Swallow-breathing coordination in Humans. Challenging cough and swallow to occur simultaneously resulted in unchanged swallow pattern with alternations in cough patterns. An increase in respiratory drive during ascent to high altitude did not alter swallow behavior regardless of the alterations in breathing patterning, giving insight into the stability of swallow behavior. Our work in the human identified a number of different strategies to reach a certain lung volume termed volume targeting. Humans will use any strategy to reach the targeted lung volume before swallowing. These studies concluded, regardless of increased respiratory drive or challenging the system with simultaneous behaviors, swallow is restricted to a narrow range of lung volume. We believe humans are using enhanced pulmonary feedback to maintain cough-swallow-breathing coordination. These studies shed light on 1) the stability of swallow and 2) phase preference versus volume targeting.
- Huff A, Reed MD, Smith BK, Brown EH, Ovechkin AV & Pitts T. (2018) Strategies for the Integration of Cough and Swallow to Maintain Airway Protection in Humans. Lung: 196 (5), 601-608.
- Huff A, Day TA, English M, Reed MD, Zouboules S, Saran G, Leacy JK, Mann C, Peltonen JD, O’Halloran KD (2018) Swallow-breathing coordination during incremental ascent to altitude. Respiratory Physiology & Neurobiology: 625:121-126.
Both vagal and pulmonary spinal afferent feedback are necessary for swallow pattern maintenance. Swallow, and its coordination with breathing is dependent on a balance of both vagal (e.g. pulmonary stretch receptors within the lungs), and spinal (e.g. proprioceptive stretch receptors near the lungs) afferent feedback. These studies are important for characterizing the controversial postinspiratory/expiratory phases of breathing. We introduced the concept of “yield” component of breathing, which marks the remnant diaphragm activity during postinspiration (early expiration). We hypothesized that yield acts to cushion forces from the chest wall on the lungs aiding in mechanical expiratory braking. We found, there is tonic vagal inhibition on the yield phase, while this phase is spinally mediated, and a balance of vagal and spinal afferent feedback is necessary to maintain this phase of breathing. These studies also shed light on sex-related differences: male rodents rely on lung volume feedback via vagal pulmonary stretch receptors. Whereas female rodents rely more on volume feedback via spinal, chest wall proprioceptive feedback suggesting the importance of separate evaluation of males and females.
- Huff A, Reed MD, Iceman KE, Howland DR, Pitts T. (2020) Sex-Specific Vagal and Spinal Modulation of Breathing with Chest Compression. PlosOne 15(6).
- Huff A, Reed MD, Iceman KE, Howland DR, Pitts T. (2020) Sex-Specific Vagal and Spinal Modulation of Swallow and Its Coordination with Breathing. PlosOne 15(6).
Sagittal section rat hindbrain in-vitro preparation evaluates swallow at the central network level. This is a novel technique that allowed real time optical recording of the central coordination of swallow and breathing using calcium imaging, while simultaneously using electrophysiology to record from the hypoglossal and cervical nerve rootlets. This preparation established for the first time 1) swallow can be centrally stimulated using electrical stimulation in the slice preparation and 2) novel locations of swallow related neuron populations that are involved in both swallow and breathing.
- Pitts T, * Huff A, * Reed M., Iceman KE, & Mellen N. (2021). Evidence of intermediate reticular formation involvement in swallow pattern generation, recorded optically in the neonate rat sagittally sectioned hindbrain. Journal of Neurophysiology, 125(4), 993-1005
Develop an in-vivo mouse model with access to the ventral brainstem recording swallow and breathing related muscles and nerves. The use of optogenetics led to manipulation of cell-type specific preBötzinger complex neurons, identifying novel roles of the preBötzinger complex in swallow production and coordination with breathing. This study revealed 1) the inspiratory rhythm generator does not inhibit the swallow pattern generator, making it possible for swallows to occur during inspiration and 2) established a clinically relevant obstructive sleep apnea (OSA) dysphagia model implicating disruption of the preBötzinger complex as a mechanism for dysphagia in OSA patients. Additionally, use of the optogenetic model led to manipulation of cell-type specific postinspiratory (PiCo) neurons, identifying PiCo as 1) a hub for swallow and laryngeal behaviors and 2) important for coordinating swallow and breathing in a healthy and OSA mouse model.
- Huff, A, Karlen-Amarante M, Oliveira L. M., & Ramirez J. M. (2024). Chronic Intermittent Hypoxia reveals role of the Postinspiratory Complex in the mediation of normal swallow production. Elife, 12, RP92175.
- Huff A, Karlen-Amarante M, Oliveira LM, Ramirez JM. (2023) Role of the Postinspiratory Complex in regulating swallow-breathing coordination and other laryngeal behaviors. Elife, 12, e86103.
- Huff A, Karlen-Amarante M, Pitts T, Ramirez JM. (2022) Optogenetic stimulation of preBotzinger complex reveals novel circuit interactions in swallow-breathing coordination. Proceedings of the National Academy of Sciences, 119(29), e2121095119
Develop a preclinical model of Leigh Syndrome (LS) that assess swallow and breathing. Symptoms of this neurometabolic disorder first appear as difficulties in feeding and airway protection, causing a failure to thrive and recurrent cases of aspiration pneumonia before 1 year of age. Mice with the NDUFS4 gene knocked out in all Vglut2 cells have 1) discoordination of swallow and breathing as well as the inability of the respiratory rhythm to recover following swallow. 2) LS mice also have abnormal and increased variability in swallow motor patterns. 3) Changes in breathing patterns, increased number of apnea and breath-holds. 4) Placement of these mice in 11% oxygen (Chronic Hypoxia) for 6 months prevented swallow-breathing discoordination, variable swallow motor patterns, apneas, disease onset, premature death, and any accompanying symptoms.
- Huff A, Oliveira L, Karlen-Amarante M, Ebiala F, Ramirez JM, Kalume F. (2025) Ndufs4 inactivation in glutamatergic neurons reveals swallow-breathing discoordination in a mouse model of Leigh syndrome. Experimental Neurology, 385, 115123.