Thesis (Ph. D.)--Harvard-MIT Program in Health Sciences and Technology, 2012. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 109-144). / The incidence of autism spectrum disorders (ASD) has risen alarmingly in the United States, and is now thought to affect approximately 1 in 110 live births. Early diagnosis and intervention is the only treatment proven effective in cases of autism, however the behavioral tests currently available cannot make this diagnosis until at least two years of age. A lack of normal attention to faces and abnormal face processing is a cognitive deficit common to nearly all individuals with autism spectrum disorder, and this deficit is likely present from a very early age. The primary goal of this dissertation is therefore to characterize the specific neural response of face processing in infants with near-infrared spectroscopy (NIRS), and to then apply these measures to the study of abnormal face processing in infants at high risk for autism. In order to achieve these objectives, the work described herein aims to: 1) characterize the hemodynamic response to faces in normal infants at six months of age as measured by the Hitachi ETG-4000 functional Near-Infrared Spectroscopy (fNIRS) system; 2) Simultaneously measure orbitofrontal hemodynamic responses to social/emotional engagement and the response to faces in infants at high risk for autism as compared to low risk controls; and 3) Utilize a novel method of condition-related component selection and classification to identify waveforms associated with face and emotion processing in 6-7-month-old infants at high risk for ASD, and matched low-risk controls. Our results indicate similarities of response waveforms, but differences in both the spatial distribution, magnitude, and timing of oxy-hemoglobin and deoxy-hemoglobin responses between groups. Our findings represent the first identification of neuroimaging markers of a functional endophenotype at six months of age that may be associated with high risk of ASD. These results support a model of altered frontal lobe structure through evidence of altered hemodynamic response and/or functional activity in the high risk infant group, and these changes may, in turn, contribute to the development of ASD in specific individuals. / by Sharon Elizabeth Fox. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2008. / Includes bibliographical references. / Developing a consensus on how to model neural and behavioral responses and to quantify important response properties is a challenging signal processing problem because models do not always adequately capture the data and different methods often yield different estimates of the same response property. The threshold, the first stimulus level for which a difference between baseline activity and stimulus-driven activity exists, is an example of such a response property for both neural and behavioral responses.In the first and second sections of this work, we show how the state-space model framework can be used to represent neural and behavioral responses to auditory stimuli with a high degree of model goodness-of-fit. In the first section, we use likelihood methods to develop a state-space generalized linear model and estimate maximum likelihood parameters for neural data. In the second section, we develop the alternative Bayesian state-space model for behavioral data. Based on the estimated joint density, we then illustrate how important response properties, such as the neural and behavioral threshold, can be estimated, leading to lower threshold estimates than current methods by at least 2 dB. Our methods provide greater sensitivity, obviation of the hypothesis testing framework, and a more accurate description of the data.Formulating appropriate models to describe neural data in response to natural sound stimulation is another problem that currently represents a challenge. In the third section of the thesis, we develop a generalized linear model for responses to natural sound stimuli and estimate maximum likelihood parameters. Our methodology has the advantage of describing neural responses as point processes, capturing aspects of the stimulus response such as past spiking history and estimating the contributions of the various response covariates, resulting in a high degree of model goodness-of-fit. / (cont) Using our model parameter estimates, we illustrate that decoding of the natural sound stimulus in our model framework produces neural discrimination performance on par with behavioral data.These findings have important implications for developing theoretically-sound and practical definitions of the neural response properties, for understanding information transmission within the auditory system and for design of auditory prostheses. / by Anna A. Dreyer. / Ph.D.

