BOLD-based cerebrovascular reactivity vascular transfer function isolates amplitude and timing responses to better characterize cerebral small vessel disease.

Cerebrovascular reactivity (CVR) is a dynamic measure of the cerebral blood vessel response to vasoactive stimulus. Conventional CVR measures amplitude changes in the blood-oxygenation-level-dependent (BOLD) signal per unit change in end-tidal CO2 (PET CO2 ), effectively discarding potential timing information. This study proposes a deconvolution procedure to characterize CVR responses based on a vascular transfer function (VTF) that separates amplitude and timing CVR effects. We implemented the CVR-VTF to primarily evaluate normal-appearing white matter (WM) responses in those with a range of small vessel disease. Comparisons between simulations of PET CO2 input models revealed that boxcar and ramp hypercapnia paradigms had the lowest relative deconvolution error. We used a T2 * BOLD-MRI sequence on a 3 T MRI scanner, with a boxcar delivery model of CO2 , to test the CVR-VTF approach in 18 healthy adults and three white matter hyperintensity (WMH) groups: 20 adults with moderate WMH, 12 adults with severe WMH, and 10 adults with genetic WMH (CADASIL). A subset of participants performed a second CVR session at a one-year follow-up. Conventional CVR, area under the curve of VTF (VTF-AUC), and VTF time-to-peak (VTF-TTP) were assessed in WM and grey matter (GM) at baseline and one-year follow-up. WMH groups had lower WM VTF-AUC compared with the healthy group (p < 0.0001), whereas GM CVR did not differ between groups (p > 0.1). WM VTF-TTP of the healthy group was less than that in the moderate WMH group (p = 0.016). Baseline VTF-AUC was lower than follow-up VTF-AUC in WM (p = 0.013) and GM (p = 0.026). The intraclass correlation for VTF-AUC in WM was 0.39 and coefficient of repeatability was 0.08 [%BOLD/mm Hg]. This study assessed CVR timing and amplitude information without applying model assumptions to the CVR response; this approach may be useful in the development of robust clinical biomarkers of CSVD.

Regional reduction in cortical blood flow among cognitively impaired adults with relapsing-remitting multiple sclerosis patients.

PURPOSE: Detection of cortical abnormalities in relapsing-remitting multiple sclerosis (RRMS) remains elusive. Structural magnetic resonance imaging (MRI) measures of cortical integrity are limited, although functional techniques such as pseudo-continuous arterial spin labeling (pCASL) show promise as a surrogate marker of disease severity. We sought to determine the utility of pCASL to assess cortical cerebral blood flow (CBF) in RRMS patients with (RRMS-I) and without (RRMS-NI) cognitive impairment. METHODS: A total of 19 age-matched healthy controls and 39 RRMS patients were prospectively recruited. Cognition was assessed using the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) battery. Cortical CBF was compared between groups using a mass univariate voxel-based morphometric analysis accounting for demographic and structural variable covariates. RESULTS: Cognitive impairment was present in 51.3% of patients. Significant CBF reduction was present in the RRMS-I compared to other groups in left frontal and right superior frontal cortex. Compared to healthy controls, RRMS-I displayed reduced CBF in the frontal, limbic, parietal and temporal cortex, and putamen/thalamus. RRMS-I demonstrated reduced left superior frontal lobe cortical CBF compared to RRMS-NI. No significant cortical CBF differences were present between healthy controls and RRMS-NI. CONCLUSION: Significant cortical CBF reduction occurs in RRMS-I compared to healthy controls and RRMS-NI in anatomically significant regions after controlling for structural and demographic differences.

Multisite evaluations of a T2 -relaxation-under-spin-tagging (TRUST) MRI technique to measure brain oxygenation.

