Wei Gao, Ph.D. - US grants

DESCRIPTION (provided by applicant): Prenatal cocaine exposure (PCE) is related to deficits in cognitive function in infants, children and adolescents, however little is known about the effects of in utero cocaine exposure on early brain development that may contribute to these deficits. The long term goal is to better understand neural mechanisms underlying the cognitive impairments attributable to PCE. The objective of this proposal is to quantify the effects of PCE on functional connectivity networks in a pre-existing dataset from 148 infants, tested at 2-6 weeks of age, in which cocaine-related prefrontal and frontal cortical gray matter (GM) loss has already been determined. The central hypothesis is that effects of PCE will entail reductions in patterns of functional connectivity that are related to GM loss in prefrontal and frontal cortex, and that greater in utero exposure will be related to more widespread reductions in connectivity. This hypothesis has been formulated on the basis of preliminary data produced by the applicants that: 1) describes the presence of functional networks in typically developing infants as early as 2 weeks of age; 2) shows that infants exposed to cocaine in utero display reduced prefrontal and frontal gray matter volumes compared to drug-free controls and to infants exposed to other drugs (nicotine, alcohol, marijuana, opiates). The rationale for the proposed research is that measurement of functional connectivity in infants with PCE in the first weeks of life will lay the foundation for study of developmental changes in neural circuitry that underlie cognitive deficits, suggest factors that bolster resilience against these deficits, and reveal targets for early intervention. This hypothesis will be tested by pursuit of two specific aims: 1) Quantify the effects of PCE on multi-level functional connectivity using pre-existing data from 46 infants exposed to cocaine and other drugs (PCE), 58 drug-free controls (CTL) and 44 exposed to the same drugs experienced by the PCE group (nicotine, alcohol, marijuana and/or opiates) but without cocaine; 2) Determine the relationship of frontal and prefrontal connectivity to cognitive, behavioral and biological markers of infant development. Under the first aim, a proven approach of seed-based analysis, independent components analysis (ICA) and graph theoretic analysis, which is well-established as feasible in the applicants' hands, will be used to describe strength and density of prefrontal and frontal neonatal functional networks anchored by structural deficits. Under the second aim regional, network level and whole brain functional connectivity at 2-6 weeks will be related to measures of infant cognitive, behavioral and physiological development measured at 3 months. The approach is innovative because it will be first to apply these well-developed analyses methods to characterize early abnormalities in brain activity in early infancy in this at-risk group. The proposed research is significant because it is expected to identify a neurophenotype of cocaine's effects on early brain function prior to exposure to the damaging environmental influences that accompany maternal drug abuse, and provide support for more detailed longitudinal study of PCE's effects on developing trajectories of brain structure and function.

? DESCRIPTION (provided by applicant): Mental disorders are chronic and disabling disorders in need of effective treatments. They affect a large portion of the world's population, with significant impairment in their social function and have devastating consequence on the quality of life. Significant progress has been made in recent years to identify genetic disruptions that increase susceptibility to mental disorders, but we have little understanding of the circuitry mechanisms linking these genetic risk factors to the widespread cognitive and affective deficits associated with these disorders. Accumulating evidence suggests that brain connectivity alteration plays an important role in the pathophysiology of mental disorders. More recently, functional imaging data garnered from patients with mental disorders and animal models of schizophrenia and autism have collectively pointed to the aberrant hippocampal activity as a central feature of pathophysiology. Together, these data suggest that aberrant hippocampal activity may be a critical factor that contributes to brain network abnormalities in mental disorders. Within the hippocampus, dentate gyrus continuously generates new neurons throughout life, therefore making significant modifications to the hippocampal circuitry activity. Cumulative evidence suggests that these adult- born neurons are involved in cognition, stress response and mood regulation; and aberrant adult neurogenesis contributes to brain disorders, such as epilepsy and mental disorders. The current project is built upon our recent discoveries, including (i) identification of critical roles of DISC1 in regulating morphogenesis, cell positionig, axon/dendritic development and synapse formation of newborn granule cells in the adult hippocampus; and (ii) DISC1 deficiency in adult-born dentate granule neurons causes cognitive and affective behavioral deficits. However, how dysregulation of adult-born neurons by genetic risk factor DISC1 leads to these behavioral deficits at the circuitry level is largely unknown. Th overall goal of this proposed project is to investigate whether aberrant adult neurogenesis mediated by DISC1 deficiency serves as a critical neural substrate for brain connectivity abnormalities associated with mental disorders. To test this hypothesis, we propose to utilize in vivo multi-channel recording to examine local hippocampal activity (Aim 1) and functional magnetic resonance imaging (fMRI) to measure global brain connectivity (Aim 2) with or without DISC1 deficiency in adult-born neurons at the baseline and upon activity stimulation of those neurons. Our proposed studies will address fundamental questions on how genetic risk factors lead to the clinical manifestation of many severe psychological disorders by focusing on adult neurogenesis as a promising but ill-defined substrate in mediating global brain connectivity. Adult neurogenesis correlates with many physiological and pathological states, such as learning and memory, epilepsy, neurodegenerative diseases and mental disorders. Therefore, targeting adult neurogenesis process could constitute a novel therapeutic strategy for treating these disorders.

