Targeted rhythmic visual stimulation at individual participants' intrinsic alpha frequency causes selective increase of occipitoparietal BOLD-fMRI and EEG functional connectivity.

Neural oscillations in distinct frequency bands are ubiquitous in the brain and play a role in many cognitive processes. The "communication by coherence" hypothesis, poses that the synchronization through phase coupling of frequency-specific neural oscillations regulate information flow across distribute brain regions. Specifically, the posterior alpha frequency band (7-12 Hz) is thought to gate bottom-up visual information flow by inhibition during visual processing. Evidence shows that increased alpha phase coherency positively correlates with functional connectivity in resting state connectivity networks, supporting alpha mediates neural communication through coherency. However, these findings have mainly been derived from spontaneous changes in the ongoing alpha rhythm. In this study, we experimentally modulate the alpha rhythm by targeting individuals' intrinsic alpha frequency with sustained rhythmic light to investigate alpha-mediated synchronous cortical activity in both EEG and fMRI. We hypothesize increased alpha coherency and fMRI connectivity should arise from modulation of the intrinsic alpha frequency (IAF) as opposed to control frequencies in the alpha range. Sustained rhythmic and arrhythmic stimulation at the IAF and at neighboring frequencies within the alpha band range (7-12 Hz) was implemented and assessed in a separate EEG and fMRI study. We observed increased cortical alpha phase coherency in the visual cortex during rhythmic stimulation at the IAF as in comparison to rhythmic stimulation of control frequencies. In the fMRI, we found increased functional connectivity for stimulation at the IAF in visual and parietal areas as compared to other rhythmic control frequencies by correlating time courses from a set of regions of interest for the different stimulation conditions and applying network-based statistics. This suggests that rhythmic stimulation at the IAF frequency induces a higher degree of synchronicity of neural activity across the occipital and parietal cortex, which supports the role of the alpha oscillation in gating information flow during visual processing.

Stronger influence of systemic than local hemodynamic-vascular factors on resting-state BOLD functional connectivity.

Correlated fluctuations in the blood oxygenation level dependent (BOLD) signal of resting-state functional MRI (i.e., BOLD-functional connectivity, BOLD-FC) reflect a spectrum of neuronal and non-neuronal processes. In particular, there are multiple hemodynamic-vascular influences on BOLD-FC on both systemic (e.g., perfusion delay) and local levels (e.g., neurovascular coupling). While the influence of individual factors has been studied extensively, combined and comparative studies of systemic and local hemodynamic-vascular factors on BOLD-FC are scarce, notably in humans. We employed a multi-modal MRI approach to investigate and compare distinct hemodynamic-vascular processes and their impact on homotopic BOLD-FC in healthy controls and patients with unilateral asymptomatic internal carotid artery stenosis (ICAS). Asymptomatic ICAS is a cerebrovascular disorder, in which neuronal functioning is largely preserved but hemodynamic-vascular processes are impaired, mostly on the side of stenosis. Investigated indicators for local hemodynamic-vascular processes comprise capillary transit time heterogeneity (CTH) and cerebral blood volume (CBV) from dynamic susceptibility contrast (DSC) MRI, and cerebral blood flow (CBF) from pseudo-continuous arterial spin labeling (pCASL). Indicators for systemic processes are time-to-peak (TTP) from DSC MRI and BOLD lags from functional MRI. For each of these parameters, their influence on BOLD-FC was estimated by a comprehensive linear mixed model. Equally across groups, we found that individual mean BOLD-FC, local (CTH, CBV, and CBF) and systemic (TTP and BOLD lag) hemodynamic-vascular factors together explain 40.7% of BOLD-FC variance, with 20% of BOLD-FC variance explained by hemodynamic-vascular factors, with an about two-times larger contribution of systemic versus local factors. We conclude that regional differences in blood supply, i.e., systemic perfusion delays, exert a stronger influence on BOLD-FC than impairments in local neurovascular coupling.

Multi-parameter quantitative mapping of R1, R2*, PD, and MTsat is reproducible when accelerated with Compressed SENSE.