PURPOSE: Venous oxygenation (Yv ) is an important index of brain physiology and may be indicative of brain diseases. A T2 -relaxation-under-spin-tagging (TRUST) MRI technique was recently developed to measure Yv . A multisite evaluation of this technique would be an important step toward broader availability and potential clinical utilizations of Yv measures. METHODS: TRUST MRI was performed on a total of 250 healthy subjects, 125 from the developer's site and 25 each from five other sites. All sites were equipped with a 3 Tesla (T) MRI of the same vendor. The estimated Yv and the standard error (SE) of the estimation εYv were compared across sites. RESULTS: The averaged Yv and εYv across six sites were 61.1% ± 1.4% and 1.3% ± 0.2%, respectively. Multivariate regression analysis showed that the estimated Yv was dependent on age (P = 0.009) but not on performance site. In contrast, the SE of the Yv estimation was site-dependent (P = 0.024) but was less than 1.5%. Further analysis revealed that εYv was positively associated with the amount of subject motion (P < 0.001) but negatively associated with blood signal intensity (P < 0.001). CONCLUSION: This work suggests that TRUST MRI can yield equivalent results of Yv estimation across different sites.

Gray matter blood flow and volume are reduced in association with white matter hyperintensity lesion burden: a cross-sectional MRI study.

Cerebral White Matter Hyperintensities (WMH) are associated with vascular risk factors and age-related cognitive decline. WMH have primarily been associated with global white matter and gray matter (GM) changes and less is known about regional effects in GM. The purpose of this study was to test for an association between WMH and two GM imaging measures: cerebral blood flow (CBF) and voxel-based morphometry (VBM). Twenty-six elderly adults with mild to severe WMH participated in this cross-sectional 3 Tesla magnetic resonance imaging (MRI) study. MRI measures of GM CBF and VBM were derived from arterial spin labeling (ASL) and T1-weighted images, respectively. Fluid-attenuated inversion recovery (FLAIR) images were used to quantify the WMH lesion burden (mL). GM CBF and VBM data were used as dependent variables. WMH lesion burden, age and sex were used in a regression model. Visual rating of WMH with the Fazekas method was used to compare the WMH lesion volume regression approach. WMH volume was normally distributed for this group (mean volume of 22.7 mL, range: 2.2-70.6 mL). CBF analysis revealed negative associations between WMH volume and CBF in the left anterior putamen, subcallosal, accumbens, anterior caudate, orbital frontal, anterior insula, and frontal pole (corrected p < 0.05). VBM analysis revealed negative associations between WMH and GM volume in lingual gyrus, intracalcarine, and bilateral hippocampus (corrected p < 0.05). The visual rating scale corroborated the regression findings (corrected p < 0.05). WMH lesion volume was associated with intra-group GM CBF and structural differences in this cohort of WMH adults with mild to severe lesion burden.

Exercise intensity modulates the change in cerebral blood flow following aerobic exercise in chronic stroke.

The mechanisms supporting functional improvement by aerobic exercise following stroke remain incompletely understood. This study investigated how cycling intensity and aerobic fitness influence cerebral blood flow (CBF) following a single exercise session. Thirteen community-living stroke survivors performed 20 min of semi-recumbent cycling at low and moderate intensities (40-50 and 60-70 % of heart rate reserve, respectively) as determined from an exercise stress test. CBF was quantified by arterial spin labeling MRI at baseline, as well as 30 and 50 min post-exercise. An intensity-dependent effect was observed in the right post-central and supramarginal gyri up to 50 min after exercise (uncorrected p < 0.005, cluster size ≥10). Regional CBF was increased 18 ± 17 % and reduced 8 ± 12 % following moderate- and low-intensity cycling, respectively. In contrast, CBF changes were similar between sessions in the right lentiform nucleus and mid-frontal gyrus, as well as the left temporal and parietal gyri. Aerobic fitness was directly related to posterior cingulate and thalamic CBF, and inversely related to precuneal CBF at rest (R (2) ≥ 0.75); however, no relationship between fitness and the post-exercise change in CBF was observed. Divergent changes in regional CBF were observed in the right parietal cortex following low- and moderate-intensity exercise, which suggests that intensity of prescribed exercise may be useful in optimizing rehabilitation.

CACNA1C rs1006737 genotype and bipolar disorder: Focus on intermediate phenotypes and cardiovascular comorbidity.