? DESCRIPTION (provided by applicant): Creating Normative Functional Brain Atlases during Infancy There is an increasing interest in exploring the mechanisms underlying early brain functional development using the resting state fMRI (rsfMRI) technique. Such explorations are promising for the detection of early functional connectivity biomarkers that are essential for the development of early diagnosis and intervention schemes for different pediatric neurological disorders such as cerebral palsy and epilepsy. However, given the dramatic functional evolution between infancy and adulthood, there are noteworthy difficulties for early developmental studies which include both the definition of infant-appropriate regions of interest (ROIs) and the accurate interpretation of the resulting functional connectivity patterns. Therefore, the establishment of infant-specific functional brain atlases represents an urgent mission for more rapid progress in the field. Our team has extensive experience in using rsfMRI to delineate normal brain functional connectivity development patterns during infancy and has accumulated a large sample of normal singleton infants (N=174) with longitudinal rsfMRI scans during the first two years of life. The availabilityof such a large-scale dataset provides us a unique opportunity to establish normative functional brain atlases during infancy. In fact, we have demonstrated the feasibility of such an endeavor and delineated the sub-regional functional segregation profile of the insula and thalamus during the first two years of life. Building on these previous experiences and leveraging the large-scale pre-existing data, the proposed study aims to establish a set of normative functional atlases for the first two years of life. Additionally, we will utilize existing behavioral data (i.e., Mullen Sores) measured at 1 and 2 years of age to evaluate the behavioral relevance and significance of the established functional atlases (Aim 1). Secondly, another equally important and unique dataset consisting of 120 dizygotic (DZ) and 88 monozygotic (MZ) twin infants scanned at the same age interval is also available and will be used to: i) independently validate the atlases established based on singleton infants; and ii) examine the associated genetic and environmental contributions to the functional atlases (Aim 2). Upon successful completion of the proposed project, we expect that a software package containing the established infant-specific normative functional brain atlases together with their behavioral correlation, genetic association, and environmental influences, will be made freely available to the early brain development research community to foster more rapid progress in the field (Aim 3). The approach is innovative because it will be the first to apply established functional connectivity clustering techniques to infant data and create normative functional brain atlases during infancy. The proposed research is significant because it is expected to provide the research community with an unprecedented set of references to expedite future explorations of the functional mechanisms underlying both normal and abnormal early brain development.

ABSTRACT Prenatal cocaine exposure (PCE) is consistently related to impaired attention and behavioral and physiological self-regulation in infants and young children, suggesting persistent negative impact on skills essential for optimal learning and social competence. Gestational exposure to cocaine occurs during a time of extraordinary brain growth and organization, which is immediately followed by massive expansion and refinement of brain structure, functional connections and network organization in the first year of life. However, little is known about the effects of PCE on early human brain development that may contribute to reported deficits in cognition and neurobehavior. The objectives of this proposal are to quantify the effects of PCE on the developmental trajectory of infant brain functional connectivity in postnatal months 0-12, to determine associations with neurobehavioral and cognitive outcomes, and to examine how specific maternal caregiving characteristics (Sensitivity, Harshness) moderate these effects. Our central hypothesis is that fetal brain development and organization are altered by PCE; deficits in developing functional connections mediate the negative effects of PCE on simultaneously developing neurobehavior and early cognition; postnatal maternal behaviors and environment interact with PCE to influence growth trajectories of developing connections and networks that subserve emerging abilities. This hypothesis is based on the Co-PIs'strong preliminary data describing normative development of functional networks from birth to 2 years (Gao), disruptions in functional connectivity due to prenatal cocaine and other drugs in neonates (Grewen, Gao), and on Co-investigator Eiden's longitudinal studies of the behavioral effects of PCE and its moderation by maternal behaviors in infants, toddlers and children. We propose to study infant resting state functional connectivity and behavioral development at 2 weeks, 6 months and 12 months in 3 groups of infants: 120 with PCE with or without exposure to other drugs (nicotine, alcohol, marijuana, and/or opiates), 100 exposed to the same other drugs but without cocaine (OD), 100 drug-free (CTL). We will measure Maternal Sensitivity (primary), Maternal Harshness (secondary) and an index of cumulative environmental risk to determine postnatal moderation of PCE effects on developing connectivity. The rationale is that longitudinal study will reveal prenatal drug effects, determine whether the postnatal trajectory of brain functional connections is merely delayed or permanently altered by initial PCE insult, and ascertain postnatal factors contributing to greater risk or resilience in func- tional network development. This innovative approach will quantify direct and interactive effects of initial neural deficit and postnatal environmental influences on patterns of brain and cognitive development, and will apply hypothesis-driven and data-driven analytic methods, including machine learning, to characterize mechanisms underlying PCE effects on trajectory of brain development. Knowledge gleaned has potential to inform earlier, more effective interventions to prevent or reduce learning and behavioral impairments in this at-risk population.

