David Paydarfar - US grants

Breathing is regulated by a central neural oscillator that produces rhythmic output to the respiratory muscles. Pathological disturbances in rhythm, or dysrhythmias, are observed in the breathing pattern of children and adults with neurological or cardiopulmonary diseases. The mechanisms responsible for genesis of respiratory dysrhythmias are poorly understood. The present studies take a novel approach to this problem. The basic postulate is that the rhythm of the respiratory oscillator can be altered by a variety of stimuli. When the oscillator recovers its rhythm after such perturbations, its phase may be reset relative to the original rhythm. The amount of phase resetting is dependent upon stimulus parameters and the level of respiratory drive. The long-range hypothesis of this proposal is that respiratory dysrhythmias can be induced by stimuli that impinge upon or arise within the respiratory oscillator at a specific time in the respiratory cycle, the phase of vulnerability. Animal studies are performed in anesthetized or decerebrate preparations. Neural respiratory rhythmicity is represented by phrenic nerve activity, allowing use of open-loop experimental conditions which avoid negative chemical feedback associated with changes in ventilation. Human studies are performed in awake healthy subjects to study effects of swallowing on respiratory rhythm. Specific aims are to study: 1) the vulnerability of the respiratory oscillator to develop apneusis at low chemical drive and in response to discrete neural stimuli, and to test the hypothesis apneusis represents the respiratory oscillator's phase singularity, 2) the influence of neural maturation on phase resetting and dysrhythmias of the respiratory oscillator, and to evaluate the hypothesis that the less mature respiratory oscillator of the newborn kitten develops dysrhythmias in response to certain perturbations more readily than the mature oscillator of the adult cat, 3) the role of respiratory phase resetting in protecting the airway from aspiration during deglutition, and to determine if increasing respiratory drive by inhalation of carbon dioxide increases the vulnerability to aspirate because of discoordination of the timing of breathing and swallowing. These studies should lead to greater understanding of rhythmicity and integrative responses of the respiratory control system, and provide insight into disturbances in control mechanism that cause apnea and aspiration in clinical disease states.

DESCRIPTION (provided by applicant): The long-term objective of our research is to better understand the neural control of swallowing and airway protection, to analyze the mechanisms of neurogenic dysphagia and aspiration in a controlled and systematic way, and to develop novel therapies based on pathogenesis. Our specific thesis is that laryngeal afferent feedback during swallowing facilitates the swallowing pattern generator's output to laryngeal and pharyngeal muscles. The internal branch of the superior laryngeal nerve (ISLN) is the principal sensory nerve of the larynx in humans. We propose to study how the ISLN regulates swallowing using nerve blocking and stimulating techniques in healthy subjects. Then, we plan to use what we learn about the ISLN to devise a method for improving glottic closure and pharyngeal contraction during swallowing in patients with dysphagia and aspiration due to cerebral lesions. Specific aims are: 1) To determine the physiological mechanism of aspiration in healthy subjects with ISLN blockade. Our preliminary studies show that the bolus usually penetrates the laryngeal inlet during the pharyngeal phase of swallowing. We will use electromygraphic, fluoroscopic and manometric techniques to analyze whether laryngeal penetration is due to reduced activation of laryngeal adductors, excessive intrapharyngeal pressure, or excessive inspiratory effort. 2) To test for extrafusal motor fibers in the ISLN. We will test the widely held view that the ISLN functions purely as an afferent by applying supramaximal current pulses to the isolated ISLN in patients undergoing laryngeal surgery. The presence of efferent fibers would be supported by a short latency (<5msec) laryngeal or pharyngeal motor response that is abolished following ISLN transection. 3) To optimize the activation of laryngeal adductors and pharyngeal constrictors evoked by ISLN stimulation. In awake healthy subjects with blocked ISLNs, we will attempt to reverse dysphagia and aspiration by electrically stimulating the ISLN central to the block, and the optimum stimuli that potentiate swallowing without causing discomfort will be determined. 4) To test the feasibility of ISLN stimulation for treatment of neurogenic dysphagia and aspiration in patients with cerebral lesions. We will stimulate the ISLN (using optimum parameters from Aim 3) in patients with neurogenic dysphagia caused by focal cerebral damage, and we will test for improvement in swallowing and decrease in aspiration.

