R01NS124767

Effects of Ventricular Volume and Cerebral Connectivity on Neurological Outcomes in Preterm Intraventricular Hemorrhage - Project Summary

Despite advances in neonatal and neurosurgical care, post-hemorrhagic hydrocephalus remains among the most frequent, severe neurological complications of very preterm birth (gestational age at birth = 32 weeks) and now represents the most common cause of pediatric hydrocephalus in North America. It also carries a heavy neurodevelopmental toll, with cognitive deficits and/or cerebral palsy diagnosed in greater than 75% of affected children.

After the failure of medical approaches to impact its neurological sequelae, recent research has centered on optimizing neurosurgical treatment of post-hemorrhagic hydrocephalus, with a focus on mitigating ongoing injury due to progressive ventricular distension, a long-recognized risk factor for poor outcomes.

The objectives of this proposal are to define the pathophysiological effects of post-hemorrhagic hydrocephalus on cerebral connectivity and neurological outcomes and, more specifically, to determine how ventricular volume modifies these relationships. Our central hypotheses are that 1) impaired structural and functional connectivity across key white matter tracts (e.g., corticospinal tracts, optic radiations, corpus callosum) and related functional networks (e.g., somatomotor, visual, default mode networks) are associated with neurological disability in post-hemorrhagic hydrocephalus, 2) ventricular distension contributes to post-hemorrhagic hydrocephalus-related connectivity deficits, and 3) these alterations in connectivity improve with neurosurgical ventricular decompression.

Recent advances in MRI now enable characterization of functional and structural connectivity in the developing brain with unparalleled spatial and temporal resolution. Analysis of these data using the highly innovative diffusion basis spectrum imaging approach affords unique capabilities to characterize the complex neuropathological changes underlying these differences in cerebral connectivity.

Here, our multidisciplinary team will employ these state-of-the-art MRI techniques in combination with detailed neurodevelopmental assessments to study a large cohort (N=180) that includes very preterm infants with and without post-hemorrhagic hydrocephalus prospectively recruited and followed longitudinally after discharge from the neonatal intensive care unit.

In addition, infants with post-hemorrhagic hydrocephalus will undergo neuroimaging studies both before and after cerebrospinal fluid shunt surgery, characterizing the reversible effects on cerebral connectivity while also defining the role of ventricle size in its pathology.

Application of these cutting-edge MRI acquisition and analysis approaches enables unprecedented characterization of the effects of post-hemorrhagic hydrocephalus on the developing brain. Further, we will extend these methods to delineate relationships between imaging measures and neurodevelopmental outcomes, improving our understanding of the modifiable effects of this devastating disease.

Critically, these results will address long-standing, clinically important questions related to the care of infants with post-hemorrhagic hydrocephalus and inform the development of innovative assessment tools to support clinical trials seeking to thwart the developmental disability observed in this high-risk population.

Washington University

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Missouri United States

State-Wide

Disease Mechanisms of Prenatal and Pediatric Hydrocephalus (R01 Clinical Trial Not Allowed) (PA-18-622)

Amendment Since initial award the total obligations have increased 370% from $642,072 to $3,019,472.