Abstract
Neurophysiological testing can provide quantitative information about motor, sensory, and autonomic system connectivity following spinal cord injury (SCI). The clinical examination may be insufficiently sensitive and specific to reveal evolving changes in neural circuits after severe injury. Neurophysiologic data may provide otherwise imperceptible circuit information that has rarely been acquired in biologics clinical trials in SCI. We reported a Phase 1 study of autologous purified Schwann cell suspension transplantation into the injury epicenter of participants with complete subacute thoracic SCI, observing no clinical improvements. Here, we report longitudinal electrophysiological assessments conducted during the trial. Six participants underwent neurophysiology screening pre-transplantation with three post-transplantation neurophysiological assessments, focused on the thoracoabdominal region and lower limbs, including MEPs, SSEPs, voluntarily triggered EMG, and changes in GSR. We found several notable signals not detectable by clinical exam. In all six participants, thoracoabdominal motor connectivity was detected below the clinically assigned neurological level defined by sensory preservation. Additionally, small voluntary activations of leg and foot muscles or positive lower extremity MEPs were detected in all participants. Voluntary EMG was most sensitive to detect leg motor function. The recorded MEP amplitudes and latencies indicated a more caudal thoracic level above which amplitude recovery over time was observed. In contrast, further below, amplitudes showed less improvement, and latencies were increased. Intercostal spasms observed with EMG may also indicate this thoracic “motor level.” Galvanic skin testing revealed autonomic dysfunction in the hands above the injury levels. As an open-label study, we can establish no clear link between these observations and cell transplantation. This neurophysiological characterization may be of value to detect therapeutic effects in future controlled studies.
Highlights
In early Phase clinical trials of biological therapeutics for spinal cord injury (SCI), the emphasis is on safety; for thoracic injuries, this is usually considered to be the maintenance of a stable neurological level of injury (NLI)
The ISNCSCI sensory levels defining the NLI and the sensory zone of partial preservation (ZPP) at baseline, 6 and 12 months are shown in Supplementary Figure 2
Despite the discomfort associated with transcranial magnetic stimulations (TMS), we found the participants to be interested in their testing, especially when we requested visualization and voluntary reinforcement maneuvers to amplify MEPs or EMG
Summary
In early Phase clinical trials of biological therapeutics for SCI, the emphasis is on safety; for thoracic injuries, this is usually considered to be the maintenance of a stable neurological level of injury (NLI). Despite the primary outcome of safety, efficacy signals are sought to inform future product development. Changes in neural connectivity can provide an important “biomarker” when there is a lack of clinically apparent therapeutic effects. Drug and biologics development is costly [3], and a lack of an apparent signal of an effect may cause a program to be terminated [4]. Standard outcome measures [5] may fail to detect changes in circuit connectivity [6], neurophysiologic findings may inform development in a therapeutics program
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
