Impaired locomotion is one of the many devastating consequences of spinal cord injury (SCI). The extent of impairment depends on the level and magnitude of the injury and the neuronal pathways disrupted. Research from our laboratory indicates that, in addition to reticulospinal pathways, brainstem monoaminergic neurons, which are the sole source of the spinal monoamines serotonin and norepinephrine, are also activated during deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR). The profound effects of monoaminergic drugs on locomotor function even when normal brainstem sources of activation have been experimentally blocked suggests that these transmitters can be used to facilitate locomotion in humans with SCI. Providing there are spared connections following SCI, this method has the potential to facilitate locomotion by artificially maximizing endogenous transmitter release in target areas of the spinal cord still innervated. As part of our long-term goal of developing and optimizing treatments for SCI based on transmitter enhancement strategies, the objectives of this application are to determine the therapeutic potential of DBS to improve locomotor function following partial SCI and to define the precise role of monoamines in this recovery. The central hypothesis is that DBS of the MLR can be used therapeutically to facilitate locomotion in chronic SCI. Preliminary data show significant improvements in locomotor capabilities with DBS in animals with contusion injury.
Our specific aims are:
Aim 1. Delimit the capabilities of spared pathways to facilitate locomotor recovery after SCI. To examine this, we shall stimulate the MLR in animals with mild-to-severe contusion and other select thoracic injuries over acute and chronic stages of injury. Motor recovery and the extent of injury will be assessed.
Aim 2. Determine the relationship between the amount of locomotor recovery with DBS and spinal monoaminergic neurotransmission. Extracellular monoamine levels will be correlated with locomotor capabilities following DBS. Monoaminergic receptor antagonists will be given to animals showing behavioral improvement in order to further delineate this relationship.
By relating monoaminergic pathway viability to locomotor performance following injuries of different severity, we shall determine the capacity of spared monoaminergic pathways to be targeted therapeutically by DBS for the purpose of facilitating locomotor recovery following iSCI. This study has the potential to lead to a Phase 1 clinical study and to further preclinical studies which may involve supplementary transmitter replacement in combination with locomotor training and functional electrical stimulation.
| Noga, Brian R; Sanchez, Francisco J; Villamil, Luz M et al. (2017) LFP Oscillations in the Mesencephalic Locomotor Region during Voluntary Locomotion. Front Neural Circuits 11:34 |
| Noga, Brian R; Turkson, Riza P; Xie, Songtao et al. (2017) Monoamine Release in the Cat Lumbar Spinal Cord during Fictive Locomotion Evoked by the Mesencephalic Locomotor Region. Front Neural Circuits 11:59 |
| Hentall, Ian D; Burns, Scott B (2009) Restorative effects of stimulating medullary raphe after spinal cord injury. J Rehabil Res Dev 46:109-22 |
