Altered basal ganglia infraslow oscillation and resting functional connectivity in complex regional pain syndrome

Abstract

Complex regional pain syndrome (CRPS) is a painful condition commonly accompanied by movement disturbances and often affects the upper limbs. The basal ganglia motor loop is central to movement, however, non-motor basal ganglia loops are involved in pain, sensory integration, visual processing, cognition, and emotion. Systematic evaluation of each basal ganglia functional loop and its relation to motor and non-motor disturbances in CRPS has not been investigated. We recruited 15 upper limb CRPS and 45 matched healthy control subjects. Using functional magnetic resonance imaging, infraslow oscillations (ISO) and resting-state functional connectivity in motor and non-motor basal ganglia loops were investigated using putamen and caudate seeds. Compared to controls, CRPS subjects displayed increased ISO power in the putamen contralateral to the CRPS affected limb, specifically, in contralateral putamen areas representing the supplementary motor area hand, motor hand, and motor tongue. Furthermore, compared to controls, CRPS subjects displayed increased resting connectivity between these putaminal areas as well as from the caudate body to cortical areas such as the primary motor cortex, supplementary and cingulate motor areas, parietal association areas, and the orbitofrontal cortex. These findings demonstrate changes in basal ganglia loop function in CRPS subjects and may underpin motor disturbances of CRPS.

Keywords: basal ganglia; chronic pain; complex regional pain syndrome; infraslow oscillations; motor dysfunction; putamen; resting-state fMRI.

FIGURE 1

(a) Locations of the basal ganglia seeds used in the infraslow oscillation (ISO) and resting functional connectivity analysis. The seed regions are located contralateral to the CRPS affected limb. (b) The mask of the frontal lobe, anterior cingulate cortex, middle temporal gyrus, and parietal lobe used to restrict the functional connectivity analysis. Slice locations in Montreal neurological institute space are indicated on the top right of each axial slice. Contra, contralateral to affected limb; dl, dorsolateral; SMA, supplementary motor area; vl, ventrolateral

FIGURE 2

Increased infraslow oscillations (ISO) in CRPS subjects as compared with matched healthy controls. Box and whisker plots of mean amplitude of low‐frequency fluctuations (ALFF) power over three standard ISO frequency bands: Slow‐5: 0.01–0.027 Hz, slow‐4: 0.027–0.073 Hz and slow‐3: 0.073–0.198 Hz in the region of the (a) putamen ISO and (b) caudate tail, ventral putamen, ventral striatum, motor tongue area of the putamen, motor hand area of the putamen, ventrolateral (vl) caudate head, motor foot area of the putamen, supplementary motor hand area of the putamen (SMA hand), dorsolateral (dl) caudate head and caudate body seeds. The seed regions are located contralateral to the CRPS affected limb. The box indicates the interquartile range: The median is indicated by the solid line inside the box, the 25th percentile by the bottom line of the box and 75th percentile by the top line of the box. The mean is represented by the black dot within the box. The whiskers extend from the 2.5th to 97.5th percentile. The blue dots above and below the whiskers represent data points that lie outside the 2.5–97.5 percentile range. Slice locations in Montreal Neurological Institute space are indicated on the top right of each axial slice. Contra: Contralateral to affected limb. (*p < 0.05 significantly different to controls; two‐sample t test)

FIGURE 3

Increased infraslow oscillations (ISO) power in CRPS subjects correlated with less disability. Scatter plots showing Pearson correlations; the line represents the best fit for the correlations. The Pearson’s correlation coefficient (r) and the FDR‐adjusted significance of correlation (p) are displayed on the plots. Patient‐rated wrist and hand evaluation (PRWHE) correlated with slow‐4 ALFF power of the (a) putamen ISO seed and (b) putamen motor hand area. Shortened disabilities of the arm, shoulder and hand (QuickDASH) outcome measure correlated with (c) slow‐4 ALFF power, and (d) slow‐3 ALFF power of the putamen motor hand area

FIGURE 4

Significantly greater functional connectivity strength of the putamen infraslow oscillations (ISO) seed in CRPS subjects as compared to controls (p < 0.05; false discovery rate corrected for multiple comparisons, hot color scale). Slice locations in Montreal neurological institute space are indicated on the top right of each axial slice. Lower panel are plots of individual subject and mean ± SEM beta values of putamen ISO seed connectivity to the orbitofrontal cortex (OFC), hand area of the primary motor cortex (M1 hand), cingulate motor area (CMA), hand area of the somatosensory cortex (S1 hand), and middle temporal gyrus. Contra, contralateral to affected limb

FIGURE 5

Increased functional connectivity of putamen motor loop seeds in CRPS subjects as compared with matched healthy controls. Increased functional connectivity of the putaminal (a) motor hand area, (b) motor foot area, (c) motor tongue area, and (d) the supplementary motor hand area of the putamen (SMA hand) (p < 0.05; false discovery rate corrected for multiple comparisons, hot color scale). Slice locations in Montreal neurological institute space are indicated on the top right of each axial slice. CMA, cingulate motor area; contra, contralateral to affected limb; M1, primary motor cortex; OFC, orbitofrontal cortex

FIGURE 6

Increased functional connectivity of the caudate body seed in CRPS subjects as compared with matched healthy controls (p < 0.05; false discovery rate corrected for multiple comparisons, hot color scale). Slice locations in Montreal neurological institute space are indicated on the top right of each axial slice. CMA, cingulate motor area; contra, contralateral to affected limb; dlPFC, dorsolateral prefrontal cortex; M1, primary motor cortex; MCC, mid‐cingulate cortex; OFC, orbitofrontal cortex; S1, primary somatosensory cortex