CURE-SCI: Clinical Utilization of CNS Growth Factor Release in Response to Electrical Stimulation Following Spinal Cord Injury

A Phase II Randomized, Single-Blinded, 80-Subject Clinical Trial of Functional Electrical Stimulation in the Treatment of Adult Spinal Cord Injury

The specific aims of the proposal are:

• To determine which functional electrical stimulation (FES) dosing regimen results in the most significant increase in CSF BDNF levels in subjects with chronic spinal cord injury (SCI).
• To measure cerebrospinal fluid (CSF) concentrations of CNTF, NGF, NT-3, NT-4, and GDNF in response to FES.
• To determine whether there is a correlation between BDNF trough concentrations in plasma and CSF.
• To determine which FES dosing regimen results in most significant decrease in spasticity levels in subjects with chronic SCI.

Rationale:

There are numerous publications demonstrating practical benefits from functional electrical stimulation (FES) in SCI patients including: increased muscle mass, improvements in bone density, enhanced cardiovascular function, improved bowel function, decreased spasticity and reductions in bladder infection rate. A growing body of evidence suggests that electrical stimulation can promote peripheral and central nervous system repair following injury. Following complete spinal cord transection in rats, lower extremity FES induced an 82-86 percent increase in cell birth in the lumbar spinal cord. FES doubled the proportion of the newly-born cells which expressed nestin and other markers suggestive of tripotential progenitors suggesting that controlled electrical activation of the CNS may enhance spontaneous regeneration after neurological injuries.

BDNF is an activity-dependent secreted protein that, along with its receptors, is expressed widely in the central nervous system and is critical to neuronal survival and activity-dependent plasticity. In paralyzed muscle groups, substitution for voluntary contractions with electrical stimulation may allow for activity and sensory feedback in which both have shown to enhance natural levels of BDNF. Chronic exercise can increase the expression of genes that encode several brain neurotrophins such as BDNF, nerve growth factor (NGF), and galanin. Voluntary exercise induces a BDNF and NT-3-mediated mechanism and promotes plasticity. In the normal CNS, neurons have a major role in the synthesis of BDNF, while in the injured CNS, glial (microglial) cells produce BDNF.

There is no controlled trial data available on the effect of FES ergometry on neurotrophins and functional recovery following neurological trauma. Our center is specializing in chronic rehabilitation of patients with SCI. In our clinical experience electrical stimulation leads to accelerated recovery of neurological function as compared to traditional rehabilitation. We speculate that this is in part due to local neurotrophin release resulting in neuroprotection and repair. Here we propose to measure CSF BDNF concentrations in response to increasing doses of FES ergometry following SCI. This data will be crucial for the design of a phase 3 clinical trial evaluating the efficacy of FES following SCI.

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