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FIRST-STIM CNS Growth Factor Release and Changes in the Inflammatory Environment in Response to Electrical Stimulation in Subjects with Inflammatory Myelopathies
A Phase II Randomized, Single-Blinded, 100-Subject Clinical Trial of Functional Electrical Stimulation in the Treatment of Inflammatory Myelopathies
The specific aims of the proposal are:
- To determine which functional elecrical stimulation (FES) ergometry dosing regimen results in the most significant increase in cerebrospinal fluid (CSF) brain derived neurotrophic factor (BDNF) levels in subjects with inflammatory myelopathy. We will test the hypothesis that 5 FES cycling sessions per week result in largest greater increase in CSF BDNF concentrations as compared to 1 or 3 sessions and passive cycling.
a. We will measure CSF concentrations of BDNF in response to FES ergometry (primary outcome).
b. We will investigate whether there is a correlation between plasma and CSF BDNF concentrations.
- To quantify changes in the CNS inflammatory environment in response to FES ergometry in subjects with inflammatory myelopathy. We will test the hypothesis that concentrations of interleukins (IL) IL-6, IL17, tumor necrosis factor alpha (TNFα), IL-1ß, IL-23, and IL-12 change in response to FES ergometry.
a. We will measure CSF concentrations of IL-6, IL17, TNFα, IL-1ß, IL-23, and IL-12 in response to FES ergometry.
Non-infectious inflammatory myelopathies were previously often categorized as idiopathic transverse myelitis, but advances in neuroimaging and neuroimmunology have allowed more specific diagnoses, such as multiple sclerosis (MS) and neuromyelitis optica (NMO). With the exception of relapsing remitting multiple sclerosis (RRMS) there are no existing therapies that alter the course of these diseases. People with these disorders inexorably accumulate disability. In virtually every person with secondary progressive MS (SPMS) ambulation will be significantly affected, leading to use of canes, walkers, and then wheelchairs.
Functional electrical stimulation (FES) cycling is a method of applying low level electrical currents to the leg and buttock muscles to cause the weakened or paralyzed muscles to contract and produce a cycling motion of the legs. It has been used most in rehabilitation of patients with traumatic spinal cord injuries (SCI). Over the recent years, FES cycling has become an increasingly important modality in rehabilitation of patients with paralysis. It has been shown to have multiple primary medical benefits including: (1) increased muscle mass, (2) improvements in bone density, (3) enhanced cardiovascular function, (4) improved bowel function, (5) decreased spasticity and (6) reductions in bladder infection rate. More importantly it has been shown to improve recovery from SCI. In a recent pilot trial with MS patients at our center we showed improvements on a broad array of functional and neurologic outcome measures including gait, upper extremity dexterity, and quality of life. Further, analysis of cerebrospinal fluid before FES and 3 months after initiating FES cycling revealed an enhanced neural repair program and a reduced inflammatory environment within the CNS.
One of the most important questions unanswered in regards to this technology is: How much FES is required to result in the most optimal recovery? We currently use an experience-based approach (3 to 5 FES cycling sessions per week, 1-hour each). From extensive clinical experience in our center, we suspect that the more FES is applied the better recovery is. In order to find the optimal dose of FES, we identified a biomarker that can be measured in the spinal fluid of individuals receiving FES. Brain derived neurotrophic factor (BDNF) levels correlate closely with functional recovery. Voluntary exercise induces a BDNF-mediated mechanism and promotes neural plasticity in the CNS. Currently, there are no controlled clinical trial data available on the effect of FES ergometry on neurotrophin release and functional recovery following neurological injury.
Our center specializes in chronic rehabilitation of patients with paralysis. In our clinical experience electrical stimulation leads to accelerated recovery of neurological function compared to traditional rehabilitation 8. We speculate that this is in part due to local neurotrophin release resulting in neuroprotection and repair. It is unclear what the optimal “dose” of FES is, i.e., what dose is required for maximal recovery of function. Here we propose to measure CSF BDNF concentrations in response to FES ergometry in patients with inflammatory myelopathies. In addition we will measure markers of inflammation in response to FES. These data will be crucial for the design of a phase 3 clinical trial evaluating the efficacy of FES in patients with inflammatory myelopathies.