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Indiana University-Purdue University Indianapolis (IUPUI) / Communication is a vital tool used by humans to share information, coordinate behavior, and survive. However, the ability to communicate can become disrupted or remain absent in individuals with neurodevelopmental disorders: two prominent examples include autism spectrum disorders and developmental language disorders, found in nearly 2% and 10% of the population, respectively. Communication disorders are devastating to the autonomy and quality of life of affected individuals, but clinical solutions are limited due to the complex and often unknown neural etiology underlying these conditions. One known disorder with high incidence of disrupted communication is Neurofibromatosis type 1, the genetic disease caused by heterozygosity of the Ras GTPase-activating protein-coding gene NF1. Mice heterozygous for their ortholog of this gene (Nf1+/-) have been shown to recapitulate neuropsychiatric conditions seen in patients. Using a courtship trial paradigm as a model for testing communication, I have demonstrated that Nf1+/- male mice showed deficits in both courtship and non-courtship social behavior as well as a decrease in the number and duration of ultrasonic vocalizations (USVs). Immediate early gene (IEG) immunohistochemistry (IHC) in neurons of courtship-relevant brain regions revealed the Shell of the Nucleus Accumbens (NAcS) as a dysfunctional brain region in Nf1+/- mice compared to WT male mice following courtship trial. Optogenetic targeting of the Nucleus Accumbens (NAc) restored courtship social behaviors and USV number, but not USV duration or non-courtship gestural social behaviors, in Nf1+/- males. This study contributes to a preclinical foundation for understanding etiology of communication disorders in patients.

A method is described for ultrasonically spraying thin films of carbon nanotubes that have been suspended in organic solvents. Nanotubes were sonicated in N-Methyl-2-pyrrolidone or N-Cyclohexyl-2-pyrrolidone and then sprayed onto a heated substrate using an ultrasonic spray nozzle. The solvent quickly evaporated, leaving a thin film of randomly oriented nanotubes. Film thickness was controlled by the spray time and ranged between 200-500 nm, with RMS roughness of about 40 nm. Also described is a method for creating thin (300 nm) conductive freestanding nanotube/polymer composite films by infiltrating sprayed nanotube films with polyimide.

M. S.

Clinical practice guidelines (CPGs) are viewed by many people with interests in health care as valuable tools for reducing practice variations that undermine patient outcomes and increase medical costs. However, guidelines themselves vary in quality. Assessment tools generally base quality measures on strength of guidelines' evidence base, but particularly for newly emerging applications of ultrasound, standards for measuring guideline quality are controversial. The validity of a guideline is considered likely when strong research-based evidence supports its recommendations, but for newer medical procedures such as emerging ultrasound applications, available evidence is sparse. Existing assessment tools must be modified if they are effectively to measure the validity of these guidelines built on immature evidence. Focusing on ways document drafting affects CPG validity, this study rated six guidelines using the Appraisal of Guidelines Research and Evaluation (AGREE) tool which was customized according to categories of guideline purposes and their differing features of validity. Fine-tuning AGREE in this way may create a more consistent, informative method of evaluating guidelines for emerging applications, and standards established in such an instrument may be useful as a template during the guideline development process. Results from my analyses illuminate several common omissions that weakened documents. Most guidelines did not describe an updating procedure or identify areas for future research, but results also highlighted some highly effective techniques for building validity. Notable examples include providing full credentials for expert drafters, and embedding statement references directly in the text. From the results of the analysis, I conclude that, although the adapted assessment tool I used needs additional adjustment, it may refine analysis of guidelines for emerging ultrasound guidelines and conversely serve as a useful tool during their development process.

Breast cancer is the most common cancer in women, accounting for almost one-thirdof new cancer diagnoses in the United States. The mortality rate has decreased by 42% since 1989 due to early diagnosis, improvements in imaging techniques and treatment regimens. Despite all the advances in imaging modalities, there is still a need for a non-invasive, nonionizing, and low-cost diagnosis technique with high sensitivity and specificity to reduce the rate of invasive biopsies. For individuals diagnosed with locally advanced breast cancer and early-stage breast cancer, neoadjuvant chemotherapy (NACT) has become the standard of care. Pathologic complete response (pCR) is the ideal outcome of NACT, which is correlated with the prognosis and overall survival of the patients. The pCR is achieved in only about 15-20% of patients determined at the time of surgery; therefore, most patients receive a treatment that is not beneficial for them and has considerable side effects. Thus, early detection and monitoring of breast tumor response to NACT is critical for treatment planning and improving overall survival. Ultrasound-based elasticity imaging techniques have gained interest in the clinic due to their potential to provide qualitative and/or quantitative information about tissue stiffness, which is presently not unachievable with standard ultrasonography. These techniques rely on the fact that a breast tumor’s stiffness or Young’s modulus is higher than that of the surrounding normal tissues. In this dissertation, the clinical feasibility of a technique called harmonic motion imaging (HMI) for breast tumor classification, as well as for NACT response prediction and monitoring of solid tumors is investigated. HMI is an ultrasound-based elasticity imaging technique that evaluates the mechanical properties of the underlying tissues by inducing amplitude modulated (AM) displacements at a specific frequency. First, we investigated whether HMI can characterize and differentiate human breast tumors based on their relative stiffness. We enrolled female patients with benign and malignant tumors and imaged them with a clinical HMI system. The malignant tumors were found to be associated with lower HMI displacements or higher stiffness than the benign tumors. Then, in order to verify our clinical findings, we estimated HMI displacements in the postsurgical breast specimens from the same subjects and compared them against the in-vivo estimations. Our findings indicated that HMI successfully differentiated tumors from the surrounding tissue in both ex-vivo and in-vivo conditions, with an excellent correlation between the results in the two different settings. Second, we introduced and characterized a new HMI setup consisted of a multi-element focused ultrasound transducer (FUS) with electronic beam steering capability. Therefore, instead of mechanical translation of the HMI setup, the acoustic force could be electronically steered in the volumetric space to accelerate the data acquisition. A pulse sequence was developed to drive the HMI transducers assembly, the FUS and imaging transducer, using a single ultrasound data acquisition system to have a compact setup that is more applicable for clinical settings. The data acquisition was further improved by investigating the effect of AM frequencies on the quality of the HMI images and tumor detection. We found that higher AM frequencies are needed in order to improve the detection and characterization of small and stiff inclusions. On the contrary, soft and large inclusions are better resolved at lower AM frequencies. Lastly, we investigated the feasibility of using HMI for early prediction of response to neoadjuvant chemotherapy in cancer mouse models and breast cancer patients. We acquired longitudinal HMI images from pancreatic and breast cancer murine tumors during treatment with chemotherapeutic drugs and monitored the changes in the mechanical properties of the tumors. The tumors were found to soften when responsive to treatment, followed by the stiffness increase in the case of drug resistance. However, the untreated mice underwent steady stiffening of the tumors. Next, we imaged breast cancer patients at different timepoints during their chemotherapy treatment. We found that tumors in the patients who achieved pCR had higher pre-treatment stiffness and higher softening from pre-treatment to a short-interval follow-up on treatment compared to the ones in patients with residual cancer cells at the completion of treatment. These findings indicate the promising potential of HMI in the early prediction of solid tumor response to chemotherapy interventions.