Cerebral blood flow and cardiovascular risk effects on resting brain regional homogeneity

Abstract

Regional homogeneity (ReHo) is a measure of local functional brain connectivity that has been reported to be altered in a wide range of neuropsychiatric disorders. Computed from brain resting-state functional MRI time series, ReHo is also sensitive to fluctuations in cerebral blood flow (CBF) that in turn may be influenced by cerebrovascular health. We accessed cerebrovascular health with Framingham cardiovascular risk score (FCVRS). We hypothesize that ReHo signal may be influenced by regional CBF; and that these associations can be summarized as FCVRS→CBF→ReHo. We used three independent samples to test this hypothesis. A test-retest sample of N = 30 healthy volunteers was used for test-retest evaluation of CBF effects on ReHo. Amish Connectome Project (ACP) sample (N = 204, healthy individuals) was used to evaluate association between FCVRS and ReHo and testing if the association diminishes given CBF. The UKBB sample (N = 6,285, healthy participants) was used to replicate the effects of FCVRS on ReHo. We observed strong CBF→ReHo links (p<2.5 × 10^-3) using a three-point longitudinal sample. In ACP sample, marginal and partial correlations analyses demonstrated that both CBF and FCVRS were significantly correlated with the whole-brain average (p<10^-6) and regional ReHo values, with the strongest correlations observed in frontal, parietal, and temporal areas. Yet, the association between ReHo and FCVRS became insignificant once the effect of CBF was accounted for. In contrast, CBF→ReHo remained significantly linked after adjusting for FCVRS and demographic covariates (p<10^-6). Analysis in N = 6,285 replicated the FCVRS→ReHo effect (p = 2.7 × 10^-27). In summary, ReHo alterations in health and neuropsychiatric illnesses may be partially driven by region-specific variability in CBF, which is, in turn, influenced by cardiovascular factors.

Keywords: Arterial-spin labeling; Correlation; Local functional connectivity; Multivariate mediation analysis; Resting state functional MRI.

Fig. 1.

Average cerebral blood flow (CBF) map (A) and regional homogeneity (ReHo) map (B) in N = 204 participants. Numbers in the images are the z-coordinate of the axial slices. The scale for CBF ranges from 10 to 100 (mL/100 g/min); the scale for ReHo ranges from 0.2 to 0.8.

Fig. 2.. Correlations among FCVRS, CBF, and ReHo across samples.

Data are from the Amish Connectome Project (ACP) sample unless specified otherwise. A. The whole-brain average cerebral blood flow (CBF) signal and regional homogeneity (ReHo) showed a significant positive correlation. B. Framingham cardiovascular risk score (FCVRS) showed a significantly negative correlation with the whole-brain average ReHo. C & D. FCVRS showed significant correlations with whole brain average CBF in ACP and UKBB samples, respectively. All the results presented in the figure are corrected for participants’ age and sex.

Fig. 3.. The regional correlation maps.

Region-by-region CBF and ReHo signals were from the parcellated brain regions using JHU-MNI atlas. A. Whole brain CBF and ReHo correlation map, where correlation analyses were performed between regional CBF and ReHo signals from the same brain region. B. The Framingham cardiovascular risk score (FCVRS) and regional CBF correlation map. C & D. FCVRS score and ReHo correlation maps in ACP (N = 204) and UKBB (N = 6285) participants, respectively. Each subplot was supplied with a colorbar, and a white horizontal mark represents the color that corresponds to corrected p < 0.05 (multiple comparison corrections). Values in the images are the z-coordinates of the displayed axial slices. Positive correlations have positive r values and negative correlations have negative r values. Note that for B, C, and D stronger correlations were more negative. The displayed images are in radiological convention.

Fig. 4.. A schematic diagram of the mediation path.

(A) Whole-brain average mediation analysis. The mediation proportion effect of FCVRS on the average ReHo through average CBF was found to be 52% (p<0.0001). All the requirements for a mediation effect are satisfied: Path a, b, and c are significant, and c’ is significantly smaller than c. Path a and b together represent the indirect (mediated) effect. Path c is the direct effect and c’ is the remaining direct effect of FCVRS on the average ReHo after controlling for mediating effect. (B) The isoregional mediation analysis involved the mediation pathway, FCVRS → a CBF region → ReHo at the same region. The strength of the mediations was mapped. Bilateral frontal and parietal areas showed the strongest effect sizes for mediation.

Fig. 5.. Hetero-regional mediation analysis results.

A. 107×107 potential mediation pathways. Correspondingly, 107×107 p-values were calculated to assess the significance of the mediation effects, shown as a heatmap of -log(p) values. The order of CBF (y axis) and ReHo (x axis) regions is in the same order as they are used to extract CBF and ReHo measures using atlas. Full names of the abbreviations are in supplementary Table 1. B. The mediation pattern detection algorithm identified a set of CBF regions that can impact a number of ReHo regions (p<0.0001), re-ordered based on the mediation bi-cluster. C. (i). The CBF regions forming a cluster based on orthogonal component analysis that significantly mediated another cluster of ReHo measurements. The ReHo regions mediated by the CBF regions in (i) are shown in (ii). This hetero-regional analysis-based mediation explained about 82% of the FCVRS direct effect on the ReHo signals in the regions shown in (ii). D. The 26 regions that overlap between the 45 CBF regions and the 43 ReHo regions.