improvements, in this thesis we focused on dementia. MRI and PET are widely used and provide complementary information in the assessment of these patients. Equally important, dementia is a great test situation for these methodological developments because the confounding factors mentioned above are especially pronounced in this patient population. In this work, we developed a unified protocol to address these limitations, an approach we termed MR-assisted PET data optimization. Specifically, we first developed methods to derive head attenuation maps from the morphological MR images. Next, we used temporally-correlated MR data for PET motion compensation and spatially-correlated MR data for anatomy-aided reconstruction. Finally, we demonstrated that after applying these tools to data acquired in dementia patients the PET data quantification was positively impacted and the image quality improved substantially.. / by Kevin Tze-Hsiang Chen. / Ph. D. in Medical Engineering and Medical Physics

Thesis: Ph. D. in Medical Engineering, Harvard-MIT Program in Health Sciences and Technology, 2017. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 99-108). / Non-invasive imaging plays an important role throughout the clinical diagnosis and management process of breast cancer. Unfortunately, existing imaging methods lack the combination of spatial resolution and soft-tissue contrast necessary to visualize pathological changes in the breast. X-ray phase-contrast imaging (XPCI) has emerged as a promising modality for providing enhanced soft tissue differentiation due to its inherent source of contrast being derived from diffraction effects rather than absorption. Studies using synchrotron sources have demonstrated the potential of XPCI in revealing structural details of the breast undetectable via existing modalities. However, the reliance on high-brilliance synchrotron sources significantly limits the use of XPCI in medical applications. In this thesis, we address this challenge by developing a compact XPCI system compatible with low-brilliance laboratory sources that retrieves phase from free-space propagation. We further combine quantitative phase imaging with computed tomography (CT) which enables us to investigate internal structures in 3D. Existing techniques for phase retrieval either require images to be acquired at multiple defocus planes, or assumptions to be made that do not hold true for many objects of interest. To address these limitations, we developed an iterative algorithm for phase retrieval using images acquired at two different energies. Our results show that this algorithm retrieves phase more accurately than existing methods. Finally, we illustrate the potential utility of our compact XPCI system in visualizing pathological features by imaging transgenic mouse models of breast cancer. These pre-clinical results show that phase CT is able to clearly distinguish tumor masses whereas the same features imaged using commercial microCT are obscured by noise. Overall, the methods developed in this thesis provide a proof of concept for conducting tomographic XPCI outside of synchrotron facilities, thus paving the way towards future clinical implementation. / by Ling Xu. / Ph. D. in Medical Engineering

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 123-139). / Cells face a core tension between studiously preventing change in certain properties from extrinsic perturbations while allowing other properties to be tuned. One way cells have resolved this tension is to utilize systems that are both robust and tunable. Systems can achieve this through network design, which can contain submodules that are themselves either robust or tunable, or through network components that are robust over only a defined set of parameter ranges. This work examines these two categories with two specific examples described below. To explore how a simple network can be both robust and tunable, we make use of the osmosensing pathway in the budding yeast Saccharomyces cerevisiae. The pathway consists of two modules: a phosphorelay module that senses the osmotic shock signal that feeds into a mitogen-activated protein kinase (MAPK) module. Using a combination of systematic complementation experiments and computational sensitivity analysis, we show that the phosphorelay module is robust to changes in the kinetic parameters characterizing signal propagation through the module while signaling through the MAPK module can be tuned by changing the rate constants. Furthermore, we show that pathway robustness to rate constant changes has consequences for the evolvability of the osmosensing cascade. Populations of yeast cells challenged to alter the input/output relationship of the cascade saw their MAPK proteins preferentially targeted by natural selection over their phosphorelay counterparts. To explore how a simple regulatory element can be both robust and tunable, we turn our attention to gene regulation by microRNA (miRNA). MiRNAs are short regulatory RNA molecules that repress gene expression in a sequence-dependent manner. By observing the strength of miRNA-mediated repression in individual cells, we show that the strength of repression depends strongly on the relative abundance of the miRNA and its target. Below a threshold level of target message miRNA robustly silences the conversion of mRNA input into protein output, but above this threshold miRNAmediated repression generates an ultrasensitive response to mRNA input allowing the strength of repression to be tuned over a wide variety of values. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Includes bibliographical references (p. 111-118). / The Magnetic Guidance Keyboard System (MaGKeyS) embodies a new haptic guidance technology designed to facilitate sensorimotor training and rehabilitation. MaGKeyS works by employing active magnetic force to guide finger pressing movements during sensorimotor learning that involves sequential key presses, such as playing the piano. By combining this haptic guidance with an audiovisual learning paradigm, we have created a core technology with possible applications to such diverse fields as musical training, physical rehabilitation, and scientific investigation of sensorimotor learning. Two embodiments of this new technology were realized in this thesis. The first embodiment, the MaGKeyS Prototype, is a 5-key acrylic USB keyboard designed for a stationary right hand. A set of three behavioral experiments were executed to investigate the manner in which haptic guidance, via the MaGKeyS Prototype, facilitates rhythmic motor learning. In particular, the experiments examined the independent effects of haptic guidance on ordinal learning, which is the order of notes in a sequence, and temporal learning, which is the order of timing variations in a rhythmic sequence. A transfer test and 24-hour retention test were also administered. Our results provide conclusive evidence that haptic guidance can facilitate learning the ordinal pattern of a key press sequence. Furthermore, our results suggest that the advantage gained with haptic guidance can both transfer to learning a new rhythmic sequence, as well as extend to a demonstrable advantage a day later. The second embodiment, the MaGKeyS Trainer Piano, is an upright piano in which the keyboard has been modified and outfitted with electromagnets in a manner similar to the MaGKeyS Prototype. The Trainer Piano helps to teach by "feel" by providing an experience in which the user feels his or her fingers being pulled down into the correct piano keystrokes as the piano plays itself. / by Craig Edwin Lewiston. / Ph.D.

Thesis (Ph. D.)--Harvard University--Massachusetts Institute of Technology Division of Health Sciences and Technology, Program in Medical Engineering and Medical Physics, 1990. / Includes bibliographical references (p. 242-247). / by Scott David Greenwald. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references (p. 67-69). / Several bioinformatic tools will be brought to bear in this thesis to identify specific genomic loci that serve as regulatory gateways of gene expression in brain. These "motifs" are short nucleotide patterns that occur in promoters and 5' or 3' untranslated regions of genes. Occurrences of motifs that function in eukaryotic genomes as, e.g., transcription factor binding sites or targets of RNA interference are assumed to lie at the nexus of several trends. Instances that are indeed regulatory and not just bits of random sequence should show evidence of actual binding of factors that have a significant effect on expression levels. Such motif instances are also expected to be significantly enriched (or de-enriched), compared to background, in the genes regulated by their binding factors and in brain structures most closely associated with these genes' functions. Finally, truly regulatory motif instances are likely to be highly conserved in orthologous genes across multiple genomes; i.e., conservation can be taken as a proxy for function. My research exploits these ideas by exploring genome-wide properties of motifs associated with the transcription factor family MEF2, some of whose members are known to play a role in synapse development. Data from chromatin immunoprecipitation and tiling-microarray (ChIP-on-chip) experiments [11 have isolated peaks of specific binding by MEF2 in developing rat brains. Conservation and enrichment of these sites are analyzed here for their association with functionality and variability of motifs in genes that have been shown to fall under the control of MEF2 in excitatory neurons. / (cont.) The relationships between regulatory motif content, motif functionality, and expression of neuronal genes investigated in this work can help elucidate how programs of gene expression are controlled---and hence how they might go awry-- -in the brain. / by David Alan Harmin. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Vita. / Includes bibliographical references. / The medial olivocochlear reflex (MOCR) is a brainstem-based neural feedback circuit by which mammals adaptively adjust the gain of their ears in response to changing environmental conditions. Activating the reflex with sound reduces cochlear gain, but the mechanisms by which the reflex produces its cochlear effects, the role(s) the reflex plays in hearing and many basic reflex properties are not well-understood. This thesis quantifies four basic properties of the reflex in humans using stimulus-frequency-otoacoustic-emissions (SFOAEs) that address the following issues: (1) The relative strengths of ipsilateral and contralateral reflex pathways (2) The reflex time-course (3) The response of the reflex to amplitude modulated (AM) noise (4;) The distribution of reflex strengths across a normal-hearing population Activating the reflex with ipsilateral or contralateral noise produced, on average, the same effect in cochlea at the 1 kHz place, contrary to expectations based upon animal studies. Simultaneous bilateral activation produced an effect that was equivalent to the sum of ipsilateral and contralateral activations, on average. Thus, no prevailing binaural interaction took place for our stimulus. Activating the reflex caused detectable changes in the cochlea within 25 ms; the changes continued to develop for 100's of milliseconds. / (cont.) The decay rate upon reflex deactivation was generally faster than the onset rate ([tau]decay= 159 ± 54 ms, [tau]onset =277 ± 62 ms). In addition, our characterization of onset and decay time-courses suggested that a single second order cellular process (probably in outer hair cells) may govern the bulk of both time-courses. The reflex is not fast enough to protect the ear against loud impulse sounds such as gunshots. Amplitude modulating a wideband noise used to activate the reflex did not, in general, produce larger effects as had been previously reported. The question of whether AM can enhance MOCR responses under some circumstances for some subjects remains unanswered. AM rates important for information in speech (2 - 11 Hz) produced a DC MOCR response. It is possible that conversational speech primes the MOCR to a level conducive to detecting speech in noise. Inter-subject differences were found in the cochlear effects at the 1 kHz place when the MOCR was activated. One difference was a subject-specific rapid frequency variation. This finding called into question basic assumptions of how MOCR activation changes SFOAEs. Averaging across frequencies revealed a second subject-specific difference that was attributed to differences in the regional strength of the reflex (near 1 kHz) between subjects. / (cont.) Regional strength varied by a factor of 7 across 24 subjects. Since a strong MOCR has been shown to protect the ear against acoustic trauma in animals, otoacoustic emission-based tests of reflex strength may help predict susceptibility to acoustic trauma in humans; this study demonstrates that such tests are feasible. The basic properties of the MOCR quantified by this thesis contribute to our understanding of the cellular mechanism that generate the reflex's effects, provides insight into the role(s) the reflex plays in hearing, and may eventually lead to clinically useful tests. / by Bradford Clark Backus. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 50-52). / In the past decade, the practice of venture philanthropy, defined in this research as the provision of capital by a nonprofit entity to a for-profit company, has become an increasingly common asset allocation strategy for nonprofit disease-focused foundations.' Both nonprofit organizations and biotechnology firms alike have praised these funding relationships as instruments that help enable, de-risk, and ultimately accelerate the development of new therapies. However, data on the composition and performance of these venture philanthropy investment portfolios remains scarce. While the field of venture philanthropy is too young to have robust outcome data as of yet, we attempted to understand the methodologies for venture philanthropy portfolio construction, the historical mix of projects funded, and the performance of these portfolios thus far. We hypothesized that our independent assessment of grant portfolio composition would be congruent with stated portfolio policy. Instead, we found that organizations did not have a predetermined asset allocation framework against which to compare their investments. We collected data on industry-funding portfolios from three major participants in venture philanthropy in three different disease areas: the Cystic Fibrosis Foundation (CFF), the Juvenile Diabetes Research Foundation (JDRF), and the Michael J. Fox Foundation for Parkinson's Research (MJFF). Data was gathered from organization websites, annual reports, and financial filings. Interviews were conducted with grant program executives at each of the three organizations. While it was not possible to confirm or reject our hypothesis on the basis of portfolio congruence, we were able to show that in the absence of articulated portfolio policy, investment choices may not be aligning with stated program aims to fund earlier-stage, risky projects. / by Sarah Fielding. