Focused Ultrasound Mediated Blood-Brain Barrier Opening in Non-Human Primates: Safety, Efficacy and Drug Delivery

The blood-brain barrier (BBB) is physiologically essential for brain homeostasis. While it protects the brain from noxious agents, it prevents almost all currently available drugs from crossing to the parenchyma. This greatly hinders drug delivery for the treatment of neurological diseases and disorders such as Parkinson’s, Alzheimer’s and Huntington’s, as well as the development of drugs for the treatment of such diseases. Current drug delivery techniques to the brain are either invasive and target specific, or non-invasive with low special specificity. Neither group of techniques are optimal for long term treatment of patients with neurological diseases or disorders. Focused ultrasound coupled with intravenous administration of microbubbles (FUS) has been proven as an effective technique to selectively and noninvasively open the BBB in multiple in vivo models including non-human primates (NHP). Although this technique has promising potential for clinical outpatient procedures, as well as a powerful tool in the lab, the safety and potential neurological effects of this technique need to be further investigated. This thesis focuses on validating the safety and efficacy of using the FUS technique to open the BBB in NHP as well as the ability of the technique to facility drug delivery. First, a longitudinal study of repeatedly applying the FUS technique targeting the basal ganglia region in four NHP was conducted to determine any potential long-term adverse side effects over a duration of 4-20 months. The safety of the technique was evaluated using both MRI as well as behavioral testing. Results demonstrated that repeated application of the FUS technique to the basal ganglia in NHP did not generate permanent side effects, nor did it induce a permanent opening of the BBB in the targeted region. The second study investigated the potential of the FUS technique as a method to deliver drugs, such as a low dose of haloperidol, to the basal ganglia in NHP and mice to elicit pharmacodynamical effects on responses to behavioral tasks. After opening the BBB in the basal ganglia of mice and NHP, a low dose of haloperidol was successfully delivered generating significant changes in their baseline motor responses to behavioral tasks. Domperidone was also successfully delivered to the caudate of NHP after opening the BBB and induced transient hemilateral neglect. In the final section of this thesis, the safety and efficacy of the FUS technique was evaluated in fully alert NHP. The FUS technique was successful in generating BBB opening volumes larger on average to that of the BBB opening volumes in anesthetized experiments. Safety results through MRI verification as well as behavioral testing during application of the technique demonstrated that the FUS technique did not generate adverse neurological effects. Conversely, the FUS technique was found to induce slight positive effects on the response of the NHP to the behavioral task. Collectively, the work presented in this thesis demonstrates the safety and effectiveness of the FUS technique to open the BBB and deliver neuroactive drugs in the NHP

Using Simulation and Domain Adaptation to Improve Efficiency of Deep Robotic Grasping

Instrumenting and collecting annotated visual grasping datasets to train modern machine learning algorithms can be extremely time-consuming and expensive. An appealing alternative is to use off-the-shelf simulators to render synthetic data for which ground-truth annotations are generated automatically. Unfortunately, models trained purely on simulated data often fail to generalize to the real world. We study how randomized simulated environments and domain adaptation methods can be extended to train a grasping system to grasp novel objects from raw monocular RGB images. We extensively evaluate our approaches with a total of more than 25,000 physical test grasps, studying a range of simulation conditions and domain adaptation methods, including a novel extension of pixel-level domain adaptation that we term the GraspGAN. We show that, by using synthetic data and domain adaptation, we are able to reduce the number of real-world samples needed to achieve a given level of performance by up to 50 times, using only randomly generated simulated objects. We also show that by using only unlabeled real-world data and our GraspGAN methodology, we obtain real-world grasping performance without any real-world labels that is similar to that achieved with 939,777 labeled real-world samples.Comment: 9 pages, 5 figures, 3 table

Suicide Screening in Primary Care: Use of an Electronic Screener to Assess Suicidality and Improve Provider Follow-Up for Adolescents

Purpose The purpose of this study was to assess the feasibility of using an existing computer decision support system to screen adolescent patients for suicidality and provide follow-up guidance to clinicians in a primary care setting. Predictors of patient endorsement of suicidality and provider documentation of follow-up were examined. Methods A prospective cohort study was conducted to examine the implementation of a CDSS that screened adolescent patients for suicidality and provided follow-up recommendations to providers. The intervention was implemented for patients aged 12–20 years in two primary care clinics in Indianapolis, Indiana. Results The sample included 2,134 adolescent patients (51% female; 60% black; mean age = 14.6 years [standard deviation = 2.1]). Just over 6% of patients screened positive for suicidality. A positive endorsement of suicidality was more common among patients who were female, depressed, and seen by an adolescent−medicine board-certified provider as opposed to general pediatric provider. Providers documented follow-up action for 83% of patients who screened positive for suicidality. Documentation of follow-up action was correlated with clinic site and Hispanic race. The majority of patients who endorsed suicidality (71%) were deemed not actively suicidal after assessment by their provider. Conclusions Incorporating adolescent suicide screening and provider follow-up guidance into an existing computer decision support system in primary care is feasible and well utilized by providers. Female gender and depressive symptoms are consistently associated with suicidality among adolescents, although not all suicidal adolescents are depressed. Universal use of a multi-item suicide screener that assesses recency might more effectively identify suicidal adolescents

