Edward G. Freedman - US grants

DESCRIPTION(adapted from applicant's abstract): The ability to coordinate movements during the performance of complex behaviors in our ever-changing environment is an essential goal of the nervous system. To accomplish this, sensory information must be integrated continuously in order to construct a representation of objects in the world. This critical function requires the ability to distinguish between self-generated and object motion, to integrate diverse sensory information, and to plan and execute simultaneous motor behaviors. The neural control of eye movements is an experimental system that has provided significant insights into the neural mechanisms mediating visual orienting behaviors. Directing the line of sight (gaze) towards interesting objects enhances our perception of the object and provides a way to construct and maintain an internal model of the world. These shifts in gaze direction are generally accomplished by coordinating movements of the eyes and head, and they provide an excellent model system for studying the neural control of orienting behavior, the coordination of multiple body segments, spatial orientation and transformation of sensory information into motor commands. By recording the activity of specific groups of neurons during performance of orienting movements it is possible to correlate neural responses with particular features of coordinated gaze shifts. The goals of the proposed research are to use these techniques to elucidate the neural computations and processes involved in eye-head coordination. Our recent experiments, recording neural activity in the brainstem of head-free monkeys, indicate that the relationships which have previously defined the rules of the oculomotor system, break down when the head and eyes move together to re-direct the line of sight (gaze). The implications of these experiments are that hypotheses of oculomotor control based on data from head restrained subjects, are a special case of a more general system. The proposed experiments are designed to identify and characterize the mechanisms of this more general control system, and will contribute directly to our understanding of the neural control of orienting movements. They also contribute to a more general understanding of the neural mechanisms involved in motor control and coordination during complex behaviors. In addition, this research will facilitate identification and treatment of spatial disorientation, saccadic and/or gaze dysmetrias, and brain stem damage resulting from trauma or disease.

Lay Abstract: NSF# 0132335 - CAREER

Using psychophysical and neurophysiological techniques, this research investigates several aspects of the important neural computations that are required for execution of visual orienting movements: 1) the mechanisms that mediate the transformation of sensory information into motor commands; 2) the neural computations required to decompose global motor commands observed at the level of the superior colliculus into signals required for coordinated contraction of muscles; and 3) the management of conflicting neural signals produced by the competition between motor commands and the sensory signals that are a direct result of the executed movements.
Specifically, this proposal will test the predictions of a hypothesis that states that a gaze-related command signal issued by the superior colliculus is decomposed by cells in the paramedian pontine reticular formation (PPRF) into separate eye and head control signals, and that eye-head coordination (observed during visual orienting movements) is mediated by the interactions of these signals. The mechanisms for controlling head movements are largely unknown, and this proposal seeks to correlate cell activity with head movements during coordinated eye-head movements, during pursuit of moving targets, and during more natural movements that combine gaze shifts and pursuit movements. This proposal will contribute to understanding how the brain accomplishes the required computations to coordinate more than 40 muscles and muscle groups to produce a smoothly coordinated re-direction of the line of sight.

In addition, this proposal will contribute to the development of courses based on the idea that students' desire to understand general principles will lead to their own investigation of the details, using in-class lectures and small group discussions. Increased numbers of undergraduate, graduate, and postdoctoral students will participate in the laboratory research proposed, both during the academic year and in a summer undergraduate internship program.