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 163-177). / Individuals with autism present with a constellation of social, behavioral, and cognitive symptoms. A striking characteristic is the contrast between their language and visual processing abilities. The work in this thesis combines behavioral, functional MRI, and diffusion tensor imaging methods to examine the neurobiological basis of the discrepancy between linguistic and visuospatial skills in autistic cognition. A pictorial reasoning task, designed to manipulate the degree to which language vs. visuospatial abilities may be differentially engaged in solving picture puzzles, was administered under three conditions: visuospatial, semantic and a hybrid visuospatial-cum-semantic condition. Whereas participants with Asperger's syndrome and typically developing controls (CTRL) were found to exhibit similar performance profiles, high-functioning individuals with autism (HFA) differed from these two groups: they were least efficient on the semantic condition and appeared to benefit from and favor the use of visuospatial mediation in problem solving. Results from functional MRI revealed a pattern of decreased activation in fronto-temporal language areas, and an increased reliance on posterior brain regions in the parietal and ventral temporal lobes in HFA, supporting the earlier behavioral findings. Specifically, the inferior frontal gyrus appeared to play an important role in verbal mediation and semantic integration in CTRL, whereas HFA relied more extensively on inferior and ventral regions of the temporal lobe, in keeping with a cognitive preference for visual strategies. / (cont.) An examination of white matter integrity yielded a similar finding in the relationship between structural neuroanatomy and cognitive profile, such that connectivity patterns were related to the semantic mediation difficulties and visual processing preference in the HFA group: tracts relevant for semantic processing in CTRL were disrupted in HFA along the superior longitudinal fasciculus and in the frontal lobe, whereas parietal and inferior temporal white matter supporting visuospatial processing were intact in HFA The results suggest that performance in high functioning autism may be related to deficits in frontal cortex connectivity, in favor of visualization strategies in higher-level cognition. The findings appear to support the use of visuospatial vs. linguistic tasks to differentiate between potential subtypes on the autism spectrum. / by Chérif P. Sahyoun. / Ph.D.

Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2016. / Cataloged from PDF version of thesis. / Includes bibliographical references. / The global hearing healthcare field is faced with two principal challenges. First, the demand for basic audiometric testing services far exceeds the capacity of trained clinicians even in high income countries, and this supply/demand mismatch is expected to worsen secondary to population aging. Next, once patients are identified as having a hearing loss, the treatments that are provided (hearing aids) do not sufficiently address their primary complaint, namely that they have trouble hearing in noisy environments. To begin to address the first problem, we executed a proof-of-concept study to ask whether mobile consumer electronics could be used to replace manually performed clinic-based testing with self-directed hearing measurements from home. We found that self-administered home hearing measurements were largely equivalent to standard clinical measures. To begin to address the second problem (hearing in noise challenges of patients), we performed three additional experiments. Inspired by promising findings of enhanced visual attention following action videogame training, we developed a closed-loop audiomotor training application and asked if playing a game that focused on tone in noise discriminations would provide generalized benefit for speech recognition in noise abilities. In young normally hearing adults, closed-loop training for one month provided a 12 percentage point improvement in speech understanding in noise scores. Next, we recruited older adults who wore hearing aids to play a similar closed-loop training game and observed a 10 percentage point enhancement of speech recognition in noise abilities secondary to gameplay, suggesting that this training could be coupled with standard treatments to improve patient outcomes. Finally, we studied the neurophysiological correlates of audiomotor signal in noise training in a rodent model, where we observed enhanced resistance to noise suppression in auditory cortical neurons following three months of training, perhaps contributing to the perceptual benefits that we observed in human subjects. / by Jonathon Whitton. / Ph. D.