An Exercise Intervention to Reduce Neuropathic Pain and Brain Inflammation After Spinal Cord Injury

This clinical trial will utilize a randomized, controlled, crossover design. Participants will be randomized to (A) 12 weeks of FES-RT followed by 12 weeks of treatment as usual or (B) 12 weeks of treatment as usual followed by 12 weeks of FES-RT.

Randomization will be computer generated and the study statistician will keep the key to appropriately conceal allocation of treatment until after obtaining baseline measures.

Exercise Intervention:

FES-RT occurs in two distinct steps - an initial strength training step, followed by FES-RT. Those with SCI can require at least two weeks and up to six weeks of strength-training. For the strength training, electrodes are placed over motor points of the quadriceps and hamstrings and intensity of the stimulus is set at the level producing full knee flexion-extension. Training is performed until subjects can complete a flexion extension protocol for 30 min without rest. During this time, the first set of PET-MR data will be obtained.

Subsequently, the FES-RT commences.

Measurements / Assessments Exercise Capacity: Volunteers will perform an incremental exercise test of FES- or arms-only rowing to determine maximal oxygen uptake on a day normally scheduled for regular exercise training. Exercise capacity and aerobic power will be determined from on-line computer-assisted open circuit spirometry. Subjects will row with increasing resistance every 2 min until volitional fatigue. To ensure attainment of maximal exercise capacity, at least 3 of these criteria will be met: 1) O2 consumption plateaus despite increasing workload, 2) respiratory exchange ratio >1.10 at end exercise, 3) age-predicted maximal heart rate is achieved, and 4) perceived exertion is rated at least 16 on the Borg scale of 6-20.

Exercise Volume: The progression of the exercise stimulus across the training program will be assessed from duration, frequency, and intensity derived from heart rate monitored during each exercise bout (i.e., Training Impulses or TRIMPs) as well as the product of average wattage and total duration for each week. TRIMPs are routinely used to quantify the exercise load and is specific to the cardiopulmonary system. The investigators will also calculate exercise load or work as the product of the weekly average of wattage and weekly total of exercise time.

PET-MR imaging

Neuroimaging metrics will be obtained at baseline, after 12 weeks and after 24 weeks. MR-PET scanning will be performed at 3 Tesla, using a Siemens whole-body MRI, whole-body PET camera (Biograph MMR). MRI data will be acquired simultaneously to the PET data.

In response to injury, microglia migrate to the site of injury, and express multiple cell surface proteins, including the translocator protein (18kDa) (TSPO). This conditional expression makes TSPO a prime target for PET imaging (127). There are multiple candidate PET tracers for glial activity , whereof 11C-PBR28 is a sensitive, second generation, high affinity TSPO radioligand suitable for imaging of microglial and astrocytic activation in neuroinflammation in humans. For glial imaging, 11C-PBR28 will be injected intravenously with a slow bolus over a 30s period (130). Dynamic data will be collected over the brain for 90 minutes in list mode, and framed post-collection. The dose will be up to 15mCi, which is equivalent to ~3.7 mSv.

For opioid imaging, 11C-diprenorphine will be injected intravenously, Dynamic data will be collected over the brain for 90 minutes in list mode, and framed post-collection. The dose will be up to 12mCi, which is equivalent to ~2.5 mSv.

For both scans, MR-based attenuation correction maps are created based on the MPRAGE data. For glial imaging, standardized uptake values (SUV), normalized to whole brain PBR28 ligand uptake, will be used. For 11CDiprenorphine, kinetic modeling is carried our using subject specific bilateral occipital cortices as the reference tissues. Nondisplaceable binding potential maps (BPND), representing the relative amount of specifically bound radioligand to that of non-displaceable radioligand, are calculated from the 90 min of dynamic PET data using a simplified reference tissue model with the occipital cortex used as the reference tissue.

A high resolution structural volume will be collected for the purposes of longitudinal structural analyses. All longitudinal data analyses will be done in native space as repeated measurements, thereby avoiding spatial normalization errors typically associated with cohort studies.

A battery of pain, quality of life and psychological well-being questionnaires to the participants on four occasions: immediately after enrollment, at the start of the 12 week wait-list or FES-RT period, at the end of the first arm, and at the end of the cross-over arm (24 weeks).

Conditioned pain modulation: Conditioned pain modulation (CPM) is a psychophysically-based laboratory method to reliably ) evaluate the individual capabilities to inhibit pain in humans. Briefly, CPM is based on the "pain inhibits pain" phenomenon when Stimulus A (test-pain) given together with Stimulus B (conditioning pain) is perceived less painful than when Stimulus A was given alone. Although the literature is not entirely consistent, CPM can be reduced with naltrexone, suggesting at least partial dependence of inhibition on endogenous opioids. CPM will be determined at baseline, 12 weeks and 24 weeks, with the hypothesis that FES-RT will lead to increased CPM.