Effect sizes of BOLD CVR, resting-state signal fluctuations and time delay measures for the assessment of hemodynamic impairment in carotid occlusion patients

Abstract

Background and purposeThe BOLD signal amplitude as a response to a hypercapnia stimulus is commonly used to assess cerebrovascular reserve. Despite recent advances, the implementation remains cumbersome and alternative ways to assess hemodynamic impairment are desirable. Resting-state BOLD signal fluctuations (rsBOLD) have been proposed however data on its sensitivity and dependence on baseline venous cerebral blood volume (vCBV) is limited. The primary aim of this study was to compare the effect sizes of resting-state and hypercapnia induced BOLD signal changes in the detection of hemodynamic impairment. The second aim of the study was to assess the dependence of BOLD signal variability on vCBV.Materials and methodsFifteen patients with internal carotid artery occlusive disease and 15 matched healthy controls were included in this study. The BOLD signal was derived from a dual-echo gradient-echo echo-planar sequence during hypercapnia (HC) and hyperoxia (HO) gas modulations. BOLD (fractional) amplitude of low frequency fluctuations ((f)ALFF) was compared to HC-BOLD, BOLD response delays derived from time delay analysis and ΔBOLD in response to progressively increasing HC. Effect sizes (i.e. the standard mean difference between patients and controls) were calculated. HO-BOLD was used to estimate vCBV, and its contribution to the variability in rsBOLD signal was evaluated.ResultsThe effect sizes of ALFF and fALFF (0.61 and 0.72) were lower than the effect sizes related to hypercapnia-based hemodynamic assessment analysis; 1.62, 1.56 and 0.90 for HC-BOLD, BOLD response delays and ΔBOLD in response to progressively increasing HC. A moderate relation was found between (f)ALFF and HC-BOLD in controls (R2 of 0.61 and 0.42), but this relation decreased in patients (R2 of 0.33 and 0.15). (f)ALFF did not differ between patients and controls whereas HC-BOLD did (p < 0.005). The ΔBOLD response to progressively increasing HC was significantly different in between patients and controls for ΔEtCO2 values ≥ 2 mmHg (at +2 mmHg F(1, 18) = 5.85, p = 0.026). Up to 31% and 53% of the variance in the ALFF and HC-BOLD spatial distribution could be explained by HO-BOLD.ConclusionALFF and fALFF demonstrated a moderate effect size to detect hemodynamic impairment whereas the effect size was large for methods employing a hypercapnia-based vascular stress stimulus. Based on our analysis of BOLD signal change as a response to a progressively increasing hypercapnia stimulus we can argue that a hypercapnia stimulus of at least 2 mmHg above baseline EtCO2 is necessary to evaluate hemodynamic impairment. We also demonstrated that a substantial amount of information imbedded in the rsBOLD and HC-BOLD was explained by HO-BOLD. HO-BOLD can serve as a proxy for vCBV and this thus indicates that one should be careful when adopting these techniques in disease cases with compromised CBV.

Cerebrovascular Reactivity Mapping Without Gas Challenges: A Methodological Guide

“…Nevertheless, a limitation of this approach is that, if the subject’s spontaneous breathing pattern yields minimal fluctuations in their PETCO 2 level, there might not be enough signal variation for reliable CVR assessment. In fact, de Vis and colleagues showed that a hypercapnic stimulus of at least 2 mmHg above baseline PETCO 2 is necessary in order to evaluate any hemodynamic impairment ( De Vis et al, 2018 ). Another challenge is isolating low-frequency BOLD fluctuations arising from CVR mechanisms versus other physiologic noise sources or neural processes described above.…”

“…While hypercapnia fMRI measures led to large effect sizes when detecting hemodynamic impairment, rs-fMRI ALFF/fALFF metrics only showed moderate effect sizes. Nevertheless, in both hypercapnia and resting-state CVR measures, resting CBV (using hyperoxia BOLD signal as a proxy) significantly explained a large portion of BOLD signal variance across the brain (hypercapnia: 53/37%; ALFF: 31/23%; fALFF: 29/14%, in healthy controls/patients, respectively) ( De Vis et al, 2018 ). Similar to ALFF, fALFF maps have also been employed as a voxelwise scaling factor of task-based fMRI analysis, significantly reducing inter-subject variability ( Kalcher et al, 2013 ).…”

Reproducibility of a ramping protocol to measure cerebral vascular reactivity using functional magnetic resonance imaging

“…To date, most studies using a ramp protocol with SGD have been conducted specifically to test different physiological CVR relationships (i.e., linear, sigmoidal, etc.) (Bhogal et al, ) in order to better describe CVR (Bhogal et al, ; Sobczyk et al, ) or, simply, the utility in diagnosing steno‐occlusive diseases (De Vis et al, , ; Duffin et al, ). To our knowledge, no studies have specifically investigated, nor reported, the reproducibility of a ramp sequence to assess changes in CVR.…”

“…A ramping method with a relatively slow rate of change may be more tolerable for participants while maximizing the P et CO 2 range sampled. This may, potentially, uncover subtle pathophysiology by measuring the point at which a cerebral vessel or a brain region reach dilatory capacity (Bhogal et al, 2014;De Vis, Bhogal, Hendrikse, Petersen, & Siero, 2018;Duffin et al, 2017), which is not possible using a single step change.…”

Resting State BOLD Variability Is Linked to White Matter Vascular Burden in Healthy Aging but Not in Older Adults With Subjective Cognitive Decline

“…Conversely, other theories in the literature purport that rsfMRI BOLD fluctuations may reflect underlying changes in cerebrovascular integrity, that which itself may be further associated with increased independent risk for AD (Makedonov et al, 2013(Makedonov et al, , 2016Jahanian et al, 2014;DeVis et al, 2018). In such interpretations, a finding of a lack of regional variation in SD BOLD between participants with SCD and controls may reasonably reflect (i) a lack of significant difference in vascular anomalies between the two groups and/or (ii) dissociable relationships between SD BOLD and vascular factors within each group.…”