ABSTRACT Opioid use during pregnancy has increased dramatically in the past decade, and may pose significant health challenges for the rapidly growing number of exposed infants born to mothers using illicit and/or prescribed opioids. Prenatal opioid exposure (OE) is inconsistently related to impaired neurobehavior, attention, and cognition in infancy and childhood, suggesting persistent, potentially life-long, consequences. This fetal exposure occurs during a time of extraordinary brain growth and organization, making it a critical period of vulnerability to environmental insult. However, little is known about the effects of OE on early human brain development that may contribute to reported deficits. The objectives of this proposal are to quantify the effects of OE on the development of infant brain functional connectivity in postnatal months 1-12, to determine associations with neurobehavioral and cognitive outcomes, and to examine how gender, other prenatal drug exposures, and postnatal environmental factors moderate these effects. Our central hypothesis is that fetal brain development and organization are altered by OE; deficits in developing connections and networks mediate the negative effects of OE on simultaneously developing neurobehavior and early cognition; gender, other drugs and postnatal environment interact with OE to influence growth trajectories of rapidly developing connections and networks that subserve emerging abilities. This hypothesis is based on the study team?s substantial research experience with mother-infant dyads with prenatal opioid and other drug exposures (Jones, Grewen), and on strong preliminary data showing normative development of functional networks from birth to 2 years (Gao), disruptions in neonatal functional connectivity due to prenatal opioids and other drugs (Grewen, Gao), and on associations between functional connections and behavioral effects (Grewen, Gao). The rationale for the proposed research is that longitudinal study will quantify direct and interactive effects of initial neural insult, infant gender and postnatal environment on developing functional connections. The hypotheses will be tested with 3 Specific Aims: 1) Quantify the extent to which OE impairs developing functional connections at 2 weeks and again at 12 months; 2) Determine the extent to which the effects of OE on neurobehavior, attention, self-regulation and cognition are related to developmental trajectories of functional connections; 3) Determine how infant gender, other prenatal drug exposures, and a Cumulative Environmental Risk Index moderate the effects of OE on developing connectivity. This approach is innovative because it will employ hypothesis-driven analyses as well as novel, exploratory data-driven and machine learning methods to quantify direct and interactive effects of OE and other drug exposures on functional circuitry. The proposed research is significant because rates of prenatal OE and NAS have increased 5-fold since 2000, in parallel with the opioid epidemic, and because knowledge gleaned has potential to identify factors that may protect or further harm growing functional networks underlying nascent cognitive abilities in this at-risk group.

This project is supported by the Chemical Measurement and Imaging program of the Chemistry Division. Professor Kim Williams of the Colorado School of Mines (CSM) is developing thermal field-flow fractionation (ThFFF) as a versatile platform for separating and characterizing complex polymers and colloids. Thermal diffusion in liquids presents a novel way of separating and analyzing mixtures of plastics and other very large molecules. This project uses the NSF Grant Opportunities for Academic Liaison with Industry (GOALI) mechanism to for a collaboration between Dr. Williams' lab and Dow Chemical Company. The academic/industrial collaboration serves as a model for combining expertise in separation science, that may lead to insights about product performance. An outreach program developed by Professor Williams brings science and discovery to students with learning disabilities (dyslexia) and introduces future teachers in the STEM Teacher Education program at CSM. Students relate well to the textural and visual nature of these polymer and colloid activities and thus, outreach activities are carried out at the Rocky Mountain Camp for Dyslexic Youths. These low cost and safe hands-on experiments introduce to students in the STEM Teacher Education program at the Colorado School of Mines. The broader impacts of this work include technical benefits through better designed (more environmentally friendly) products, and educational benefits for the students and scientists who are trained in an industrial and academic setting.