Recently, multiple genome-wide association studies have identified a genetic polymorphism (CACNA1C rs1006737) that appears to confer susceptibility for BD. This article aims to summarize the existing literature regarding the impact of rs1006737 on functional and structural neuroimaging intermediate phenotypes. Twenty eight articles, representing 2486 healthy participants, 369 patients with BD and 104 healthy first-degree relatives of patients with BD, are incorporated. Multiple studies have demonstrated structural differences, functional differences associated with emotion-related and frontal-executive tasks, and/or differences in behavioral task performance in risk allele carriers (AA or AG). Results comparing participants with BD to health controls are generally less pronounced than within-group genetic comparisons. The review concludes with an integration of how cardiovascular comorbidity may be a relevant mediator of the observed findings, and proposes future directions toward optimized therapeutic use of calcium channel blockers in BD.

Vascular risk factor burden correlates with cerebrovascular reactivity but not resting state coactivation in the default mode network.

PURPOSE: White matter hyperintensities (WMH) are prevalent among older adults and are often associated with cognitive decline and increased risk of stroke and dementia. Vascular risk factors (VRFs) are linked to WMH, yet the impact of multiple VRFs on gray matter function is still unclear. The goal of this study was to test for associations between the number of VRFs and cerebrovascular reactivity (CVR) and resting state (RS) coactivation among individuals with WMH. MATERIALS AND METHODS: Twenty-nine participants with suspected WMH were grouped based on the number of VRFs (subgroups: 0, 1, or ≥2). CVR and RS coactivation were measured with blood oxygenation level-dependent (BOLD) imaging on a 3T magnetic resonance imaging (MRI) system during hypercapnia and rest, respectively. Default-mode (DMN), sensory-motor, and medial-visual networks, generated using independent component analysis of RS-BOLD, were selected as networks of interest (NOIs). CVR-BOLD was analyzed using two methods: 1) a model-based approach using CO2 traces, and 2) a dual-regression (DR) approach using NOIs as spatial inputs. Average CVR and RS coactivations within NOIs were compared between VRF subgroups. A secondary analysis investigated the correlation between CVR and RS coactivation. RESULTS: VRF subgroup differences were detected using DR-based CVR in the DMN (F20,2 = 5.17, P = 0.015) but not the model-based CVR nor RS coactivation. DR-based CVR was correlated with RS coactivation in the DMN (r(2) = 0.28, P = 0.006) but not the sensory-motor nor medial-visual NOIs. CONCLUSION: In individuals with WMH, CVR in the DMN was inversely associated with the number of VRFs and correlated with RS coactivation.

Automated removal of spurious intermediate cerebral blood flow volumes improves image quality among older patients: A clinical arterial spin labeling investigation.

PURPOSE: To evaluate the impact of rejecting intermediate cerebral blood flow (CBF) images that are adversely affected by head motion during an arterial spin labeling (ASL) acquisition. MATERIALS AND METHODS: Eighty participants were recruited, representing a wide age range (14-90 years) and heterogeneous cerebrovascular health conditions including bipolar disorder, chronic stroke, and moderate to severe white matter hyperintensities of presumed vascular origin. Pseudocontinuous ASL and T1 -weigthed anatomical images were acquired on a 3T scanner. ASL intermediate CBF images were included based on their contribution to the mean estimate, with the goal to maximize CBF detectability in gray matter (GM). Simulations were conducted to evaluate the performance of the proposed optimization procedure relative to other ASL postprocessing approaches. Clinical CBF images were also assessed visually by two experienced neuroradiologists. RESULTS: Optimized CBF images (CBFopt ) had significantly greater agreement with a synthetic ground truth CBF image and greater CBF detectability relative to the other ASL analysis methods (P < 0.05). Moreover, empirical CBFopt images showed a significantly improved signal-to-noise ratio relative to CBF images obtained from other postprocessing approaches (mean: 12.6%; range 1% to 56%; P < 0.001), and this improvement was age-dependent (P = 0.03). Differences between CBF images from different analysis procedures were not perceptible by visual inspection, while there was a moderate agreement between the ratings (κ = 0.44, P < 0.001). CONCLUSION: This study developed an automated head motion threshold-free procedure to improve the detection of CBF in GM. The improvement in CBF image quality was larger when considering older participants.