Project 1: Producing smoothly coordinated movements during performance of complex behaviors is an essential goal of the nervous system. To accomplish this, sensory information must be integrated continuously in order to construct a representation of objects in the world. This critical function requires the ability to distinguish between self-generated and object motion, to integrate diverse sensory information, and to plan and execute simultaneous motor behaviors. The interactions among neural structures that mediate selection and execution of coordinated movements, and the mechanisms that resolve the inherent conflict between stabilizing reflexes and motor commands are critical issues in understanding the neural control of coordinated action. The neural control of coordinated eye-head movements is an experimental system that has provided significant insights into the neural mechanisms mediating visual orienting behaviors. Directing the line of sight (gaze) towards interesting objects enhances our perception of the object and provides a way to construct and maintain an internal model of the world. These changes in gaze direction are generally accomplished by coordinating the eyes and head, and provide an excellent model system for studying the neural control of orienting behaviors, the coordination of multiple body segments, spatial orientation and transformation of sensory information into motor commands. The goals of the proposed research are to elucidate the neural computations and mechanisms required for coordination within the context of visual orienting movements. The cerebellum has long been implicated in the refinement of motor commands and correction of errors between commanded and executed movements. The brainstem control of eye-head coordination during visual orienting behaviors has been and continues to be a major focus of research in this lab. The experiments proposed here extend this work in order to investigate the role of the cerebellum in modifying and/or correcting the motor commands generated by brainstem regions. The proposed research will test the differential roles of the caudal and rostral portions of the fastigial nucleus in coordinating movements of the eyes and head. Experiments will also test the hypothesis that gaze shift commands generated by activity in the superior colliculus are refined by activity in the caudal fastigial nucleus (cFN). The primary goals of the research in the lab are to understand the neural mechanisms mediating coordinated actions. Disruption of these mechanisms can result from stroke or disease and often have devastating consequences such as spatial disorientation, saccadic dysmetria and/or ataxia. The proposed research will facilitate early detection of disturbances and lead to new treatments of these disorders.

Producing smoothly coordinated movements during performance of complex behaviors is an essential goal of the nervous system. To accomplish this, sensory information must be integrated continuously in order to construct a representation of objects in the world. This critical function requires the ability to distinguish between self-generated and object motion, to integrate diverse sensory information, and to plan and execute simultaneous motor behaviors. The interactions among neural structures that mediate selection and execution of coordinated movements, and the mechanisms that resolve the inherent conflict between stabilizing reflexes and motor commands are critical issues in understanding the neural control of coordinated action. The neural control of coordinated eye-head movements is an experimental system that has provided significant insights into the neural mechanisms mediating visual orienting behaviors. Directing the line of sight (gaze) towards interesting objects enhances our perception of the object and provides a way to construct and maintain an internal model of the world. These changes in gaze direction are generally accomplished by coordinating the eyes and head, and provide an excellent model system for studying the neural control of orienting behaviors, the coordination of multiple body segments, spatial orientation and transformation of sensory information into motor commands. The goals of the proposed research are to elucidate the neural computations and mechanisms required for coordination within the context of visual orienting movements. We will record the activity of neurons in the brainstem during gaze shifts made when the head is free to move. We will determine the relationship between the activity of these cells and the metrics and/or kinematics of the gaze, eye and/or head movements, we will characterize the activity of cells in the nucleus reticularis gigantocellularis and identify their role in generation of head movements, and we will record activity simultaneously from cells in the superior colliculus (SC) and cells downstreamfrom the SC in an effort to reveal the underlying mechanisms that transform SC signals into the commands needed to move the eyes and head. These experiments will provide exciting and novel insight into the ways in which the nervous system converts sensory inputs into coordinated actions.

Advanced Development; Animal Model; Animal Models and Related Studies; Collaborations; Computer Hardware; Contact Lenses; Development; Devices; EXTMR; Engineering; Engineerings; Extramural; Extramural Activities; Eye; Eyeball; Foundations; Human; Human, General; Image; Instrumentation, Other; Investigators; Laboratory Study; Man (Taxonomy); Man, Modern; Measures; Mechanics; Medical center; Movement; Operation; Operative Procedures; Operative Surgical Procedures; Optics; Productivity; Research; Research Personnel; Researchers; Resolution; Retinal; Role; Surgical; Surgical Interventions; Surgical Procedure; System; System, LOINC Axis 4; Technology; Universities; Vision research; adaptive optics; body movement; computer system hardware; design; designing; experience; imaging; improved; innovate; innovation; innovative; instrumentation; interest; model organism; new approaches; new technology; next generation; novel; novel approaches; novel strategies; novel strategy; sensor; social role; surgery; virtual reality; visual control

