Neuronal Mechanisms of Hyperexcitability in Individuals with Spasticity after Spinal Cord Injury and Individuals with Bruxism

Abstract

Motoneuron hyperexcitability is a characteristic of several different motor disorders. We examined neuronal mechanisms of hyperexcitability in two of these disorders: spasticity after spinal cord injury (SCI) and bruxism. Involuntary muscle spasms after SCI occur as a result of uncontrolled increases in motoneuron excitability. Brainstem-derived serotonin (5HT) and noradrenaline (NA) normally facilitate motoneuron excitability and inhibit sensory transmission to motoneurons. After SCI, monoamine levels are drastically reduced below the lesion. In this thesis we first examined the role of various monoamine receptors in modulating motoneuron excitability after SCI in humans. In individuals with incomplete SCI we showed that ligand-activated 5HT2 and NA-α1 receptors on motoneurons activate large persistent inward currents (PICs) which drive long-lasting involuntary muscle spasms after injury. These results indicate that the residual levels of monoamines below an incomplete lesion can affect motoneuron function. In contrast, PIC activation after motor complete SCI is solely mediated by constitutive or "spontaneously" active 5HT2/NA-α1 receptors. The emergence of constitutively-active receptors after motor complete SCI appears to be an adaptive mechanism to recovery motoneuron excitability in response to a severe loss of 5HT and NA. Although the emergence of constitutively-active receptors is beneficial in restoring lost motoneuron function after injury, it also contributes to spasticity when combined with the disinhibition of sensory afferent transmission. Sensory afferent transmission is normally inhibited by the activation of 5HT1 receptors located on excitatory interneurons and sensory afferent terminals. We examined in motor complete SCI participants whether application of a 5HT1 agonist, zolmitriptan, could restore lost inhibition after injury. Zolmitriptan effectively restored inhibition of sensory transmission to the motoneurons and reduced the triggering of PIC-mediated spasms. Lastly, we examined whether enhanced PIC activation contributed to sustained masseter muscle activity in persons suffering from bruxism. Periods of involuntary masseter activity occur during sleep microarousals where monoaminergic drive to motoneurons is increased. Despite the increase in PIC-activating monoamines during periods of bruxism, we did not find enhanced PIC activation in individuals with bruxism when compared to age-matched controls. Further work is needed to elucidate the mechanisms behind this disorder.