In the United States, one in eight infants is born prematurely. These high risk infants require specialized monitoring of their physiology not only in Neonatal Intensive Care Units (NICU) but also in home environments. They are prone to apnea (pause in breathing), bradycardia (slowness of heart) and hypoxia (oxygen de-saturation), which are life threatening. This project aims at developing a biosensor system with wireless network for the remote detection and anticipation of such life threatening events in infants. The proposed research goes beyond traditional health monitoring systems by incorporating body sensor networks (BSN) along with advanced signal processing approaches, tailored specifically to an individual infant's physiology, to accurately detect and anticipate precursors of life threatening events. The proposed research can have a significant impact on non-intrusive ambulatory health monitoring for infants through a wireless biosensor system that integrates lightweight sensor solutions into the sensing, communication, and computing for monitoring physiology. The system framework, theories, models, and code developed by this project can be used by researchers as well as engineers to evaluate the performance of infant monitoring applications. The project also includes: (1) disseminating the project information and knowledge to the academic community and industry; (2) engaging undergraduate, graduate and medical students, especially women and minorities, into the proposed research; and (3) developing new courses and revising the existing courses.

The current physiological monitoring systems used in NICU consist of relatively large sensors attached to the infants, which are then connected to a data acquisition system with multiple wires. These sensors along with the wires are a hindrance to the clinical care. In addition, the existing system cannot be used for home environments because of the size and cost. While there is an abundance of physiological signals streaming across NICU monitoring systems, it is challenging for clinicians caring for preterm infants to determine pathological states, as there is no method available to translate these signals into validated indices to define pathology. The primary objective of this proposed research is to explore whether a dedicated compact device with wearable biosensors along with wireless networks can be built for the detection and anticipation of life threatening events in infants in both NICU and home environments. The secondary objective is to explore whether computational tools that provide real-time indices of cardio-respiratory risk can be developed to assist clinicians for neonatal care. Specifically, the project is to develop a comprehensive system, involving four important components: (1) development of miniature biosensors that can be attached to infants who are very small and vulnerable; (2) development of wireless devices with efficient communication protocols that can transmit the physiological signals from the biosensors; (3) development of efficient signal processing algorithms that can extract useful information from the biosensor data for risk stratification and anticipation of life threatening events (data to knowledge to decisions) and (4) testing and validation of the systems in real life environment at NICU. The proposed approaches in the project can eventually lead to a medical device for the remote detection of life threatening events in infants and also provide guidelines for the design of wearable wireless biosensor systems for healthcare monitoring applications in general.

Each year in the United States, one in ten live births or roughly 380,000 babies are born prematurely, with a mortality of 27%. Nearly one third of those surviving suffer from lifelong neurological conditions including cerebral palsy, autism, and psychiatric disorders with substantial personal and societal costs. Despite advances in neonatal intensive care, little progress has been made in monitoring maturation of neurological function in preterm infants. This proposal addresses an urgent need for continuous monitoring of neurological function in the neonatal intensive care unit to advance our understanding of normal and abnormal neurological maturation and to develop timely clinical interventions to improve the health outcomes and reduce costs of prematurity.

The research program aims to show that bodily movements of infants are a vital marker for the functional integrity of the nervous system. In Objective 1 the team will quantify movement bouts in routinely obtained data sets over ~3 months, from birth (<29 weeks gestational age) until discharge from the neonatal intensive care unit (NICU). Pursuing the hypothesis that complexity of movement patterns increases with age as a sign of maturation, they will examine the evolving entropy of movement signals over several months. Objective 2 will quantify the strong physiological interactions of movement bouts with the respiratory and cardiac rhythms, and correlate movement to apneic events and cardiorespiratory instability. Objective 3 seeks to develop machine learning algorithms using features of movement and other physiological events for online prediction of apneic episodes. In return, the algorithms will reveal physiological features and mechanisms that enhance clinical insights. Preliminary data promise results that support our thesis that movement in newborn infants is an important vital sign. Taken together, this quantitative approach will advance understanding maturation of the neonatal nervous system and how movement can stabilize or disrupt cardiorespiratory control in neonates. The team has also identified multiple outreach activities to foster the integration of scientific research, technology and STEM education, including a workshop on Movement Science, Data, and Technology, in collaboration with a minority-serving institution to increase minority representation in the movement, data, and computational sciences.

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.