DESCRIPTION (provided by applicant): Adolescence is a critical neurodevelopmental period associated with dramatic increases in rates of substance use. Identifying the pathways to substance use and its effects on child and adolescent development is critically important, as the effects of substance use during ongoing maturation likely have long-lasting effects on brain functioning and behavioral, health, and psychological outcomes. This Research Project Site application from the University of California, San Diego and Laureate Institute for Brain Research is in response to RFA-DA-15-015 as part of the ABCD-USA Consortium (5/13), to prospectively determine the neurodevelopmental and behavioral predictors and consequences of substance use on children and adolescents. A representative community sample of 1086 9-10 year olds enriched for high- risk characteristics will be recruited, contributing to the sample of 11,111 to be collected from 11 hubs across the ABCD- USA Consortium. All participants will undergo a comprehensive baseline assessment, including state-of-the-art brain imaging, comprehensive neuropsychological testing, bioassays, mobile monitoring and careful assessment of substance use, environment, psychopathological symptoms, and social functioning every 2 years. Interim annual interviews and quarterly web-based assessments will provide refined temporal resolution of behaviors, development, and life events with minimal participant burden. These Consortium-wide data obtained during the course of this project will elucidate: 1) the effects of substance use patterns on the adolescent brain; 2) the effects of substance use on behavioral and health outcomes; 3) the bidirectional relationship between psychopathology and substance use patterns; 4) the effects of individual genetic, behavioral, neurobiological, and environmental differences on risk profiles and substance use outcomes; and 5) the gateway interactions between use of different substances. This hub's Research Project focuses on mechanisms of substance use disorder, special populations with high use prevalence, and the use of drugs other than marijuana. (1) We will determine whether individual differences in neural processing of antireward (i.e., negative reinforcement mechanisms) in amygdala, insula, and anterior cingulate are associated with increased negative emotionality and pain, predict initiation of use and problem use, and are in turn further dysregulated by substance use. (2) We will determine whether protective environment factors and ethnic identification in minority youth are linked to healthier antireward processing and better substance use outcomes. (3) We will determine whether antireward neural processing predicts increased use of illicit drugs other than MJ including misuse of prescription drugs, if such use predicts subsequent exaggerated antireward processing, and if gateway interactions exist between substances. Finally, we will use machine learning approaches to develop a youth-specific risk calculator that will enable us to identify individually- based modifiable risk factor, providing brain-based targets of future novel prevention and intervention approaches.

Abstract Adolescent Brain Cognitive Development (ABCD) is the largest long-term study of brain development and child health in the United States. The ABCD Research Consortium consists of 21 research sites across the country, a Coordinating Center, and a Data Analysis and Informatics Resource Center. In its first five years, under RFA-DA-15-015, ABCD enrolled a diverse sample of 11,878 9-10 year olds from across the consortium, and will track their biological and behavioral development through adolescence into young adulthood. All participants received a comprehensive baseline assessment, including state-of-the-art brain imaging, neuropsychological testing, bioassays, careful assessment of substance use, mental health, physical health, and culture and environment. A similar detailed assessment recurs every 2 years. Interim in-person annual interviews and mid-year telephone or mobile app assessments provide refined temporal resolution of developmental changes and life events that occur over time with minimal burden to participating youth and parents. Intensive efforts are made to keep the vast majority of participants involved with the study through adolescence and beyond, and retention rates thus far are very high. Neuroimaging has expanded our understanding of brain development from childhood into adulthood. Using this and other cutting-edge technologies, ABCD can determine how different kinds of youth experiences (such as sports, school involvement, extracurricular activities, videogames, social media, unhealthy sleep patterns, and vaping) interact with each other and with a child?s changing biology to affect brain development and social, behavioral, academic, health, and other outcomes. Data, securely and privately shared with the scientific community, will enable investigators to: (1) describe individual developmental pathways in terms of neural, cognitive, emotional, and academic functioning, and influencing factors; (2) develop national standards of healthy brain development; (3) investigate the roles and interaction of genes and the environment on development; (4) examine how physical activity, sleep, screen time, sports injuries (including traumatic brain injuries), and other experiences influence brain development; (5) determine and replicate factors that influence mental health from childhood to young adulthood; (6) characterize relationships between mental health and substance use; and (7) specify how use of substances such as cannabis, alcohol, tobacco, and caffeine affects developmental outcomes, and how neural, cognitive, emotional, and environmental factors influence the risk for adolescent substance use.