Rebecca German - US grants

Although the behavior of the oral apparatus during feeding is well known for several mammals, there is no precise quantitative representation of the observed movements of jaws, hyoid and tongue, or the activity of their associated muscles. This research will develop a model to explain statistically the variation in movement, activity, and coordination among the elements of the orofacial complex during normal feeding behavior. This model will also be used to investigate variation in feeding activity with respect to food type and consistency, as well as differences among species of mammals, particularily differences between higher primates and those other mammals studied to date. Documentation of the coordinated movements in the three musculo-skeletal systems for several species will support the hypothesis that mastication in mammals, including man, is controlled by a central pattern generator. Variation in the coordination due to anatomical differences in mammals versus primates, and the response of each system to changes in input, such as food consistency, can suggest the nature and possibly the extent of such a pattern generator. By providing new insight into the regulation of mastication in man, this work will enhance our understanding of dysphagia and other regulatory disturbances of human feeding behavior.

If an infant cannot suckle it will not survive, save through extraordinary medical intervention. Primate studies to date have, by and large of necessity, been behavioral. Therefore little information exists on the mechanisms by which infants suckle or juveniles drink. Nor is it known how the vital transition from suckling to drinking and mastication occurs during normal development. Suckling mechanisms, in terms of movements of the tongue, jaws and hyoid, and patterns of muscle activity, are understood for a few nonprimate mammals. These mammals, however, are sufficiently different from primates in anatomy and adult function that the information is of little value in understanding problems of primate suckling and swallowing. If the basic questions "how do infants suckle and swallow?" and "how do juvenile drinking and mastication replace suckling?" are to be answered, there is no alternative but to conduct a well designed series of experiments on a viable and acceptable human analog. Experimental manipulation of laboratory primates is essential because a complete model of oral function must include data not readily available form information collected in a clinical situation. This study proposes a carefully controlled cineradiologic and electromyographic investigation of infant oral function in macaques as the basis for a model of normal human behavior. Data collected on the movements of tongue, hyoid and jaws, changes in shape of the tongue, and activity of craniomandibular muscles will be the basis of a biomechanical model of oral function. By quantifying how tongue movements and muscle activity change as a function of normal ontogeny, we will discover how an infant acquires, transports and swallows liquid, as well as how these functions change during growth. These experiments will provide the qualitative and quantitative data needed on nonimpaired function to facilitate future interpretations of clinical data on neonatal infants with dysfunctional oropharyngeal behavior.

Although normal infants can successfully suckle at birth, the difficulties low birthweight infants experience have implications for both adequate nutrition and the subsequent transition to ingestion of solid food. Most clinical studies to date have, of necessity, been behavioral. Therefore little information exists on the mechanisms by which low birthweight infants suckle or juveniles drink. Nor is it known what role reflex maturation plays in the vital transition from suckling to drinking and mastication during the development and growth of low birthweight infants in oralpharyngeal kinematics and craniomandibular motor patterns?", is to be answered, there is no alternative but to conduct a well designed series of experiments on a viable and acceptable human analog. Of all mammals whose adult feeding and drinking patterns resemble humans, (i.e., the use of negative pressure as opposed to lapping mechanisms), only infant miniature pigs ate readily available, inexpensive, and can be managed to produce low birthweight infants in sufficient quantity for experimental studies. We are proposing to investigate the development of the feeding mechanisms in term and low birthweight (pre-term) infants in miniature pigs as an animal model of human function. Techniques of cineradiography with synchronized electromyography will be used to determine the patterns of kinematics and muscle control of elements of the craniofacial apparatus relevant to infant feeding and weaning in both term controls and low birthweight infants of different gestational ages. The project will also include an investigation of the coordination of respiration associated with feeding in both term and preterm infants. The time course of oral reflex maturation, the impact of premature birth on oral reflexes, and the correlation between weaning and reflex development will be additional facets of this project. Finally, we well quantitatively compare the ontogenetic allometry and development of musculoskeletal morphology in term and low birth weight infants. The ultimate objective of this study is to develop an animal model that can be used to address problems of feeding, as well as of coordination of feeding and respiration, that arise in low birthweight human infants.

With the general goals of better understanding the ecological and evolutionary consequences of behavioral, anatomical, developmental, and physiological variation, we will use the capacity to adequately record and analyze animal motion for the study of a wide variety of behaviors and functions in vertebrates and invertebrates. By studying different individuals within a single species and different species, motion analysis will be used to define, quantify and compare different behaviors (movements) and determine the relative effectiveness of animals performing tasks such as sprinting locomotion, feeling, and communicating with potential mates. Simultaneous records of motion and muscle activity, will be used to examine the neural control of animal movements and its evolutionary interrelationships with anatomical variation. Playback experiments using video images modified with animation techniques will be used to asses the relative importance of different movements versus anatomy in the species recognition and mating behaviors.

