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


Other title
sensory transmission
spinal cord injury
Type of item
Degree grantor
University of Alberta
Author or creator
D'Amico, Jessica M
Supervisor and department
Gorassini, Monica (Biomedical Engineering)
Examining committee member and department
Fouad, Karim (Rehabilitation Medicine)
Jones, Kelvin (Physcial Education and Recreation)
Collins, David (Physical Education and Recreation)
Thomas, Christine (Neurological Surgery, University of Miami)
Centre for Neuroscience

Date accepted
Graduation date
Doctor of Philosophy
Degree level
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.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
D'Amico JM, Murray KC, Li Y, Chan KM, Finlay M, Bennett DJ and Gorassini MA. Constitutively active 5HT2/α1 receptors facilitate muscle spasms after human spinal cord injury. J Neurophysiology 109(6): 1473-1484, 2013.D'Amico JM, Li Y, Bennet DJ and Gorassini MA. Reduction of spinal sensory transmission by facilitation of 5HT1 receptors in non-injured and spinal cord injured humans. J Neurophysiology 109(6): 1485-1493, 2013.Murray KC, Stephens MJ, Rank M, D’Amico JM, Gorassini MA, Bennett DJ. Polysynaptic excitatory postsynaptic potentials that trigger spasms after spinal cord injury in rats are inhibited by 5HT1B and 5HT1F receptors. Journal of Neurophysiology 106: 925-943, 2011Rank M, Murray K, Stephens M, D’Amico JM, Gorassini M, and Bennett D. Adrenergic receptors modulate motoneuron excitability, sensory synaptic transmission and muscle spasms after chronic spinal cord injury. Journal of Neurophysiology 105:410-422, 2011.Murray KC, Nakae A, Stephens MJ, Rank M, D'Amico JM, Harvey PJ, Li X, Harris RLW, Ballou EW, Anelli R, Heckman CJ, Mashimo T, Vavrek R, Sanelli L, Gorassini MA, Bennet DJ and Fouad K. Recovery of motoneuron and locomotor function after spinal cord injury depends on constitutive activity in 5-HT2C receptors. Nature Medicine 16:694-700, 2010.Udina E, D’Amico JM, Bergquist AJ, Gorassini MA. Amphetamine increases persistent inward currents in human motoneurons estimated from paired motor unit activity. Journal of Neurophysiology 103: 1295-1303, 2010.

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