Thesis (S.M.)--Harvard-MIT Division of Health Sciences and Technology, 2010. / Cataloged from PDF version of thesis. / Includes bibliographical references (p. 78-84). / Autism spectrum disorder (ASD) is characterized by many behavioral symptoms, including delays in social and communicative development. A cluster of symptoms concentrate on speech and language development, especially manipulation of non-verbal information conveyed in prosody. It is largely unknown whether this is due to functional or structural differences in the brain regions involved in auditory and speech processing, although recent studies have shown that ASD individuals do exhibit different activation patterns in various brain regions in response to speech stimuli. This study investigated responses in regions of the auditory pathway to short recorded and synthesized vowel stimuli. These regions were the Inferior Colliculus, the Left Thalamus, the left Posterior Insula, the Auditory Cortex, Wernicke's area, and Broca's area. The stimuli were parametrized so as to target different signal processing capabilities associated with each region. They were presented to ASD and typically developing (TD) subjects while the salient regions were subject to a functional magnetic resonance imaging (fMRI). The results suggest that there were not gross differences in how ASD individuals responded from TD individuals in the subcortical regions. Results from the Auditory Cortex, however, showed a significant hemisphere dominance in TD subjects with more temporally complex stimuli that did not appear in ASD subjects. Moreover, the results showed that it was temporally-measured periodicities in the signal that were responsible for this difference. The results also show slightly different activation patterns in cortical regions which could have implications for attentiveness, and semantic and emotional processing. These results suggest that deficiencies in the temporal processing capabilities of the left Auditory Cortex play a major role in ASD speech processing. / byBennett Bullock. / S.M.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2003. / Includes bibliographical references (p. 119-122). / In conventional optical microscopy, the numerical aperture (NA) of the objective lens intrinsically links the resolution, depth of field (DOF), working distance (WD) and field of view (FOV). In a diffraction-limited system, changing the NA to improve resolution is not possible without degrading the other optical performances. This linkage, which represents an important limitation in conventional microscopy, has now been broken. In the new method, a target is illuminated by a sequence of finely textured light patterns generated by interference of multiple coherent beams that converge in a cone. The corresponding sequence of brightness values, measured by a single photodetector (e.g., a single pixel of a CCD), encodes the target's sub-pixel contrast pattern. Fourier domain components at spatial frequencies contained in the probing illumination patterns can be recovered from the pixel brightness sequence by solving a set of over-determined linear equations. For a given wavelength, the resolution of the reconstructed image is primarily determined by the NA of the cone of beams, rather than the NA of the microscope objective. A low NA objective, with large DOF, long WD, and large FOV, can be used without compromising resolution. A cone of 31 coherent beams with NA of 0.98 is produced from a single source beam ([lambda] = 488 nm) using an acousto-optic deflector (AOD) and an all-reflective beam delivery system. The target is placed where the beams overlap. Fluoresced light from the target is collected with a 0.2 NA objective for 930 different interference patterns. Brightness sequences are decoded to reconstruct an image with resolution comparable to what would be obtained / using a conventional system with a 0.98 NA objective. Further, changing the NA of the actual objective from 0.2 to 0.1 causes negligible change in resolution, demonstrating that resolution is primarily determined by the illumination produced by the cone of beams. Another restriction of conventional systems is removed by the use of reflective elements. The illumination system, which determines resolution, can be constructed using only reflective elements. Ultraviolet or x-ray illumination can be used with fluorescing targets to obtain resolution beyond what is possible using visible light. The well-known problems of refractive optics at short wavelengths can be avoided. / by Jekwan Ryu. / Ph.D.

Thesis: Ph. D. in Speech and Hearing Biosciences and Technology, Harvard-MIT Program in Health Sciences and Technology, 2014. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 103-111). / Aphasia is an impairment in the expression or comprehension of language that results from stroke, traumatic brain injury or progressive neurological disease. Approximately one million people in the United States suffer from aphasia, with the prevalence projected to increase to two million by 2020. Research has shown that speech-language therapy, the treatment for aphasia, can significantly improve people's ability to communicate. However, a major limitation in the field of aphasia rehabilitation is the lack of predictability in patients' response to therapy and the inability to tailor treatment to individuals. We hypothesize that learning represents a critical, underexplored factor in aphasia rehabilitation. Predicting whether a patient will improve following therapy may depend more upon that individual's ability to learn new information in general than upon a specific ability to relearn and master language. In this thesis I report a series of experiments that introduce a new approach that looks beyond language, proposing that the answer to developing efficacious, individually tailored therapies lies in a better understanding of the mechanisms of nonverbal learning in individuals with aphasia. We first explore learning success on a test of nonlinguistic category learning to examine whether learning differences arise among individuals with aphasia and non-aphasic controls. In Experiment 2, we probe the impact of stimulus manipulations on learning success. Experiment 3 presents an investigation into the relationship between learning score and language therapy outcomes. Finally, in Experiment 4, we examine the strategies used to perform our task in order to better understand how information is processed during probabilistic category learning. Results support the hypothesis that aphasia differentially affects language and learning networks. Instruction method and stimulus complexity were found to impact learning success and strategy use in individuals with aphasia. Furthermore, a positive correlation was found between learning scores and success with language therapy, suggesting that there is an informative relationship between learning ability and therapy outcomes. Findings draw attention to underlying processes that have not yet been the focus of research in aphasia, yet likely contribute to outcomes with therapy and present a gateway towards individualizing therapy and improving the predictability of patient outcomes. / by Sofia Vallila Rohter. / Ph. D. in Speech and Hearing Biosciences and Technology

Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2014. / 331 / "June 2014." Cataloged from PDF version of thesis. / Includes bibliographical references (pages 124-139). / Systemically infused mesenchymal stem cells (MSC) are being explored for their immunomodulatory therapeutic potential in multiple inflammatory pathologies. This therapeutic potential has been associated with the ability of MSC to accumulate at sites of inflammation following infusion. However, there is a poor understanding of the mechanisms that mediate MSC trafficking to inflamed tissue. Here, we first introduce key concepts in MSC biology and cellular trafficking, and highlight the relevance of MSC trafficking. We also introduce key concepts in cellular trafficking, particularly the leukocyte homing cascade, as a framework to approach MSC trafficking. Then, we review the field of MSC trafficking in the second chapter, particularly the methods employed to study MSC trafficking and associated challenges. In the third chapter, we study MSC ability to perform transendothelial migration, a specific step in the process of MSC trafficking, using high resolution confocal and dynamic imaging techniques. We found that MSC transmigration is associated with both leukocyte-like and novel mechanisms, including nonapoptotic migratory blebbing. In the fourth chapter, we address the importance of non-endothelial factors in MSC trafficking to inflamed tissues, including mechanical trapping in small vessels, secondary interactions with endogenous immune cells and vascular permeability. Finally, we conclude by proposing an integrated model of mesenchymal trafficking versus hematopoietic trafficking, and highlight the potential role of the intravascular compartment as a major site of MSC immunomodulation. We believe that this body of work has a broad impact on our understanding of MSC biology and therapeutic potential, our comprehension of mesenchymal cell trafficking (including metastasis) and the design of cell delivery strategies for clinical translation. / by Grace Sock Leng Teo. / Ph. D. in Medical Engineering and Medical Physics

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2011. / Cataloged from PDF version of thesis. / Includes bibliographical references. / Magnetic resonance imaging (MRI) has demonstrated the potential for non-invasive mapping of structure and function (fMRI) in the human brain. In this thesis, we propose a series of methodological developments towards improved fMRI of auditory processes. First, the inefficiency of standard fMRI that acquires brain volumes one slice at a time is addressed. The proposed single-shot method is capable, for the first time, of imaging the entire brain in a single-acquisition while still maintaining adequate spatial resolution for fMRI. This method dramatically increases the temporal resolution of fMRI (20 fold) and improves sampling efficiency as well as the ability to discriminate against detrimental physiological noise. To accomplish this it exploits highly accelerated parallel imaging techniques and MRI signal detection with a large number of coil elements. We then address a major problem in the application of fMVIRI to auditory studies. In standard fMRI, loud acoustic noise is generated by the rapid switching of the gradient magnetic fields required for image encoding, which interferes with auditory stimuli and enforces inefficient and slow sampling strategies. We demonstrate a fMRI method that uses parallel imaging and redesigned gradient waveforms to both minimize and slow down the gradient switching to substantially reduce acoustic noise while still enabling rapid acquisitions for fMRI. Conventional fMRI is based on a hemodynamic response that is secondary to the underlying neuronal activation. In the final contribution of this thesis, a novel image contrast is introduced that is aimed at the direct observation of neuronal magnetic fields associated with functional activation. Early feasibility studies indicate that the imaging is sensitive to oscillating magnetic fields at amplitudes similar to those observed by magnetoencephalography. / by Thomas Witzel. / Ph.D.

Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2014. / Cataloged from PDF version of thesis. / Includes bibliographical references (pages 101-113). / Gene therapy has been heralded as a possible approach to a variety of diseases and conditions, ranging from cancer and heart disease to blindness and neurodegenerative diseases. However, progress in gene therapy requires a delivery system that can control when and where the therapeutic proteins will be generated. Our study was performed to determine the feasibility of attaching heat-inducible promoters to genes of interest in order to control activation of the gene in vivo via ultrasound-induced hyperthermia monitored by MRI thermometry. We first demonstrated that gene therapy-mediated gene expression could be spatially and temporally controlled with this method. Further studies were subsequently performed to determine if the activation of a particular heat-inducible gene, Hsp70b, could be quantified and predicted a priori during hyperthermia, thus allowing advance knowledge of the protein levels over time. Experiments indicated that as the temperature and duration of a hyperthermic shock increased, peak expression levels of Hsp70b mRNA also increased until a saturation level was reached. In addition, as the duration of a hyperthermic shock increased, the time during which Hsp70b mRNA remained elevated also increased. Most significantly, a correlation was found between total Hsp70b mRNA production generated by thermal shock and thermal dose, a predictor of dose often used in hyperthermia therapies. The relationship found between total Hsp70b mRNA production and thermal dose suggests that a real-time predictive model of therapeutic protein dose kinetics after ultrasound-induced hyperthermia for gene therapy is feasible. However, the creation of such a model would require further precision experimentation for which ultrasonically-induced hyperthermia is not suited. A final study was performed and found that Hsp70b was not activated by the mechanical stress caused by ultrasound. These results confirm that a predictive model applicable to ultrasonically-induced hyperthermia could be developed using waterbath techniques that will allow tighter control of temperature. / by Christina Elise Silcox. / Ph. D. in Medical Engineering and Medical Physics