Ultrahigh molecular weight or ultralarge polymers and colloid surface characterizations are analytical challenges. Reliable methods for determining molecular weight distributions do not currently exist for these materials. The objectives for this work are to develop and test thermal field-flow fractionation (ThFFF) for ultralarge (>100 nm or >103 kDa) polymers. The researchers determine experimental approaches that provide additional control of thermal diffusion of colloids and demonstrate their use for surface composition/charge separations and analyses. They also identify a working particle thermophoresis theory. An outreach program developed by Professor Williams brings science and discovery to students with learning disabilities (dyslexia) and introduces future teachers in the STEM Teacher Education program at CSM. The broader impacts of this work include potential societal benefits through better designed (more environmentally friendly) products, students and scientists who are trained in an industrial and academic setting, and more experienced future STEM teachers. Innovative analytical methods that result from this work may impact science and technologies associated with polymers and colloids (natural, biological, and synthetic). The close collaboration between CSM and Dow scientists improves research impact and develops the next generation work force through students' exposure to industry.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

A key to combat the Coronavirus Disease (COVID-19) pandemic is to prevent the pandemic from overloading the public healthcare system, so that sufficient medical resources could be available for hospitalized patients. This project will develop new mobile sensing and Artificial Intelligence (AI) techniques for in-home evaluation of COVID-19 infection in order to pursue automated and non-invasive screening of potential viral disease carriers. It aims to timely identify negative cases caused by other diseases with similar symptoms, and hence avoids unnecessary hospital visits as many as possible.

The proposed techniques will use commodity smartphones to measure the changes of humans? airway mechanics, which are uniquely correlated to COVID-19 infection. These measurements build on acoustic sensing with smartphones? built-in speakers and microphones. First, new acoustic waveforms will be designed to minimize acoustic signal distortion in human airways. Second, new signal processing techniques will be developed for accurate measurements. Third, deep learning techniques will be used to develop generic models that depict the core characteristics of airway mechanics. These techniques will be evaluated by lab testing and experiments with student volunteers. This research will enable identifying false positives of COVID-19 infection out of the clinic and could contribute to the containment of the virus spread and damage. The proposed technologies will be applicable to a wide variety of commodity smartphones and could also be used in daily practice with handmade mouthpieces. Broader impacts will also result from a variety of education and outreach activities. New courses will be developed to incorporate the outcome of this research, and the research outcome will be disseminated through technology transfer to industry. The outcome of this project, including source codes and collected data from student volunteers, will be maintained at the project repository (http://www.pitt.edu/~weigao/research_COVID19.html) for at least five years, and will be made available to the public community.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Pulmonary diseases constitute a major public health challenge, and pulmonary function testing (PFT) is the main method of evaluating the changes in human airway mechanics, which are the key symptoms of pulmonary diseases. Due to the possibility of frequent exacerbations in pulmonary diseases, it is important that PFT is accessible to patients anytime and anywhere out of clinic, but most of current in-clinic PFT techniques are too cumbersome and expensive to be used out of clinic. This project addresses these challenges to enable PFT anytime and anywhere, by developing new and integrated artificial intelligence (AI) and sensing systems on commodity smartphones. As pulmonary diseases widely affect the human society and result in billions of annual healthcare related costs, this project has great potential to benefit society by enabling efficient disease monitoring, diagnosis and management out of clinic. This project is also contributing to society by producing datasets that help understand the disease mechanisms, as well as developing new curricula, disseminating research for education and training, and engaging underrepresented students in research.<br/><br/>The primary goal of this project is to enable highly accurate, adaptable and generic PFT out of clinic using commodity smartphones. The project consists of four research tasks: (1) designing new acoustic sensing systems on commodity smartphones that measure the humans’ airway lumen dimensions and characteristics; (2) extracting appropriate biomarker profiles from acoustic sensory data for disease evaluation; (3) developing generalizable machine learning (ML) models that can be applied to evaluating different pulmonary diseases; (4) exploring distributed and asynchronous methods of training the ML models with new federated learning techniques.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.