Kinematic and dynamic gait compensations in a rat model of lumbar radiculopathy and the effects of tumor necrosis factor-alpha antagonism

Abstract

Introduction: Tumor necrosis factor-α (TNFα) has received significant attention as a mediator of lumbar radiculopathy, with interest in TNF antagonism to treat radiculopathy. Prior studies have demonstrated that TNF antagonists can attenuate heightened nociception resulting from lumbar radiculopathy in the preclinical model. Less is known about the potential impact of TNF antagonism on gait compensations, despite being of clinical relevance. In this study, we expand on previous descriptions of gait compensations resulting from lumbar radiculopathy in the rat and describe the ability of local TNF antagonism to prevent the development of gait compensations, altered weight bearing, and heightened nociception.

Methods: Eighteen male Sprague-Dawley rats were investigated for mechanical sensitivity, weight-bearing, and gait pre- and post-operatively. For surgery, tail nucleus pulposus (NP) tissue was collected and the right L5 dorsal root ganglion (DRG) was exposed (Day 0). In sham animals, NP tissue was discarded (n = 6); for experimental animals, autologous NP was placed on the DRG with or without 20 μg of soluble TNF receptor type II (sTNFRII, n = 6 per group). Spatiotemporal gait characteristics (open arena) and mechanical sensitivity (von Frey filaments) were assessed on post-operative Day 5; gait dynamics (force plate arena) and weight-bearing (incapacitance meter) were assessed on post-operative Day 6.

Results: High-speed gait characterization revealed animals with NP alone had a 5% decrease in stance time on their affected limbs on Day 5 (P ≤0.032). Ground reaction force analysis on Day 6 aligned with temporal changes observed on Day 5, with vertical impulse reduced in the affected limb of animals with NP alone (area under the vertical force-time curve, P <0.02). Concordant with gait, animals with NP alone also had some evidence of affected limb mechanical allodynia on Day 5 (P = 0.08) and reduced weight-bearing on the affected limb on Day 6 (P <0.05). Delivery of sTNFRII at the time of NP placement ameliorated signs of mechanical hypersensitivity, imbalanced weight distribution, and gait compensations (P <0.1).

Conclusions: Our data indicate gait characterization has value for describing early limb dysfunctions in pre-clinical models of lumbar radiculopathy. Furthermore, TNF antagonism prevented the development of gait compensations subsequent to lumbar radiculopathy in our model.

Figure 1

Unbalanced, asymmetric gait in rats with lumbar radiculopathy (five days post-operation). Unbalanced, asymmetric gaits were observed in animals with NP alone (∀, P <0.032), while all other groups did not differ significantly from the mathematical definition of balanced, symmetric gait. The percentage stance time imbalance observed in animals with NP alone differed from both preoperative (*, P = 0.025) and sham controls (#, P = 0.013), and this imbalance was improved in animals receiving NP and sTNFRII relative to animals with NP alone (^, P = 0.012). Gait symmetry of animals with NP alone was also significantly different from pre-operative controls (*, P = 0.009). Data are presented as mean ± standard error.

Figure 2

Affected and contralateral percentage stance time in rats with lumbar radiculopathy (five days post-operation). A significant correlation between percentage stance time and velocity is observed in walking rats (upper left and right); raw data with a linear fit of the pre-operative data are shown. As velocity increases, percentage stance time decreases in both the affected (right) and contralateral (left) limb. After accounting for this correlation, decreased affected limb percentage stance times (bottom right), but not contralateral limb stance times (bottom left) can be identified in animals with NP alone relative to pre-operative and sham controls (P = 0.010, P = 0.013, respectively). While sTNFRII treatment improved stance time imbalance resulting from NP application to the L5 DRG (see Figure 1), improvement in the stance time balance in the sTNFRII treated rats appears to result from a relative decrease in both the affected and contralateral limb stance times relative to pre-operative and sham controls.

Figure 3

Stride length and step widths in rats with lumbar radiculopathy (five days post-operation). A significant correlation between stride length and velocity is observed in walking rats (upper left); raw data with a linear fit of the pre-operative data are shown. As velocity increases, stride length increases. Even after accounting for this correlation, stride lengths were found to increase in sham controls, animals with NP alone, and animals with NP and sTNFRII (*, lower left, P <0.016). A weaker, but important, correlation is also seen between step width and velocity (upper right); again, raw data with a linear fit of the pre-operative are shown. Here, as velocity increases, step widths narrow; however, after accounting for this correlation, no differences were observed in step width between groups (lower right). Data in lower graphs are presented as mean ± standard error.

Figure 4

Weight-bearing characteristics of rats with lumbar radiculopathy (six days post-operation). Rats with NP alone had unbalanced weight-distribution, supporting significantly less weight on their affected limb relative to their contralateral limb (∀, P = 0.048). This weight-distribution was significantly different from pre-operative controls (*, P = 0.022). Rats with NP and sTNFRII treatment had improved weight distribution relative to rats with NP alone (^, P = 0.005). Data are presented as mean ± standard error.

Figure 5

Normalized force curves for the affected limbs of rats with lumbar radiculopathy (six days post-operation). Ground reaction forces represented in these plots were created by normalizing forces to body weight and time to the total limb stance time. Fx curves show a breaking phase (Force <0), during which, the limb is loaded and resists the translation of mass forward. Fx curves also show a propulsion phase (Force >0) during which the limb is generating push-off forces in the direction of travel. Fy force curves show a peak between approximately 0 to 50% of stance time, during which the limb is being loaded as mass is transferred onto the limb for single limb support. A second peak is seen from approximately 50 to 100% of stance time; here, the limb is generating push-off forces that translate mass toward the contralateral limb. Fz force curves show a loading phase from 0 to 30% of stance time, a support phase from 30 to 80% of stance time, and an unloading phase from 80 to 100% of stance time. In general, the shape of the force curves were as expected for each group; however, differences between generalized terms for each group were observed (See Table 2). Each data point is presented as mean ± 95% confidence interval.

Figure 6

Mechanical sensitivity in the affected and contralateral limb of rats with lumbar radiculopathy (five days post-operation). Rats with NP alone had significant decreases in the mechanical withdrawal threshold of their affected limb relative to their contralateral limb (∀, P = 0.032) and pre-operative controls (*, P = 0.001). Sham controls also had significant decreases in their mechanical withdrawal threshold relative to pre-operative controls (* P = 0.030). Rats receiving NP and sTNFRII treatment had improved mechanical withdrawal thresholds relative to rats with NP alone (^, P = 0.013). Data presented as mean + standard error.