Thesis (Ph.D.)--Harvard--Massachusetts Institute of Technology Division of Health Sciences and Technology, 2002. / Includes bibliographical references (p. 169-184). / This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. / Cochlear implants are prosthetic devices that seek to restore hearing in profoundly deaf patients by electrically stimulating the auditory-nerve (AN). With current implants, the representation of the sound waveform in temporal discharge patterns of the auditory nerve is severely distorted. The distortion is particularly significant at higher (>600 Hz) frequencies, for which the period of the electric stimulus is near the AN refractory period. For example, in response to a 1000-Hz pulse train, most AN fibers may fire on every other stimulus cycle, so that the AN population would represent half of the stimulus frequency rather than the actual frequency. Rubinstein et al. [Hearing. Res. 127, 108] proposed that the coding of electric waveforms in cochlear implants can be improved if a sustained, electric high-rate (5 kpps) desynchronizing pulse train (DPT) is presented in addition to the information-carrying electric stimulus. The DPT may amplify the inherent noise in ANfibers so as to produce ongoing, stochastic discharges similar to the spontaneous activity in a healthy hear. We tested this hypothesis by recording responses of ANfibers of deafened cats to sustained electric pulse trains. For most fibers, responses to the DPT showed adaptation during the first 2 minutes, followed by a sustained response for the remainder of the 10-minute stimulus. These sustained responses partially resembled spontaneous activity in terms of discharge rate and interspike interval distributions. AN fibers were extremely sensitive to modulations of the DPT, responding tomodulations as small as 0.5%. / (cont.) Responses to sinusoidal modulations resembled AN responses to pure tones over a 15-25 dB range of modulation depths. Responses to complex modulations simultaneously represented several spectral components of the modulator in their temporal discharge patterns. However, for modulation depths above 10%, the representation of both sinusoidal and complex modulators was more distorted. These results demonstrate that strategies that incorporate a DPT, and that use low modulation depths to encode sounds, may evoke AN responses that more accurately represent the modulator in their temporal discharge patterns. If the central nervous system can utilize this information, then these strategies may substantially improve performance enjoyed by cochlear implant users. / by Leonid Litvak. / Ph.D.

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2005. / Includes bibliographical references. / Imaging speed is a crucial consideration for magnetic resonance imaging (MRI). The speed of conventional MRI is limited by hardware performance and physiological safety measures. "Parallel" MRI is a new technique that circumvents these limitations by utilizing arrays of radiofrequency detector coils to acquire data in parallel, thereby enabling still higher imaging speeds. In parallel MRI, coil arrays are used to accomplish part of the spatial encoding that was traditionally performed by magnetic field gradients alone. MR signal data acquired with coil arrays are spatially encoded with the distinct reception patterns of the individual coil elements. T[he quality of parallel MR images is dictated by the accuracy and efficiency of an image reconstruction (decoding) strategy. This thesis formulates the spatial encoding and decoding of parallel MRI as a generalized linear inverse problem. Under this linear algebraic framework, theoretical and empirical limits on the performance of parallel MR image reconstructions are characterized, and solutions are proposed to facilitate routine clinical and research applications. Each research study presented in this thesis addresses one or more elements in the inverse problem, and the studies are collectively arranged to reflect three progressive stages in solving the inverse problem: 1) determining the encoding matrix, 2) computing a matrix inverse, 3) characterizing the error involved. First, a self-calibrating strategy is proposed which uses non-Cartesian trajectories to automatically determine coil sensitivities without the need of an external scan or modification of data acquisition, guaranteeing an accurate formulation of the encoding matrix. / (cont.) Second, two matrix inversion strategies are presented which, respectively, exploit physical properties of coil encoding and the phase information of the magnetization. While the former allows stable and distributable matrix inversion using the k-space locality principle, the latter integrates parallel image reconstruction with conjugate symmetry. Third, a numerical strategy is presented for computing noise statistics of parallel MRI techniques which involve magnitude image combination, enabling quantitative image comparison. In addition, fundamental limits on the performance of parallel image reconstruction are derived using the Cramer-Rao bounds. Lastly, the practical applications of techniques developed in this thesis are demonstrated by a case study in improved coronary angiography. / Ph.D.