Activity Dependent Stimulation Increases Synaptic Efficacy In Spared Pathways In An Anesthetized Rat Model Of Spinal Cord Contusion Injury

Abstract

Objective. The purpose of this study was to assess the ability of intraspinal microstimulation, triggered by action potentials (spikes) recorded in motor cortex, to alter synaptic efficacy in descending motor pathways in an anesthetized rat model of spinal cord injury. Approach. Experiments were carried out in adult, male, Sprague Dawley rats with a moderate contusion injury at T8. Four weeks after SCI, and under ketamine/xylazine anesthesia, fine wire electromyographic (EMG) electrodes were implanted into four muscles of the right hindlimb. After exposure of the left motor cortex hindlimb area and laminectomy of the T13-L1 vertebrae, intracortical microstimulation (ICMS) and intraspinal microstimulation (ISMS) were used to determine the location of evoked hip movements in cortex and spinal cord, respectively. For activity-dependent stimulation sessions, a single shank, 16-channel, recording microelectrode was used to detect neuronal spikes in motor cortex that triggered ISMS in the spinal cord grey matter. Spinal cord injured rats were randomly assigned to one of four experimental groups differing by: a) cortical spike-ISMS stimulus delay (10 or 25 ms) and b) number of ISMS pulses (1 or 3). Activity-dependent stimulation sessions were conducted in three consecutive 1-hour conditioning bouts for a total of 3 hours. At the end of each conditioning bout, changes in synaptic efficacy were assessed using ICMS to examine the number of spikes evoked in spinal cord neurons during five minute test bouts. Evoked spikes were recorded, sorted, and displayed in post-stimulus spike histograms in 1ms bins. Post-stimulus spike histograms and EMG recordings were characterized using stimulus triggered averaging techniques. Main results. The results showed that activity-dependent stimulation resulted in an increase in cortically-evoked spikes in spinal cord neurons at specific combinations of spike-ISMS delays and numbers of pulses. Efficacy in descending motor pathways was increased throughout all dorsoventral depths of the hindlimb spinal cord, including the ventral horn, in the vicinity of motor neurons. Changes were evident in some conditions as early as 1 hour after conditioning. EMG responses were never evoked with ICMS pre-or post-conditioning. Significance. These results show that after a spinal cord contusion injury, activity-dependent stimulation, consisting of cortical spike-driven ISMS, can increase synaptic efficacy in spared pathways between motor cortex and spinal cord. This suggests that activity-dependent stimulation may serve as an effective therapeutic approach for enhancing descending motor control after spinal cord injury. Muscle EMG Wires ICMS RecordRecord ISMS Catch Trial: ADS:

Spike-Triggered Intraspinal Microstimulation Improves Motor Performance in an Ambulatory Rat Model of Spinal Cord Injury

“…Spinal cord contusion procedures followed those described in our previous studies (Krizsan-Agbas et al, 2014; Borrell et al, 2020a; Borrell et al, 2020b). Animals underwent a T8 laminectomy and 175 kDyn moderate impact contusion injury using an Infinite Horizon spinal cord impactor (Precision Systems and Instrumentation, LLC, Fairfax Station, VA).…”

“…For placement of the stimulating electrode in the spinal cord, a laminectomy was performed on the T13 vertebrae similar to previous studies (Borrell et al, 2020a; Borrell et al, 2020b). The dura mater was left intact to minimize cerebrospinal fluid leakage.…”

“…Stimulation amplitude was set at 50% movement threshold determined during the implantation surgery to mitigate interference with the rat's motor performance or muscle fatigue. A time delay of 10 ms between recorded cortical spike and triggered spinal cord stimulation pulse was used because this delay resulted in enhanced ICMS-evoked spinal cord responses in ADS sessions conducted in anesthetized SCI rats (Borrell et al, 2020b). A blanking interval of 28 ms following each spike discrimination was used to reduce the possibility of producing a positive-feedback loop, in which spinal stimulation might drive action potentials in HLA, retriggering stimulation of spinal cord (Guggenmos et al, 2013).…”

“…The ability of the motor cortex to evoke spinal cord activity below the level of an injury demonstrates that some descending motor pathways to the lumbar cord remain intact after a moderate spinal cord contusion (Borrell et al, 2020a). Furthermore, the administration of ADS between the hindlimb motor cortex and hindlimb spinal cord has shown that ADS causes a plastic change in the intact pathways of rats with a thoracic contusion to the spinal cord (Borrell et al, 2020b). The current study was conducted to determine if application of ADS therapy (i.e., spike-triggered intraspinal microstimulation) results in improved motor performance in an ambulatory rat model of SCI.…”

“…These efforts encouraged us to develop an understanding of the connection between the brain and spinal cord after a bilateral thoracic spinal cord contusion that mimics those seen in clinical spinal cord injuries (Krizsan-Agbas et al, 2014; Frost et al, 2015; Borrell et al, 2020a; Borrell et al, 2020b). Through using SCI models, we can create neuromodulation protocols that can more easily translate into clinical use for rehabilitation.…”