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Neuromodulators are neurotransmitter-like substances, delivered by the bloodstream or more rapidly via synaptic terminals, that enhance or diminish the effect of the primary neurotransmitters in nerve terminals. These substances alter the functional properties of neuron circuits by facilitating, depressing, or initiating motor activity as well as by modifying the cellular and synaptic characteristics of neurons. Within CPG networks, neuromodulators are classified as intrinsic (being an integral part of the CPG) or extrinsic (modulating CPG activity from other areas of the nervous system). Neurotransmitters (glutamate, GABA, glycine), as well as the neuromodulators (serotonin, dopamine), have been shown to influence locomotor CPG behavior. In addition, certain peptides have neuromodulatory effects on the locomotor CPGs.

Inconclusive studies have been conducted which measured improvements in mobility and EMG activity induced by treadmill training. What remains unclear is the relative contribution of plastic changes in neural pathways versus changes in the circuitry of CPGs. It has been argued that part of the training effect is due to strengthening of the lower-extremity muscles, although little evidence of a strengthening effect has been reported. Better understanding of neuromodulators on CPG activity and interlimb coordination; and the nature of mechanisms that seem to be prohibiting spinal locomotion in humans are practical importance. Locomotor CPGs may be manipulated to improve the quality of movement, and thus quality of life, for people with movement dysfunction.