DESCRIPTION (provided by applicant): Swallowing requires the coordination of a large number of muscles; this complexity arises partly from the need for airway protection. In the previous funding period, we added to the understanding of muscle activity and oropharyngeal kinematics in infant deglutition. However, the role of the majority of muscles during emptying of the valleculae and in the transport of the bolus past the laryngeal opening or the natural stimuli that initiate the emptying of the valleculae over maturation is not well understood. Our preliminary data suggest that two distinct pathways of bolus movement exist, either around the epiglottis/laryngeal opening (in the newborn) or over it (by the age of weaning). However the timing of the transition, from one path to the other and the associated changes in the kinematics or motor patterns, are unknown. The decerebrate pig is an excellent model for studying vallecular emptying because this phase of the swallow can be isolated experimentally. We propose to apply our existing techniques both to this model and to intact animals, in order to answer the following questions. What natural stimuli initiate vallecular emptying, and do they change during maturation? What is the pattern of muscle activity during vallecular emptying in terms of the order and amplitude of muscle activation? Does change in the consistency of the bolus alter the motor pattern during vallecular emptying, and does this change over developmental time? Does epiglottal movement result from: (i) direct muscle contraction; (ii) indirect movement of the rest of the larynx, (iii) the mechanical action of food on the epiglottis, or a combination of all three? Current studies of human dysphagia and rehabilitation rely heavily on several older studies of oral function in adult man and animal; these studies did not have the means to examine the ontogeny of vallecular function in detail. The proposed study of the maturation of motor patterns will provide an important baseline for treatment strategies aimed at human infant dysphagia.

[unreadable] DESCRIPTION (provided by applicant): Parkinson's Disease occurs with high incidence in the elderly (Kondziolka et al., 1999; Shulz and Grant, 2000). Dysphagia, abnormal swallowing, is a significant component of Parkinson's disease (Basset, 1999; Bushman et al., 1989; Nagaya et al., 1998; Logemann, 1998; Potulska et al., 1999), impacting on nutrition, quality of life, and most significantly, airway protection. Given the inevitable restrictions on the acquisition of human dysfunction data, there are limited data on the quantitative kinematics of swallowing in patients with Parkinson's Disease (e.g. Wintzen et al., 1994). Synchronous electromyographic data from the muscles critical for normal deglutition, while essential for characterizing the motor patterns, and ultimately the neural control of swallowing, are virtually impossible to collect from either normal or Parkinsonian human subjects. Over the last 20 years, our research group has developed extensive expertise in analyzing the kinematics and motor pattern of oral and pharyngeal function in animal models with the ultimate goal of a better understanding of human dysfunction. The recent development of a chemically induced model of Parkinson's Disease in pigs presents an obvious opportunity for us to bring our methods and experience to bear on the feeding problems associated with this disease entity. The aim of this study is to collect preliminary data, in the pig model of Parkinson's Disease, to establish the extent of dysfunction in the different phases of swallowing by comparing them with our extensive control data on normal function. We will use our proven techniques of synchronized videoradiography and electromyography to establish the utility of this model. Our ultimate goal is to use these data for the development of an R01 proposal aimed at the systematic characterization of the Parkinsonian disruption of normal oral and pharyngeal swallowing function. [unreadable] [unreadable]

This award was made to transform the current prototype of the Feeding Experiments End-user Database (FEED) into a data-rich, publicly-available source of physiological data on feeding in mammals that incorporates a novel ontology module. An important innovation is the development of five non-overlapping ontologies related to feeding behavior, function, and structure that will provide the constrained definitions of terms necessary to permit computational comparisons in analyses of phenotypic diversity. Ontology construction begins with an ontology workshop. Ontology and database development will be driven by a set of six use cases that comprise synthetic, phylogenetically-informed analyses aimed at understanding the integrated roles of physiology and morphology during a variety of feeding behaviors in mammals. The research will to initiate new collaborations involving FEED as a primary data source by engaging three scientific communities (reptile feeding physiologists, bioengineers, and developmental biologists) in a series of interdisciplinary use case development workshops. During the workshops, the project team will design and commence work on new use cases that will guide efforts to extend the infrastructure of FEED and permit synthetic studies that cut across traditional knowledge domains. This project is innovative because it generates a proof-of-concept database to facilitate understanding of the complexity and connectivity between behaviors, physiological mechanisms, and structures involved in mammalian feeding across multiple scales of organization, and because it includes work to insure that FEED is a tool that is extensible to other scientific communities.

Broader impacts include development and public release of novel bioinformatic research infrastructure for physiology, a field that has traditionally been on the periphery of bioinformatics. This project promotes interdisciplinary collaborations among scientists across four knowledge domains. Training of undergraduate and graduate students in research on morphological and physiological analysis as well as database and ontology construction is an important focus. FEED will also be utilized as a teaching tool in bioinformatics courses aimed at undergraduate and graduate education in informatics. Dissemination of project outcomes and public access to the FEED database will be available at www.feedexp.org.

