Priming locomotor training with transspinal stimulation in people with spinal cord injury: study protocol of a randomized clinical trial

Abstract

Background: The seemingly simple tasks of standing and walking require continuous integration of complex spinal reflex circuits between descending motor commands and ascending sensory inputs. Spinal cord injury greatly impairs standing and walking ability, but both improve with locomotor training. However, even after multiple locomotor training sessions, abnormal muscle activity and coordination persist. Thus, locomotor training alone cannot fully optimize the neuronal plasticity required to strengthen the synapses connecting the brain, spinal cord, and local circuits and potentiate neuronal activity based on need. Transcutaneous spinal cord (transspinal) stimulation alters motoneuron excitability over multiple segments by bringing motoneurons closer to threshold, a prerequisite for effectively promoting spinal locomotor network neuromodulation and strengthening neural connectivity of the injured human spinal cord. Importantly, whether concurrent treatment with transspinal stimulation and locomotor training maximizes motor recovery after spinal cord injury is unknown.

Methods: Forty-five individuals with chronic spinal cord injury are receiving 40 sessions of robotic gait training primed with 30 Hz transspinal stimulation at the Thoracic 10 vertebral level. Participants are randomized to receive 30-minutes of active or sham transspinal stimulation during standing or active transspinal stimulation while supine followed by 30-minutes of robotic gait training. Over the course of locomotor training, the body weight support, treadmill speed, and leg guidance force are adjusted as needed for each participant based on absence of knee buckling during the stance phase and toe dragging during the swing phase. At baseline and after completion of all therapeutic sessions, neurophysiological recordings registering corticospinal and spinal neural excitability changes along with clinical assessment measures of standing and walking, and autonomic function via questionnaires regarding bowel, bladder and sexual function are taken.

Discussion: The results of this mechanistic randomized clinical trial will demonstrate that tonic transspinal stimulation strengthens corticomotoneuronal connectivity and dynamic neuromodulation through posture-dependent corticospinal and spinal neuroplasticity. We anticipate that this mechanistic clinical trial will greatly impact clinical practice because in real-world clinical settings, noninvasive transspinal stimulation can be more easily and widely implemented than invasive epidural stimulation. Additionally, by applying multiple interventions to accelerate motor recovery, we are employing a treatment regimen that reflects a true clinical approach.

Trial registration: ClinicalTrials.gov: NCT04807764; Registered on March 19, 2021.

Keywords: combined interventions; locomotor training; neurophysiology; rehabilitation; spinal cord injury; standing; stepping; transspinal stimulation.

Figure 1

Representative transspinal evoked potentials (TEPs) recorded from knee (vastus lateralis) and ankle (medial gastrocnemius and soleus) muscles in one person with AIS D SCI lying supine upon paired transspinal stimuli at 60 ms interstimulus interval. Note that the TEP depression is larger in ankle muscles compared to TEPs recorded from the knee muscle.

Figure 2

Intervention: Noninvasive transspinal stimulation at 30 Hz for 30 minutes is delivered during standing (1a) with body weight support as needed to avoid knee buckling and/or while supine with legs semi-flexed at a neutral position (1b) followed by 30 minutes of locomotor training with the Lokomat 6 Pro (2) within the same training session. In Figures 1a and 1b the position of the stimulating electrodes is shown.

Figure 3

Arrangement of stimuli during stepping. EMG channel, along with reflex and conditioning stimuli are shown as detected in LabVIEW data acquisition software. Test and/or conditioning stimulation (that can be directed to primary motor cortex, skin, or peripheral nerve as single pulses or pulse trains at variable frequencies) are indicated for an interval that can be adjusted based on the experimental protocol. Through foot switches (not shown) we determine the exact phase that stimulation occurs, i.e. the exact bin. Stimulation is delivered randomly across the 16 bins that make up each step cycle.

Figure 4

Standard Protocol Items Recommendations for Interventional Trials (SPIRIT) figure indicating the procedures for each participant that occur at each visit. Each participant comes at least 45 times to the lab receiving a total of 40 treatment sessions.