Estimating the sample size required to detect an arterial spin labelling magnetic resonance imaging perfusion abnormality in voxel-wise group analyses.

BACKGROUND: Voxel-based analyses are pervasive across the range of neuroimaging techniques. In the case of perfusion imaging using arterial spin labelling (ASL), a low signal-to-noise technique, there is a tradeoff between the contrast-to-noise required to detect a perfusion abnormality and its spatial localisation. In exploratory studies, the use of an a priori region of interest (ROI), which has the benefit of averaging multiple voxels, may not be justified. Thus the question considered in this study pertains to the sample size that is required to detect a voxel-level perfusion difference between groups and two algorithms are considered. NEW METHOD: Empirical 3T ASL data were acquired from 25 older adults and simulations were performed based on the group template cerebral blood flow (CBF) images. General linear model (GLM) and permutation-based algorithms were tested for their ability to detect a predefined hypoperfused ROI. Simulation parameters included: inter and intra-subject variability, degree of hypoperfusion and sample size. The true positive rate was used as a measure of sensitivity. RESULTS: For a modest group perfusion difference, i.e., 10%, 37 participants per group were required when using the permutation-based algorithm, whereas 20 participants were required for the GLM-based algorithm. COMPARISON WITH EXISTING METHODS: This study advances the perfusion power calculation literature by considering a voxel-wise analysis with correction for multiple comparison. CONCLUSIONS: The sample size requirement to detect group differences decreased exponentially in proportion to increased degree of hypoperfusion. In addition, sensitivity to detect a perfusion abnormality was influenced by the choice of algorithm.

A single session of exercise increases connectivity in sensorimotor-related brain networks: a resting-state fMRI study in young healthy adults.

Habitual long term physical activity is known to have beneficial cognitive, structural, and neuro-protective brain effects, but to date there is limited knowledge on whether a single session of exercise can alter the brain's functional connectivity, as assessed by resting-state functional magnetic resonance imaging (rs-fMRI). The primary objective of this study was to characterize potential session effects in resting-state networks (RSNs). We examined the acute effects of exercise on the functional connectivity of young healthy adults (N = 15) by collecting rs-fMRI before and after 20 min of moderate intensity aerobic exercise and compared this with a no-exercise control group (N = 15). Data were analyzed using independent component analysis, denoising and dual regression procedures. Regions of interest-based group session effect statistics were calculated in RSNs of interest using voxel-wise permutation testing and Cohen's D effect size. Group analysis in the exercising group data set revealed a session effect in sub-regions of three sensorimotor related areas: the pre and/or postcentral gyri, secondary somatosensory area and thalamus, characterized by increased co-activation after exercise (corrected p < 0.05). Cohen's D analysis also showed a significant effect of session in these three RSNs (p< 0.05), corroborating the voxel-wise findings. Analyses of the no-exercise dataset produced no significant results, thereby providing support for the exercise findings and establishing the inherent test-retest reliability of the analysis pipeline on the RSNs of interest. This study establishes the feasibility of rs-fMRI to localize brain regions that are associated with acute exercise, as well as an analysis consideration to improve sensitivity to a session effect.

Cardiopulmonary fitness correlates with regional cerebral grey matter perfusion and density in men with coronary artery disease.

