Resting state connectivity within the basal ganglia and gait speed in older adults with cerebral small vessel disease and locomotor risk factors

Abstract

Background and aim: The basal ganglia are critical for planned locomotion, but their role in age-related gait slowing is not well known. Spontaneous regional co-activation of brain activity at rest, known as resting state connectivity, is emerging as a biomarker of functional neural specialization of varying human processes, including gait. We hypothesized that greater connectivity amongst regions of the basal ganglia would be associated with faster gait speed in the elderly. We further investigated whether this association was similar in strength to that of other risk factors for gait slowing, specifically white matter hyperintensities (WMH).

Methods: A cohort of 269 adults (79-90 years, 146 females, 164 White) were assessed for gait speed (m/sec) via stopwatch; brain activation during resting state functional magnetic resonance imaging, WMH, and gray matter volume (GMV) normalized by intracranial volume via 3T neuroimaging; and risk factors of poorer locomotion via clinical exams (body mass index (BMI), muscle strength, vision, musculoskeletal pain, cardiometabolic conditions, depressive symptoms, and cognitive function). To understand whether basal ganglia connectivity shows distinct clusters of connectivity, we conducted a k-means clustering analysis of regional co-activation among the substantia nigra, nucleus accumbens, subthalamic nucleus, putamen, pallidum, and caudate. We conducted two multivariable linear regression models: (1) with gait speed as the dependent variable and connectivity, demographics, WMH, GMV, and locomotor risk factors as independent variables and (2) with basal ganglia connectivity as the dependent variable and demographics, WMH, GMV, and locomotor risk factors as independent variables.

Results: We identified two clusters of basal ganglia connectivity: high and low without a distinct spatial distribution allowing us to compute an average connectivity index of the entire basal ganglia regional connectivity (representing a continuous measure). Lower connectivity was associated with slower gait, independent of other locomotor risk factors, including WMH; the coefficient of this association was similar to those of other locomotor risk factors. Lower connectivity was significantly associated with lower BMI and greater WMH.

Conclusions: Lower resting state basal ganglia connectivity is associated with slower gait speed. Its contribution appears comparable to WMH and other locomotor risk factors. Future studies should assess whether promoting higher basal ganglia connectivity in older adults may reduce age-related gait slowing.

Keywords: Cerebrovascular Burden; Connectivity; Gait; Late-Life; Resting State; WMH.

Fig. 1

(A) Regions-of-interest (ROIs) used of the basal ganglia overlaid on an average structural image of participants in the study. (B) An example of a single participant’s connectivity matrix, which generates 120 unique connectivity pairs (8 regions and 2 hemispheres, 16 × 16 total connections but half used since connectivity is bidirectional and not including diagonal since values equal one). Values represent the Pearson correlation coefficient between any pair of eigenvariate timeseries; negative values often represent low correlation rather than anticorrelation since they may be a product of covariate signal regression rather than a true anticorrelation.

Fig. 2

(A) Variance Ratio criterion by number of clusters. Optimal clustering should be given by the first local maximum of the ratios, in our case a value of 2 clusters was returned. (B) Each individual has a distance between each cluster centroid (in our case two clusters), and a plot of distance to cluster 1 against distance to cluster 2 helps visualize the separation of the two clusters. (C) Silhouette plot displays the Silhouette value for each individual and is a measure of how close each point in one cluster is to points in the neighboring clusters. Most points have a moderate level of separation in both clusters, however a small number of points in cluster 1 are not well separated. (D) Histogram of adjusted Rand index across the 5,000 random resampling (sampling either 75% or 50% of original data). Adjusted Rand index is a measure of similarity between our original clustering and clustering with only a subset of the sample.

Fig. 3

(A) Histogram of connectivity (mean zero and standard deviation of 1) across all pairwise connectivity, which indicates that cluster 2 has low basal ganglia connectivity while cluster 1 has high basal ganglia connectivity. Connectivity matrix of a single participant with low basal ganglia connectivity (B) and high basal ganglia connectivity (C) is shown to demonstrate the differences between clusters.

Fig. 4

Slower gait speed was associated with greater BMI (A), lower quadricep strength (B), greater WMH volume (C), lower average basal ganglia connectivity (D), and being Black race compared to White race (E).

Fig. 5

Lower average basal ganglia connectivity is significantly associated with lower BMI (A) and greater WMH volume (B).