Gait analysis and the cumulative gait index (CGI): Translational tools to assess impairments exhibited by rats with olivocerebellar ataxia

Abstract

Deviations from ‘normal’ locomotion exhibited by humans and laboratory animals may be determined using automated systems that capture both temporal and spatial gait parameters. Although many measures generated by these systems are unrelated and independent, some may be related and dependent, representing redundant assessments of function. To investigate this possibility, a treadmill-based system was used to capture gait parameters from normal and ataxic rats, and a multivariate analysis was conducted to determine deviations from normal. Rats were trained on the treadmill at two speeds, and gait parameters were generated prior to and following lesions of the olivocerebellar pathway. Control (non-lesioned) animals exhibited stable hindlimb gait parameters across assessments at each speed. Lesioned animals exhibited alterations in multiple hindlimb gait parameters, characterized by significant increases in stride frequency, braking duration, stance width, step angle, and paw angle and decreases in stride, stance, swing and propulsion durations, stride length and paw area. A principal component analysis of initial hindlimb measures indicated 3 uncorrelated factors mediating performance, termed rhythmicity, thrust and contact. Deviation in the performance of each animal from the group mean was determined for each factor and values summed to yield the Cumulative Gait Index (CGI), a single value reflecting variation within the group. The CGI for lesioned animals increased 2.3-fold relative to unlesioned animals. This study characterizes gait alterations in laboratory rats rendered ataxic by destruction of the climbing fiber pathway innervating Purkinje cells and demonstrates that a single index can be used to describe overall gait impairments.

Analysis of gait in rats with olivocerebellar lesions and ability of the nicotinic acetylcholine receptor agonist varenicline to attenuate impairments

“…The DigiGait ™ Imaging System and software (version 12.2; Mouse Specifics, Boston, MA) were used to generate temporal and spatial gait parameters as described [25]. Gait parameters, analyzed by a rater blinded to experimental condition, were generated from the hind limbs and included both temporal (swing duration, braking duration, propulsion duration, stance duration, stride duration and stride frequency) and spatial (stride length, stance width, paw angle, step angle, and paw area) measures, all of which are affected by the administration of 3-AP [25].…”

“…The treadmill belt and enclosure were wiped with 70% ethanol between trials. At 2–3 days following completion of training, baseline performance was assessed for 2 minutes at each speed, and gait parameters were generated from a sequence consisting of at least 3 uninterrupted strides per paw, i.e., a total of 6 strides [25]. Animals that did not perform this sequence on a given trial were retested once at that speed.…”

“…Of the 63 animals tested at baseline, 4 failed to meet this criterion and were removed from further study. For each animal, the number of sequences generated within the 2 minute trial at each speed was quantified, similar to a prior study [25]. …”

“…The factor loadings generated from this analysis were used to weight z-transformed gait variable data, which were then summed to produce deviation values for each identified factor. These values were summed to yield the CGI, an index representing overall deviations from prototypical gait patterns [25]. CGI values were calculated for each animal at each assessment time, and the group means determined.…”

“…The variability confound has been addressed in the clinical literature by the use of principal component analysis (PCA) and the subsequent determination of a gait index to express gait deviations from a normal population [21–24]. A similar approach has been used in our laboratory for preclinical studies in rats following the administration of the neurotoxin 3-acetylpyridine (3-AP), which destroys the olivocerebellar pathway [25]. These studies demonstrated that ataxic animals exhibited a nearly 3-fold increase in deviation from normal gait compared to age-matched non-lesioned animals.…”