PURPOSE: Physical activity is associated with positive effects on the brain but there is a paucity of clinical neuroimaging data in patients with coronary artery disease (CAD), a cardiovascular condition associated with grey matter loss. The purpose of this study was to determine which brain regions are impacted by cardiopulmonary fitness and with the change in fitness after 6 months of exercise-based cardiac rehabilitation. METHODS: CAD patients underwent magnetic resonance imaging at baseline, and peak volume of oxygen uptake during exercise testing (VO2Peak) was measured at baseline and after 6 months of training. T1-weighted structural images were used to perform grey matter (GM) voxel-based morphometry (VBM). Pseudo-continuous arterial spin labeling (pcASL) was used to produce cerebral blood flow (CBF) images. VBM and CBF data were tested voxel-wise using VO2Peak and age as explanatory variables. RESULTS: In 30 men with CAD (mean age 65±7 years), VBM and CBF identified 7 and 5 respective regions positively associated with baseline VO2Peak. These included the pre- and post-central, paracingulate, caudate, hippocampal regions and converging findings in the putamen. VO2Peak increased by 20% at follow-up in 29 patients (t = 9.6, df = 28, p<0.0001). Baseline CBF in the left post-central gyrus and baseline GM density in the right putamen predicted greater change in VO2Peak. CONCLUSION: Perfusion and GM density were associated with fitness at baseline and with greater fitness gains with exercise. This study identifies new neurobiological correlates of fitness and demonstrates the utility of multi-modal MRI to evaluate the effects of exercise in CAD patients.

Modeling and correction of bolus dispersion effects in dynamic susceptibility contrast MRI.

PURPOSE: Bolus dispersion in DSC-MRI can lead to errors in cerebral blood flow (CBF) estimation by up to 70% when using singular value decomposition analysis. However, it might be possible to correct for dispersion using two alternative methods: the vascular model (VM) and control point interpolation (CPI). Additionally, these approaches potentially provide a means to quantify the microvascular residue function. METHODS: VM and CPI were extended to correct for dispersion by means of a vascular transport function. Simulations were performed at multiple dispersion levels and an in vivo analysis was performed on a healthy subject and two patients with carotid atherosclerotic disease. RESULTS: Simulations showed that methods that could not address dispersion tended to underestimate CBF (ratio in CBF estimation, CBFratio = 0.57-0.77) in the presence of dispersion; whereas modified CPI showed the best performance at low-to-medium dispersion; CBFratio = 0.99 and 0.81, respectively. The in vivo data showed trends in CBF estimation and residue function that were consistent with the predictions from simulations. CONCLUSION: In patients with atherosclerotic disease the estimated residue function showed considerable differences in the ipsilateral hemisphere. These differences could partly be attributed to dispersive effects arising from the stenosis when dispersion corrected CPI was used. It is thus beneficial to correct for dispersion in perfusion analysis using this method.

Modeling the residue function in DSC-MRI simulations: analytical approximation to in vivo data.

PURPOSE: An exponential residue function is commonly used in numerical simulations to assess the accuracy of perfusion quantification using dynamic susceptibility contrast (DSC) MRI. Although this might be a reasonable assumption for normal tissue, microvascular hemodynamics are likely to be significantly altered in pathology. Thus the exponential function may no longer be appropriate and the estimated accuracy of DSC-MRI quantification might be inappropriate. The purpose of this study was to characterize in vivo residue function variations in normal and infarcted tissue in a chronic atherosclerotic disease cohort, and to find the most appropriate model for use in DSC simulations. METHODS: Residue functions were measured in vivo in patients with atherosclerotic disease using a nonparametric Control Point Interpolation method, which has been shown to provide a robust characterization of the shape of the residue function. The observed residue functions were approximated with five commonly used analytical expressions: exponential, bi-exponential, Lorentzian, and Fermi functions, and a previously proposed Vascular Model. RESULTS: The lowest error was found with the bi-exponential function approximations to the in vivo residue functions from both normal and infarcted tissue. CONCLUSION: A bi-exponential model should therefore be used in future numerical simulations of DSC-MRI instead of the exponential function.

Impact of a single bout of aerobic exercise on regional brain perfusion and activation responses in healthy young adults.

