Activation of Central Pattern Generator for Respiration Following Complete High Cervical Spinal Cord Interruption
Abstract
Cervical spinal cord injury (SCI) results in a vast range of motor and sensory deficits among which impaired breathing is one of the most devastating. The respiratory system includes central (spinal cord and brainstem) and peripheral (lungs and respiratory muscles) components. Breathing is controlled by coordinated activity among many different respiratory muscles, but the diaphragm is often considered the most essential. Diaphragm paralysis usually results in an inability to sustain breathing (respiratory arrest) and the need for assisted ventilation. The brainstem (lower part of the brain) generates respiratory rhythm under normal circumstance, resulting in a smooth alternation between the two respiratory phases - inspiration and expiration. Accordingly, these respiratory brainstem neurons are thought to comprise the "central pattern generator" for breathing. Signals from the brainstem are sent down the spinal cord to motor neurons -- nerve cells mediating contraction of respiratory muscles. In addition, some neurons provide a relay between respiratory cells in the brainstem and the spinal motor neurons. These "interneurons" may help to modulate respiratory activity by exciting or inhibiting motor neurons activity. They may also comprise a "spinal pattern generator" that is capable of mediating breathing patterns even when connections from the brainstem are lost. Following SCI, the connections between brainstem and spinal cord are partially or completely disrupted. Injury at cervical levels can compromise the pathways controlling diaphragm function, resulting in respiratory failure. Some research has shown that there is some progressive partial recovery of diaphragm function in the months following injury, but the extent of recovery is minimal. Recent studies by our research group have found that some spinal interneurons may be inhibiting motor neuron function and limiting the potential for recovery. Building upon this novel discovery, the present research aims to target these inhibitory cells to allow for greater spontaneous recovery. This will be tested following a complete, high-cervical transection -- the most severe spinal cord injury -- which is characterized by paraplegia and respiratory arrest. The proposed work will then also test a second therapeutic strategy -- epidural stimulation. There is a rapidly growing interest in epidural stimulation as a means of improving motor function following SCI, and research in locomotor systems has received a great deal of media attention. However, very little effort has been made to assess the therapeutic potential for this strategy in improving breathing function. Furthermore, the existence of inhibitory spinal interneurons may limit the full therapeutic potential of epidural stimulation. Therefore, the second goal of the present research is to assess whether decreasing activity in inhibitory spinal interneurons will unmask greater therapeutic potential of promising epidural stimulation strategies These experiments will help to better define our knowledge of respiratory function following cervical SCI and assess the benefit of two novel treatment strategies with significant translational potential. Improving respiratory recovery in people with cervical SCI will enable greater independence, reduce morbidity and the risk of mortality, and lower the economic burden.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510324
Entities
People
- Vitaliy Marchenko
Organizations
- Drexel University
- United States Army