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 Division of Health Sciences and Technology, 2005. / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Includes bibliographical references (p. 153-166). / The basal ganglia (BG) are a group of highly interconnected nuclei buried deep in the brain. They are involved in an important range of brain functions, including both lower-level movement control and higher-level cognitive decision making. Dysfunction of the BG has been linked to human neurological disorders such as Parkinson's disease, Huntington's disease, and schizophrenia. This thesis proposes a unified functional model of the BG, called multi-input multi-output adaptive switching (MIMOAS) model that attempts to account for the role of the BG in both higher-level rote behavior and lower-level motor control. In the model, BG circuitry effectively implements a large set of parallel noncompetitive logical OR and NOR circuits that can be driven by specific patterns of cortical activity. These afford selective gating of target thalamocortical neurons. This process can be viewed as a general mapping between binary context and response vectors. The mapping is proved to be learnable via a reinforcement mechanism that is consistent with actions commonly proposed for nigro-striatal dopaminergic pathways in the striatum and homeostasis in synaptic physiology. It appears that the cortico-striatal connections provide a biologically plausible realization of winner-take-all dynamics that is different from many engineering alternatives implementing the same function. With the winner-take-all units as functioning as a hidden layer, using corticostriatal weights as the only tunable parameters, the adaptive BG network can develop the capacity to perform universal binary mappings. In this way, the model can simulate important features of procedural learning in human experiments. At the same time, it can be shown that derangement of the winner-take-all dynamics could underlie the tremor and rigidity seen in Parkinson's disease. / by Zhi-Hong Mao. / Ph.D.

Thesis (Ph. D.)--Harvard University--MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (leaves 112-125). / Speech is perhaps the most ecologically important acoustic stimulus to human beings, because it remains the primary means by which people interact socially. Despite many significant advances made in the development of cochlear implants, even the most successful cochlear-implant users do not hear as well as normal-hearing listeners. The differences in performance between normal-hearing listeners and cochlear-implant users are especially pronounced in understanding speech in complex auditory environments. For normal-hearing listeners, voice pitch or the fundamental frequency (FO) of voicing has long been thought to play an important role in the perceptual segregation of speech sources. The aim of this dissertation was to examine the role of voice pitch in speech perception in the presence of background interference, specifically simulating aspects of envelope-vocoder style implant processing. The findings of the studies show that FO encoded via envelope periodicity does not provide a sufficiently salient cue for the segregation of speech. This suggests that the poor speech reception performance of implant users in background interference may, at least in part, be due to the lack of salient voice pitch cues. When low-frequency fine-structure information was added to envelope- vocoder processed high-frequency information, some FO segregation benefits returned and the reception of speech in complex backgrounds improved. Taken as a whole, the dissertation suggests that low frequency fine-structure information is important to the task of speech segregation, and that every effort should be made to present such information to cochlear-implant users. / by Michael Kaige Qin. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (p. 36-37). / Failure to follow-up on abnormal tests is a common clinical concern comprising the quality of care. Although many clinicians track their patient follow-up by scheduling follow-up visits or by leaving physical reminders, most feel that automated, computerized systems to track abnormal test results would be useful. While existing clinical decision support systems and computerized clinical reminders focus on providing assistance with choosing the appropriate follow-up management, they fail by not tracking that follow-up effectively. We believe that clinicians do not want suggestions how to manage their patients, but instead want help tracking follow-up results once they have decided the management plan. We believe that a well-designed system can successfully track this follow-up and only require a small amount of information and time from the clinician. We have designed and implemented a complete tracking system including 1) an authoring tool to define tracking guidelines, 2) a query tool to search electronic medical records and identify patients without follow-up, and 3) a clinical tool to send reminders to clinicians and allow them to easily choose the follow-up management. Our tracking system has made improvements on previous reminder systems by 1) using our unique risk-management guideline model that more closely mirrors, yet does not attempt to replicate, the clinical decision process, 2) our use of massive population-based queries for tracking all patients simultaneously, and 3) our longitudinal approach that documents all steps in the patient follow-up cycle. With these developments, we are able to track 450 million pieces of clinical data for 1.8 million patients daily. / (cont.) Keyword follow-up tracking; reminder system; preventive medicine; computerized medical record system; practice guidelines; clinical decision support system / by Daniel Todd Rosenthal. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2004. / Includes bibliographical references (p. 163-185). / The cardiovascular response to changes in posture has been the focus of numerous investigations in the past. Yet despite considerable, targeted experimental effort, the mechanisms underlying orthostatic intolerance (OI) following spaceflight remain elusive. The number of hypotheses still under consideration and the lack of a single unifying theory of the pathophysiology of spaceflight-induced OI testify to the difficulty of the problem. In this investigation, we developed and validated a comprehensives lumped-parameter model of the cardiovascular system and its short-term homeostatic control mechanisms with the particular aim of simulating the short-term, transient hemodynamic response to gravitational stress. Our effort to combine model building with model analysis led us to conduct extensive sensitivity analyses and investigate inverse modeling methods to estimate physiological parameters from transient hemodynamic data. Based on current hypotheses, we simulated the system-level hemodynamic effects of changes in parameters that have been implicated in the orthostatic intolerance phenomenon. Our simulations indicate that changes in total blood volume have the biggest detrimental impact on blood pressure homeostasis in the head-up posture. If the baseline volume status is borderline hypovolemic, changes in other parameters can significantly impact the cardiovascular system's ability to maintain mean arterial pressure constant. In particular, any deleterious changes in the venous tone feedback impairs blood pressure homeostasis significantly. This result has important implications as it suggests that al-adrenergic agonists might help alleviate the orthostatic syndrome seen post-spaceflight. / by Thomas Heldt. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references (p. 31-33). / Background A number of important applications in medicine and biomedical research, including quality of care surveillance and identification of prospective study subjects, require identification of large cohorts of patients with specific clinical characteristics. Currently used conventional techniques are either labor-intensive or imprecise, while natural language processing-based applications are relatively slow and expensive. Specific Aims In this thesis we describe the design and formal evaluation of PACT - a suite of rapid, accurate, and easily portable software tools for identification of patients with specific clinical characteristics through analysis of the text of physician notes in the electronic medical record. Methods PACT algorithm is based on sentence-level semantic analysis. The major steps involve identification of word tags (e.g. name of the disease or medications exclusively used to treat the disease) specific for the clinical characteristics in the sentences of the physician notes. Sentences with word tags and negative qualifiers (e.g. "rule out diabetes") are excluded from consideration. PACT can also identify quantitative (e.g. blood pressure, height, weight) and semi-quantitative (e.g. compliance with medical treatment) clinical characteristics. PACT performance was evaluated against blinded manual chart review (the "gold standard") and currently used computational methods (analysis of billing data). Results Evaluation of PACT demonstrated it to be rapid and highly accurate. PACT processed 6.5 to 8.8x 10⁵ notes/hour (1.0 to 1.4 GB of text / hour). / (cont) When compared to the gold standard of manual chart review, PACT sensitivity ranged (depending on the patient characteristic being extracted from the notes) from 74 to 100%, and specificity from 86 to 100%. K statistic for agreement between PACT and manual chart review ranged from 0.67 to 1.0 and in most cases exceeded 0.75, indicating excellent agreement. PACT accuracy substantially exceeded the performance of currently used techniques (billing data analysis). Finally, index of patient non-compliance with physician recommendations computed by PACT was shown to correlate with the frequency of annual Emergency Department visits: patients in the highest quartile for the index of non-compliance had 50% as many annual visits as the patients in the lowest quartile. Conclusion PACT is a rapid, precise and easily portable suite of software tools for extracting focused clinical information out of free text clinical documents. It compares favorably with computation techniques currently available for the purpose (where ones exist). It represents an important advance in the field, and we plan to continue to develop this concept further to improve its performance and functionality. / by Alexander Turchin. / S.M.