Effect of Biceps Brachii Muscle Stimulation on Respiration before and after Cervical Spinal Cord Injury.
Cervical spinal cord injuries (SCI) often lead to respiratory impairments, significantly increasing morbidity and mortality in affected individuals. Limb muscle/afferent stimulation has been suggested as a potential approach to enhance breathing when supraspinal control over spinal respiratory circuits is compromised due to cervical SCI. Using a combination of intact, C2 Hemisected (C2Hx), and complete C1 Transected (C1Tx) rat models, we systematically evaluated the influence of forelimb muscle afferent input on phrenic motor output and respiratory patterns. Computational modeling was employed to replicate our experimental data and generate predictions. The developed computational model incorporates bilaterally located spinal and supraspinal respiratory circuits, allowing us to simulate their specific contributions to phrenic motor output under different conditions. In this study, we hypothesize that, in addition to supraspinal control, spinal circuits integrate limb sensory input to modulate the activity of phrenic motor neurons through local excitatory and inhibitory interneurons. These intraspinal pathways, normally suppressed by inhibition, can be recruited during movement to adapt breathing to motor demands. Our experimental and computational modeling results following biceps stimulation after C2Hx and C1Tx support this hypothesis, demonstrating that activation of limb afferent pathways can enhance phrenic motor output even after partial or complete loss of supraspinal drive. In the fully transected preparation, this effect required pharmacological disinhibition, confirming the presence of latent spinal pathways. This study provides the first evidence for functionally relevant intraspinal interactions between limb muscles and respiratory circuits and identifies a potential spinal mechanism that could be leveraged to promote breathing recovery after cervical SCI. Key PointsO_LIBiceps brachii electrical stimulation can increase breathing frequency and tidal volume in spontaneously breathing rats and variably induce transient increases or entrainment of phrenic nerve activity in intact rats under controlled ventilation. C_LIO_LIBiceps stimulation enhances ipsilateral phrenic activity in acute C2 hemisected (C2Hx) rats. C_LIO_LIBiceps stimulation drives bilateral phrenic output in C1 transected (C1Tx) rats under conditions of pharmacologically induced spinal disinhibition. C_LIO_LIA computational model incorporating bilateral brainstem and cervical spinal respiratory circuits is developed to simulate cervical spinal cord injuries (C2Hx and C1Tx) and to examine how biceps stimulation affects respiratory activity under different conditions. C_LIO_LIThese findings demonstrate a critical role for spinal circuits in locomotor-respiratory interactions. C_LI