PURPOSE: Despite the generally accepted view that aerobic exercise can have positive effects on brain health, few studies have measured brain responses to exercise over a short time span. The purpose of this study was to examine the impact within one hour of a single bout of exercise on brain perfusion and neuronal activation. METHODS: Healthy adults (n = 16; age range: 20-35 yrs) were scanned using Magnetic Resonance Imaging (MRI) before and after 20 minutes of exercise at 70% of their age-predicted maximal heart rate. Pseudo-continuous arterial spin labeling (pcASL) was used to measure absolute cerebral blood flow (CBF) prior to exercise (pre) and at 10 min (post-10) and 40 min (post-40) post-exercise. Blood oxygenation level dependent (BOLD) functional MRI (fMRI) was performed pre and post-exercise to characterize activation differences related to a go/no-go reaction time task. RESULTS: Compared to pre-exercise levels, grey matter CBF was 11% (±9%) lower at post-10 (P<0.0004) and not different at post-40 (P = 0.12), while global WM CBF was increased at both time points post-exercise (P<0.0006). Regionally, the hippocampus and insula showed a decrease in perfusion in ROI-analysis at post-10 (P<0.005, FDR corrected), whereas voxel-wise analysis identified elevated perfusion in the left medial postcentral gyrus at post-40 compared to pre (pcorrected = 0.05). BOLD activations were consistent between sessions, however, the left parietal operculum showed reduced BOLD activation after exercise. CONCLUSION: This study provides preliminary evidence of regionalized brain effects associated with a single bout of aerobic exercise. The observed acute cerebrovascular responses may provide some insight into the brain's ability to change in relation to chronic interventions.

A control point interpolation method for the non-parametric quantification of cerebral haemodynamics from dynamic susceptibility contrast MRI.

DSC-MRI analysis is based on tracer kinetic theory and typically involves the deconvolution of the MRI signal in tissue with an arterial input function (AIF), which is an ill-posed inverse problem. The current standard singular value decomposition (SVD) method typically underestimates perfusion and introduces non-physiological oscillations in the resulting residue function. An alternative vascular model (VM) based approach permits only a restricted family of shapes for the residue function, which might not be appropriate in pathologies like stroke. In this work a novel deconvolution algorithm is presented that can estimate both perfusion and residue function shape accurately without requiring the latter to belong to a specific class of functional shapes. A control point interpolation (CPI) method is proposed that represents the residue function by a number of control points (CPs), each having two degrees of freedom (in amplitude and time). A complete residue function shape is then generated from the CPs using a cubic spline interpolation. The CPI method is shown in simulation to be able to estimate cerebral blood flow (CBF) with greater accuracy giving a regression coefficient between true and estimated CBF of 0.96 compared to 0.83 for VM and 0.71 for the circular SVD (oSVD) method. The CPI method was able to accurately estimate the residue function over a wide range of simulated conditions. The CPI method has also been demonstrated on clinical data where a marked difference was observed between the residue function of normally appearing brain parenchyma and infarcted tissue. The CPI method could serve as a viable means to examine the residue function shape under pathological variations.

Evaluating quantitative approaches to dynamic susceptibility contrast MRI among carotid endarterectomy patients.

PURPOSE: To evaluate two dynamic susceptibility contrast (DSC) quantification methods in symptomatic carotid artery disease patients undergoing carotid endarterectomy (CEA) surgery by comparing methods directly and assessing the reliability of each method in the hemisphere contralateral to surgery. MATERIALS AND METHODS: Absolute cerebral blood flow (CBF) and volume (CBV) was calculated in putamen and sensorimotor gray matter of 17 patients using two methods: 1) The Bookend method that scales relative DSC images to CBV values calculated from the ratio of pre- and postcontrast T1-weighted images, and 2) the Tail-scaling method that uses the ratio of area under the tails of the venous and arterial concentration time-courses to scale the DSC images. RESULTS: There was a positive correlation between the methods with significant correlation post-CEA (P < 0.035). Intersession correlation was greater when using the Tail-scaling method contralateral to surgery (P < 0.004). CONCLUSION: We have demonstrated correlation between methods that is significant after surgery and have found that the Tail-scaling method produces better test-retest reliability than our implementation of the Bookend method. Results from this study suggest that DSC has the potential to measure hemodynamic changes after endarterectomy and future work is required to establish clinical value.