Undirected compensatory plasticity contributes to neuronal dysfunction after severe spinal cord injury

Abstract

Severe spinal cord injury in humans leads to a progressive neuronal dysfunction in the chronic stage of the injury. This dysfunction is characterized by premature exhaustion of muscle activity during assisted locomotion, which is associated with the emergence of abnormal reflex responses. Here, we hypothesize that undirected compensatory plasticity within neural systems caudal to a severe spinal cord injury contributes to the development of neuronal dysfunction in the chronic stage of the injury. We evaluated alterations in functional, electrophysiological and neuromorphological properties of lumbosacral circuitries in adult rats with a staggered thoracic hemisection injury. In the chronic stage of the injury, rats exhibited significant neuronal dysfunction, which was characterized by co-activation of antagonistic muscles, exhaustion of locomotor muscle activity, and deterioration of electrochemically-enabled gait patterns. As observed in humans, neuronal dysfunction was associated with the emergence of abnormal, longlatency reflex responses in leg muscles. Analyses of circuit, fibre and synapse density in segments caudal to the spinal cord injury revealed an extensive, lamina-specific remodelling of neuronal networks in response to the interruption of supraspinal input. These plastic changes restored a near-normal level of synaptic input within denervated spinal segments in the chronic stage of injury. Syndromic analysis uncovered significant correlations between the development of neuronal dysfunction, emergence of abnormal reflexes, and anatomical remodelling of lumbosacral circuitries. Together, these results suggest that spinal neurons deprived of supraspinal input strive to re-establish their synaptic environment. However, this undirected compensatory plasticity forms aberrant neuronal circuits, which may engage inappropriate combinations of sensorimotor networks during gait execution.

Dendritic spine dysgenesis contributes to hyperreflexia after spinal cord injury

“…Although microglial activation has been implicated in altering the excitability of sensory neurons after injury (Tan et al 2012a;Zhao et al 2007a), administration of NSC23766 does not appear to affect the activation of microglia after nerve injury (Tan et al 2011). In agreement with previous studies (Beauparlant et al 2013;Kitzman 2007), we report that VGluT1 expression did not change after SCI, suggesting that the presence of H-reflex hyperexcitability is not due to increased excitatory presynaptic afferent inputs (Kitzman 2007). Although it is possible that Rac1 inhibition may have affected presynaptic elements, NSC23766 treatment only decreased VGluT1 areal density in the intermediate zone and ventral horn.…”

From the Rodent Spinal Cord Injury Model to Human Application: Promises and Challenges

“…There are rodent studies indicating an undirected neuroplasticity as a possible mechanism. 40 In which way can this neuronal dysfunction be avoided or inversed? The proper functioning of neuronal circuits below the level of lesion is the prerequisite for a successful regeneration.…”

Abnormal cutaneous flexor reflex activity during controlled isometric plantarflexion in human spinal cord injury spasticity syndrome

“…43 At the spinal level, dysfunction of spinal inhibitory mechanisms mediated by gamma-aminobutyric acid is related to cutaneous hyperreflexia after SCI, 44,45 whereas other structural spinal changes are associated with reflex dysfunction as a consequence of the loss of supraspinal descending control mechanisms. 21 Damage to descending supraspinal pathways, 20,46 including the corticospinal 47,48 or extrapyramidal control systems, 19,46,49 also may contribute specifically to the change in CR modulation observed during controlled plantarflexion. Indeed, higher long-latency (200-300 ms) reflex activity observed in the SCI spasticity group during controlled plantarflexion suggests in part that a loss of supraspinal modulation may be implicated as an underlying mechanism.…”

“…[10][11][12] In addition, abnormal flexor reflex excitability is present during subacute 4,13 and chronic SCI, 14,15 impacts on residual gait function after SCI 16 and interferes with daily activities. 17 Lower limb CR activity in humans is modulated by several segmental and descending control mechanisms, [18][19][20][21] and the loss of descending modulatory mechanisms may contribute to the SCI spasticity syndrome. Tibialis Anterior (TA) muscle reflex activity evoked following cutaneous stimulation of the plantar surface (Pl-TA CR) [22][23][24] has been used as a test to assess the integrity of segmental and descending motor control mechanisms in healthy subjects with physiological reflex modulation during the step-cycle in healthy subjects.…”