Let them speak for themselves: Improving adolescent self-report rate on pre-visit screening

Background Adolescent pre-visit screening on patient-generated health data is a common and efficient practice to guide clinical decision making. However, proxy informants (e.g., parents or caregivers) often complete these forms, which may lead to incorrect information or lack of confidentiality. Our objective was to improve the adolescent self-report rate on pre-visit screening. Methods We conducted an interventional study using an interrupted time-series design to compare adolescent self-report rates (percent of adolescents ages 12-18 years completing their own pre-visit screening) over 16 months in general pediatric ambulatory clinics. We collected data using a computerized clinical decision support system with waiting room electronic tablet screening. Pre-intervention rates were low, and we created and implemented two electronic workflow alerts, one each to the patient/caregiver and clinical staff, reminding them that the adolescent should answer the questions independently. We included the first encounter from each adolescent and evaluated changes in adolescent self-reporting between pre- and post-intervention periods using interrupted time series analysis. Results Patients or caregivers completed 2,670 qualifying pre-visit screenings across 19 pre-intervention, 7 intervention, and 44 post-intervention weeks. Self-reporting by younger adolescents nearly doubled with a significant increase of 19.3 percentage points (CI 9.1-29.5) from the baseline 20.5%. Among older adolescents, the stable baseline rate of 53.6% increased by 9.2 absolute percentage points (CI -7.0-25.3). There were no significant pre- or post-intervention secular trends. Conclusions Two automated alerts directing clinic personnel and families to have adolescents self-report significantly and sustainably improved younger adolescent self-reporting on electronic patient-generated health data instruments

Residency Exposures and Anticipated Future Involvement in Community Settings

Objective— To assess how exposures to community activities in residency impact anticipated future involvement in community child health settings. Methods— Prospective cohort study of pediatric residents from 10 programs (12 sites) who completed training between 2003 and 2009. Residents reported annual participation for ≥8 days in each of 7 community activities (eg, community settings, child health advocacy) in the prior year. At the start and end of residency, residents reported anticipated involvement in 10 years in 8 community settings (eg, school, shelter). Anticipated involvement was dichotomized: moderate/ substantial (“high”) versus none/limited (“low”). Logistic regression modeled whether residency exposures independently influenced anticipated future involvement at the end of residency. Results— A total of 683 residents completed surveys at the start and end of residency (66.8% participation). More than half of trainees reported ≥8 days’ of involvement in community settings (65.6%) or child health advocacy (53.6%) in residency. Fewer anticipated high involvement in at least 1 community setting at the end of residency than at the start (65.5% vs 85.6%, P < .001). Participation in each community activity mediated but did not moderate relations between anticipated involvement at the start and end of residency. In multivariate models, exposure to community settings in residency was associated with anticipated involvement at end of residency (adjusted odds ratio 1.5; 95% confidence interval 1.2, 2.0). No other residency exposures were associated. Conclusions— Residents who anticipate high involvement in community pediatrics at the start of residency participate in related opportunities in training. Exposure to community settings during residency may encourage community involvement after training

Barriers and facilitators to treatment participation by adolescents in a community mental health clinic

An estimated 40–60% of children in mental health treatment drop out before completing their treatment plans, resulting in increased risk for ongoing clinical symptoms and functional impairment, lower satisfaction with treatment, and other poor outcomes. Research has focused predominately on child, caregiver, and family factors that affect treatment participation in this population and relatively less on organizational factors. Findings are limited by focus on children between 3 and 14 years of age and included only caregivers’ and/or therapists’ perspectives. The purpose of this descriptive qualitative study was to identify organizational factors that influenced participation in treatment, with special attention to factors that contributed to dropout in adolescents. The sample included 12 adolescent–caregiver dyads drawn from two groups in a large public mental health provider database. Analysis of focus group interview data revealed several perceived facilitators and barriers to adolescent participation in treatment and provided several practical suggestions for improving treatment participation. Implications of the findings for psychiatric mental health nurses and other clinicians who provide services to families of adolescents with mental health concerns are discussed