Ventilatory arrhythmia plays a pathogenic role in many common respiratory disorders ranging from sleep apnea, and acute lung injury to ventilatory support in the setting of chronic lung disease. Brainstem neural circuits that control cardiopulmonary functions generate oscillatory patterns that drive respiratory as well as sympathetic motor activities. These patterns exhibit highly structured variability and patients with various chronic diseases exhibit aberrations of these patterns and their variabilities. Analytic tools for quantifying ventilatory arrhythmia and for stratification of severity or prognosis are unavailable, representing a major barrier to defining its pathogenic contribution to disease, or to developing novel non-invasive or therapeutic markers. The long-term objectives of this exploratory project are these targets by determining the neurophysiologic mechanisms for ventilatory arrhythmia, specifically the physiological balance between central (pontomedullary) and afferent (pulmonary and baro) feedback mechanisms in the control of respiratory phase switching and pattern stabilization. The applicants hypothesize that alterations in this balance are evident in the pathology of the pulmonary conditions, but lie dormant due to lack of quantitative understanding of the dynamic properties of the respiratory control system. This hypothesis will be tested by analyzing breathing patterns in: 1) a mouse model of Rett syndrome, in which ventilatory arrhythmia originates primarily from central deficits and 2) in humans with lung disease and a rat model of lung injury, in which ventilatory arrhythmia originates primarily from altered afferent feedback. The central aim is to develop analytical methods that incorporate new characteristics of breathing pattern variability, and a computational model that accurately predicts respiratory rhythm variability resulting from internal (e.g. network modulation of feedback gain, neuromodulator interactions etc.) and external factors (peripheral chemoreceptor function, lung mechanics). An interdisciplinary research team that includes four experienced groups at different Universities will collaborate closely to perform this project.
The specific aims are: 1) to expand a computational model of the brainstem respiratory network to include not only the ponto-medullary circuits but pulmonary and baro-feedback and their interactions (Rybak); 2) to test novel tools permitting the identification of disturbed breathing patterns (Loparo/Wilson); 3) to elucidate the cellular mechanisms involved in reciprocal ponto-vagal interactions by synaptic inputs to pontine and medullary respiratory neurons elicited by vagal afferent activation, including an influence of brain derived neurotrophic factor on the balance of pontine-vagal control of phase duration (Dutschmann); 4) to determine how the network interactions are altered by activation of vagal or dorsolateral pontine neurons in normal and disease states (Dick/Jacono); and 5) to describe the relative role of heritable vagal mechanisms in generating breathing pattern variability in adult twins; and the impact of ventilatory coupling to cardiac activation (cardioventilatory coupling) on breathing variability in twins and patients with lung disease (Strohl/ Jacono). The quantitative tools and insights created from this unique collaboration will permit insight into new diagnostic, prognostic and therapeutic avenues to promote stable breathing and improve patient outcomes in acute and chronic lung injury. (End of Abstract) ? ? ?
| Dhingra, Rishi R; Zhu, Yenan; Jacono, Frank J et al. (2013) Decreased Hering-Breuer input-output entrainment in a mouse model of Rett syndrome. Front Neural Circuits 7:42 |
| Smith, Jeffrey C; Abdala, Ana P L; Borgmann, Anke et al. (2013) Brainstem respiratory networks: building blocks and microcircuits. Trends Neurosci 36:152-62 |
| Jasinski, Patrick E; Molkov, Yaroslav I; Shevtsova, Natalia A et al. (2013) Sodium and calcium mechanisms of rhythmic bursting in excitatory neural networks of the pre-Bötzinger complex: a computational modelling study. Eur J Neurosci 37:212-30 |
| Chung, Augustine; Fishman, Mikkel; Dasenbrook, Elliott C et al. (2013) Isoflurane and ketamine anesthesia have different effects on ventilatory pattern variability in rats. Respir Physiol Neurobiol 185:659-64 |
| Molkov, Yaroslav I; Bacak, Bartholomew J; Dick, Thomas E et al. (2013) Control of breathing by interacting pontine and pulmonary feedback loops. Front Neural Circuits 7:16 |
| Namas, Rami; Zamora, Ruben; Namas, Rajaie et al. (2012) Sepsis: Something old, something new, and a systems view. J Crit Care 27:314.e1-11 |
| Dick, Thomas E; Molkov, Yaroslav I; Nieman, Gary et al. (2012) Linking Inflammation, Cardiorespiratory Variability, and Neural Control in Acute Inflammation via Computational Modeling. Front Physiol 3:222 |
| Friedman, Lee; Dick, Thomas E; Jacono, Frank J et al. (2012) Cardio-ventilatory coupling in young healthy resting subjects. J Appl Physiol (1985) 112:1248-57 |
| Lindsey, Bruce G; Rybak, Ilya A; Smith, Jeffrey C (2012) Computational models and emergent properties of respiratory neural networks. Compr Physiol 2:1619-70 |
| Shevtsova, Natalia A; Manzke, Till; Molkov, Yaroslav I et al. (2011) Computational modelling of 5-HT receptor-mediated reorganization of the brainstem respiratory network. Eur J Neurosci 34:1276-91 |
Showing the most recent 10 out of 18 publications
