Altered Behavioral and Autonomic Pain Responses in Alzheimer’s Disease Are Associated with Dysfunctional Affective, Self-Reflective and Salience Network Resting-State Connectivity

Figures

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  Figure 1. Flow chart describing general study methods. AD, Alzheimer’s disease; HS, Healthy senior; rs-fMRI, resting-state functional magnetic resonance imaging; PAINAD, Pain Assessment in Advanced Dementia scale; HR, Heart Rate; mAD, mild AD; sAD, severe AD; RSNs, Resting-State Networks; GLM, General Linear Model; *Beach et al. (2015).

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  Figure 2. Independent Components (ICs) of interest resulting from Group ICA of all HS and AD subjects. These ICs were used in permutational tests exploring relationships between connectivity and PAINAD score differences between groups. ICs of interest determined via consideration of brain regions/networks typically associated with pain, emotion and behavior. Resultant ICs of non-interest, as well as those representing non-neuronal signal not shown. MNI coordinates (x, y, z) shown below each map.

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  Figure 3. ICs of interest resulting from Group ICA of only AD subjects. These ICs were used in permutational tests exploring relationships between connectivity and HR change differences between mAD and sAD patients. ICs of interest determined via consideration of brain regions/networks typically associated with autonomic responses and regulation. Resultant ICs of non-interest, as well as those representing non-neuronal signal not shown. MNI coordinate shown below each map.

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  Figure 4. Group level behavioral pain responses (Pain Assessment in Advanced Dementia, PAINAD scale). (A) Average PAINAD scores for each pressure intensity (kilograms, kg) among HS and full AD groups; mild/moderate and severe (mAD and sAD) subgroups are also included. Associated linear regression lines are superimposed for HS and AD groups, allowing for visualization of slope of change and intercept across stimulus levels. (B) All PAINAD summary measures visualized as group averages, including slope of change, intercept and mean response. Asterisk indicates significant group difference at p ≤ 0.05 between HS and AD groups. Error bars represent standard error of the mean (SEM).

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  Figure 5. Group level autonomic pain responses (HR in beats per minute, bpm). (A) Average HR changes from baseline (bpm) for each pressure intensity (kilograms, kg) among mild Alzheimer’s (mAD; black circles) and severe Alzheimer’s (sAD; gray triangles) patient sub-groups. Associated linear regression lines are superimposed, allowing for visualization of slope of change and intercept across stimulus levels. (B) HR response summary measures across pressure levels, including slope of change, intercept and mean response. Asterisk (*) indicates significant group difference at p ≤ 0.05. Plus (+) indicates marginal significance (p < 0.06). Error bars represent SEM.

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  Figure 6. Differential resting state network (RSN) functional connectivity (from GICA1) associated with greater PAINAD slope of change and mean PAINAD scores in AD patients vs. HS. RSNs are presented in blue, while clusters are red-yellow (encircled in green). (A) Top, significant interaction effects for group (HS vs. AD) × PAINAD slope of change; top—greater connectivity in AD vs. HS between right (R) temporal pole and ventromedial prefrontal cortex (vmPFC) clusters to a temporal limbic network (TLN, IC3; clusters thresholded at p < 0.10 for visualization purposes); the interaction is visualized on the right with connectivity (beta values) plotted against PAINAD slope with superimposed linear regression lines; bottom—reduced connectivity in AD vs. HS between posterior and ventral components of the DMN (pDMN and vDMN, ICs 1 and 8, left); group connectivity strength differences (Z-transformed partial correlations) visualized on the right. (B) Right—significant interaction effect for group × mean PAINAD score with greater connectivity in AD vs. HS for an anterior DMN (aDMN, IC 6) component and ventral SN (vSN, IC 4) component; left—group connectivity strength differences visualized…

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  Figure 7. RSN connectivity significantly correlated with HR response intercept and mean HR response within AD subjects. Associated ICs are presented in blue, clusters are red-yellow. Mean cluster beta-values, representing cluster–network connectivity strength for each subject, are plotted against HR responses (mild/moderate AD (mAD) green circles, sAD purple circles). (A) Top—plot of positive association between precuneus—posterior DMN component (pDMN, IC 1) and HR change intercept; bottom—visualization of the cluster. (B) Top—plots of positive and negative associations of precuneus–pDMN and vmPFC–ventral SN (vSN, IC 14) component, respectively, for mean HR change; bottom—visualization of clusters. Clusters visualized at p < 0.05, family-wise error (FWE). Coordinates are MNI space.