The physiology of mammalian feeding has proven to be a fertile ground for research amongst experimental biologists. Over the last 40 years, researchers have been particularly interested in understanding the physiology and functional anatomy of two behaviors that distinguish mammals from other vertebrates: suckling and chewing. In this symposium, experts on mammalian feeding physiology will highlight a newly developed database, the Feeding Experiments End-User Database (F.E.E.D.), through presentations of comparative and functional analysis of suckling and chewing between and within the major groups of mammals. Some of the presentations will also highlight the major gaps in our understanding of mammalian feeding physiology, with an eye toward generating new research avenues and approaches in the field. F.E.E.D. was developed as a means of storing and sharing physiological data to promote collaborations across labs and support meta-analysis of mammalian feeding physiology. Presentations in the symposium will include data that will be made available in F.E.E.D. from the major research labs around the world. As access to the database will ultimately be made available to other researchers and the general public, a major goal of the symposium is to promote the use of F.E.E.D. We will also solicit feedback on database functionality and the potential for expansion to include other vertebrate groups. Additional broader impacts of this work include training of graduate students and post-doctoral associates, some of which are co-authors on talks or presenters in the symposium.

Coordination among the functional components of the aerodigestive system, particularly between swallowing and respiration, is critical for successful airway protection in infants. Disruption of this coordination can produce failure of airway protection, manifest as pulmonary aspiration. Preterm birth is one cause of this disruption and subsequent aspiration. These problems may be compounded with damage to the recurrent laryngeal nerve (RLN) resulting from cardiovascular repairs necessitated by prematurity. Because the current understanding of the pathologies in these fragile patients is based largely on non-invasive technologies, the causal relationship between disordered coordination and airway protection, including how development impacts this system, is unknown. In particular, we do not know the biomechanical alterations that cause aspiration nor what, if any, longitudinal changes occur in biomechanics that may promote airway protection. We propose to investigate the longitudinal course of maturation of airway protection in preterm/term infants, with and without RLN damage. The use of a validated preterm animal model will permit the collection of detailed data, using invasive methods, including high-speed, biplanar videofluoroscopy, that are not appropriate for human patients. The work proposed here will determine how preterm birth effects the sensorimotor interactions that underlie successful airway protection as well as how RLN damage impacts those interactions through three specific aims: (SA1) Determine the longitudinal development of coordination between respiration and swallowing in control infant pigs born at term from birth through weaning; (SA2) Determine the longitudinal development of the coordination between respiration and swallowing after preterm birth using pigs delivered at the equivalent of human gestational age of 30-32 weeks; (SA3) Determine the interaction between the maturation of airway protection and RLN injury in both (SA3a) control term infants and (SA3b) preterm infants. By working with a proven and validated animal model of translational importance, the study proposed here will provide data on the underlying normal and pathophysiologic mechanisms that cause failure of airway protection in preterm infants. These data, collected longitudinally and in sufficient quantity to assess within individual variation and ontogenetic changes within individuals, will provide insight not possible from human patients. Such data will change our understanding of the potential for recovery and treatment recommendations. Furthermore these data can be the basis for designing intervention strategies based on understanding of the mechanisms underlying the pathophysiology.

Sucking, swallowing, and their coordination with breathing, are often compromised in preterm infants, yet are critical to their long-term health outcomes. Current work suggests that external oral sensory stimuli induce rhythmic sucking, and that such stimuli hold potential as rehabilitation strategies. However, our understanding of the impact of these interventions on aerodigestive function is limited because human preterm infants are a fragile research population, with restrictions on experimental manipulations. We also do not know the role that the degree of prematurity and the subsequent neurological maturation of the preterm infant brain plays in determining the effectiveness of oral stimulation in facilitating feeding. Thus, the translation of these promising results into effective interventions for promoting sustained oral feeding in preterm infants is inadequate. Using an animal model of preterm infants, we propose to test how nutritive stimulation, in the form of rhythmic milk delivery, functions as an intervention for improving aerodigestive function. We will test two factors that may determine the success of this intervention: the duration of intervention and degree of prematurity. We will apply the intervention for either a short term (early infancy) or for a longer term (entire infancy prior to weaning). Within each treatment duration, there will be two independent age groups, defined by respiratory status at birth: (1) capable of independent respiration or (2) requiring bubble CPAP ventilation support. We will compare these infants to bottle fed individuals who receive only non-nutritive stimulation and to individuals who are only bottle fed. We have proven and validated this model for studying aerodigestive function in preterm infants, as well as the interventions proposed. The experimental methods will include high-speed biplanar videoflurography, electromyography and respiration, from which we will extract outcome variables assessing airway protection, rhythmicity of respiration, sucking and swallowing, and coordination amongst these behaviors. The significance of this work is the determination of how, and at what age, oral stimuli change the function and the underlying physiology of preterm infant feeding- respiration coordination. By testing the relationship between infant neuromotor maturation and the effectiveness of stimulation-based treatment, this work will provide a basis for the subsequent development of new therapeutic interventions for neurological and physiological complications which affect feeding in all infants.