Electrophysiological biomarkers of neuromodulatory strategies to recover motor function after spinal cord injury

Abstract

The spinal cord contains the circuitry to control posture and locomotion after complete paralysis, and this circuitry can be enabled with epidural stimulation [electrical enabling motor control (eEmc)] and/or administration of pharmacological agents [pharmacological enabling motor control (fEmc)] when combined with motor training. We hypothesized that the characteristics of the spinally evoked potentials after chronic administration of both strychnine and quipazine under the influence of eEmc during standing and stepping can be used as biomarkers to predict successful motor performance. To test this hypothesis we trained rats to step bipedally for 7 wk after paralysis and characterized the motor potentials evoked in the soleus and tibialis anterior (TA) muscles with the rats in a non-weight-bearing position, standing and stepping. The middle responses (MRs) to spinally evoked stimuli were suppressed with either or both drugs when the rat was suspended, whereas the addition of either or both drugs resulted in an overall activation of the extensor muscles during stepping and/or standing and reduced the drag duration and cocontraction between the TA and soleus muscles during stepping. The administration of quipazine and strychnine in concert with eEmc and step training after injury resulted in larger-amplitude evoked potentials [MRs and late responses (LRs)] in flexors and extensors, with the LRs consisting of a more normal bursting pattern, i.e., randomly generated action potentials within the bursts. This pattern was linked to more successful standing and stepping. Thus it appears that selected features of the patterns of potentials evoked in specific muscles with stimulation can serve as effective biomarkers and predictors of motor performance.

Neuromodulation of the neural circuits controlling the lower urinary tract

“…1A), the patterns of the evoked potentials were stochastic with little to no time-linked responses observed. Note that the animals were tested at 6 weeks post-injury and had completely recovered their ability for bipedal stepping, thus we did not expect any MRs in either the flexor or extensor muscles (Gad et al, 2015a). As the state of the bladder transitioned to a pre-voiding state, however, time-linked MRs appeared in both the flexor and extensor hindlimb muscles and several LRs appeared at the start of the burst.…”

“…The wires were secured in the belly of the muscle via a suture on the wire at its entrance into and exit from the muscle belly. The proper placement of the electrodes was verified during the surgery by stimulating through the head connector and post-mortem via dissection (Gad et al, 2013, 2015a). …”

“…Five SCI rats were step trained bipedally (Ichiyama et al, 2008a; Shah et al, 2012) on a specially designed motor-driven rodent treadmill using a body weight support system (de Leon et al, 2002a,b) under the influence of ES between L2 and S1 (40 Hz) and quipazine a 5-HT 2 agonist (Gad et al, 2013, 2015a; Ichiyama et al, 2008b) (0.3 mg/kg, i.p.) and strychnine a glycinergic antagonist (Gad et al, 2013, 2015a) (0.5 mg/kg, i.p.)…”

“…and strychnine a glycinergic antagonist (Gad et al, 2013, 2015a) (0.5 mg/kg, i.p.) at a treadmill speed of 13.5 cm/s (Courtine et al, 2009) (pharmacological agents were administered 10 min prior to training).…”

“…Custom scripts written in Matlab were used to measure the evoked potentials from the hindlimb and EUS muscles (Lavrov et al, 2008b, 2006). Step cycle durations and EMG burst amplitudes and durations were determined using a custom program written in the LabView development environment (Gad et al, 2015a). Integrated EMG (iEMG) values were calculated as EMG amplitude x duration.…”