Uncontrollable Stimulation Undermines Recovery after Spinal Cord Injury

Abstract

Prior studies have shown that neurons within the spinal cord are sensitive to response-outcome relations, a form of instrumental learning. Spinally transected rats that receive shock to one hind leg learn to maintain the leg in a flexed position that minimizes net shock exposure (controllable shock). Prior exposure to uncontrollable stimulation (intermittent shock) inhibits this spinally mediated learning. Here it is shown that uncontrollable stimulation undermines the recovery of function after a spinal contusion injury. Rats received a moderate injury (12.5 mm drop) and recovery was monitored for 6 weeks. In Experiment 1, rats received varying amounts of intermittent tailshock 1-2 days after injury. Just 6 min of intermittent shock impaired locomotor recovery. In Experiment 2, rats were shocked 1, 4, or 14 days after injury. Delaying the application of shock exposure reduced its negative effect on recovery. In Experiment 3, rats received controllable or uncontrollable shock 24 and 48 h after injury. Only uncontrollable shock disrupted recovery of locomotor function. Uncontrollably shocked rats also exhibited higher vocalization thresholds to aversive stimuli (heat and shock) applied below the injury. Across the three experiments, exposure to uncontrollable shock, (1) delayed the recovery of bladder function; (2) led to greater mortality and spasticity; and (3) increased tissue loss (white and gray matter) in the region of the injury. The results indicate that uncontrollable stimulation impairs recovery after spinal cord injury and suggest that reducing sources of uncontrolled afferent input (e.g., from peripheral tissue injury) could benefit patient recovery.

Tonic Pain Experienced during Locomotor Training Impairs Retention Despite Normal Performance during Acquisition

“…All subjects were right-foot dominant according to the Waterloo footedness questionnaire (Elias et al, 1998). The application of capsaicin cream caused a moderate level of pain throughout the experiment.…”

“…Singlepulse transcranial magnetic stimulation (TMS) studies have shown changes in motor-evoked potential (MEP) size during gait adaptation to a force field that cannot simply be explained by a change in motoneuron excitability, suggesting a role for supraspinal structures such as M1 in the adaptive process (Barthélemy et al, 2012;Zabukovec et al, 2013). Moreover a recent study has investigated the effect of lowfrequency (presumably inhibitory) repetitive TMS applied over M1, S1, and posterior parietal cortex (PPC) on force field adaptation of gait (Choi et al, 2014). While repetitive TMS (rTMS) over S1 or PPC had no effect, disruption of M1 activity reduced aftereffects without affecting adaptation, further suggesting a role of M1 in retention of this motor learning during gait.…”

“…Repeated exposure to pain has also been shown to induce plasticity in the spinal cord, a phenomenon called central sensitization (Woolf, 2011). It has been proposed that spinal plasticity associated with central sensitization and with motor training share similar neural mechanisms and may interact with each other (Ferguson et al, 2012b). This hypothesis is supported by animal studies showing that exposure to uncontrollable nociceptive stimulation can inhibit adaptive spinal learning in spinalized rats (Crown et al, 2002;Ferguson et al, 2006Ferguson et al, , 2012aHook et al, 2008) and locomotor recovery following spinal concussion (Grau et al, 2004).…”

“…Training-induced gait recovery following a lesion is known to involve adaptive plasticity in the spinal cord (Carrier et al, 1997;Whelan and Pearson, 1997;Bouyer et al, 2001;Rossignol and Bouyer, 2004). Repeated exposure to pain has also been shown to induce plasticity in the spinal cord, a phenomenon called central sensitization (Woolf, 2011).…”

“…It has been proposed that spinal plasticity associated with central sensitization and with motor training share similar neural mechanisms and may interact with each other (Ferguson et al, 2012b). This hypothesis is supported by animal studies showing that exposure to uncontrollable nociceptive stimulation can inhibit adaptive spinal learning in spinalized rats (Crown et al, 2002;Ferguson et al, 2006Ferguson et al, , 2012aHook et al, 2008) and locomotor recovery following spinal concussion (Grau et al, 2004). While these results are very important, they cannot be directly transferred to clinical practice for two main reasons: (1) gait rehabilitation is typically performed in patients with incomplete SCI, and thus the contribution of supraspinal structures needs to be taken into account; and (2) the learning protocol used in these animal studies was very different (involving nociceptive stimuli) from locomotor training performed in rehabilitation.…”