Multi-parameter mapping (MPM) magnetic resonance imaging (MRI) provides quantitative estimates of the longitudinal and effective transverse relaxation rates R1 and R2*, proton density (PD), and magnetization transfer saturation (MTsat). Thereby, MPM enables better comparability across sites and time than conventional weighted MRI. However, for MPM, several contrasts must be acquired, resulting in prolonged measurement durations and thus preventing MPM's application in clinical routines. State-of-the-art imaging acceleration techniques such as Compressed SENSE (CS), a combination of compressed sensing and sensitivity encoding, can be used to reduce the scan time of MPM. However, the accuracy and precision of the resulting quantitative parameter maps have not been systematically evaluated. In this study, we therefore investigated the effect of CS acceleration on the fidelity and reproducibility of MPM acquisitions. In five healthy volunteers and in a phantom, we compared MPM metrics acquired without imaging acceleration, with the standard acceleration (SENSE factor 2.5), and with Compressed SENSE with acceleration factors 4 and 6 using a 32-channel head coil. We evaluated the reproducibility and repeatability of accelerated MPM using data from three scan sessions in gray and white matter volumes-of-interest (VOIs). Accelerated MPM provided precise and accurate quantitative parameter maps. For most parameters, the results of the CS-accelerated protocols correlated more strongly with the non-accelerated protocol than the standard SENSE-accelerated protocols. Furthermore, for most VOIs and contrasts, coefficients of variation were lower when calculated from data acquired with different imaging accelerations within a single scan session than from data acquired in different scan sessions with the same acceleration method. These results suggest that MPM with Compressed SENSE acceleration factors up to at least 6 yields reproducible quantitative parameter maps that are highly comparable to those acquired without imaging acceleration. Compressed SENSE can thus be used to considerably reduce the scan duration of R1, R2*, PD, and MTsat mapping, and is highly promising for clinical applications of MPM.

Resting-state BOLD functional connectivity depends on the heterogeneity of capillary transit times in the human brain A combined lesion and simulation study about the influence of blood flow response timing.

Functional connectivity (FC) derived from blood oxygenation level dependent (BOLD) functional magnetic resonance imaging at rest (rs-fMRI), is commonly interpreted as indicator of neuronal connectivity. In a number of brain disorders, however, metabolic, vascular, and hemodynamic impairments can be expected to alter BOLD-FC independently from neuronal activity. By means of a neurovascular coupling (NVC) model of BOLD-FC, we recently demonstrated that aberrant timing of cerebral blood flow (CBF) responses may influence BOLD-FC. In the current work, we support and extend this finding by empirically linking BOLD-FC with capillary transit time heterogeneity (CTH), which we consider as an indicator of delayed and broadened CBF responses. We assessed 28 asymptomatic patients with unilateral high-grade internal carotid artery stenosis (ICAS) as a hemodynamic lesion model with largely preserved neurocognitive functioning and 27 age-matched healthy controls. For each participant, we obtained rs-fMRI, arterial spin labeling, and dynamic susceptibility contrast MRI to study the dependence of left-right homotopic BOLD-FC on local perfusion parameters. Additionally, we investigated the dependency of BOLD-FC on CBF response timing by detailed simulations. Homotopic BOLD-FC was negatively associated with increasing CTH differences between homotopic brain areas. This relation was more pronounced in asymptomatic ICAS patients even after controlling for baseline CBF and relative cerebral blood volume influences. These findings match simulation results that predict an influence of delayed and broadened CBF responses on BOLD-FC. Results demonstrate that increasing CTH differences between homotopic brain areas lead to BOLD-FC reductions. Simulations suggest that CTH increases correspond to broadened and delayed CBF responses to fluctuations in ongoing neuronal activity.

Comparing myelin-sensitive magnetic resonance imaging measures and resulting g-ratios in healthy and multiple sclerosis brains.

The myelin concentration and the degree of myelination of nerve fibers can provide valuable information on the integrity of human brain tissue. Magnetic resonance imaging (MRI) of myelin-sensitive parameters can help to non-invasively evaluate demyelinating diseases such as multiple sclerosis (MS). Several different myelin-sensitive MRI methods have been proposed to determine measures of the degree of myelination, in particular the g-ratio. However, variability in underlying physical principles and different biological models influence measured myelin concentrations, and consequently g-ratio values. We therefore investigated similarities and differences between five different myelin-sensitive MRI measures and their effects on g-ratio mapping in the brains of both MS patients and healthy volunteers. We compared two different estimates of the myelin water fraction (MWF) as well as the inhomogeneous magnetization transfer ratio (ihMTR), magnetization transfer saturation (MTsat), and macromolecular tissue volume (MTV) in 13 patients with MS and 14 healthy controls. In combination with diffusion-weighted imaging, we derived g-ratio parameter maps for each of the five different myelin measures. The g-ratio values calculated from different myelin measures varied strongly, especially in MS lesions. While, compared to normal-appearing white matter, MTsat and one estimate of the MWF resulted in higher g-ratio values within lesions, ihMTR, MTV, and the second MWF estimate resulted in lower lesion g-ratio values. As myelin-sensitive measures provide rough estimates of myelin content rather than absolute myelin concentrations, resulting g-ratio values strongly depend on the utilized myelin measure and model used for g-ratio mapping. When comparing g-ratio values, it is, thus, important to utilize the same MRI methods and models or to consider methodological differences. Particular caution is necessary in pathological tissue such as MS lesions.

Investigating the effect of flow compensation and quantitative susceptibility mapping method on the accuracy of venous susceptibility measurement.

Quantitative susceptibility mapping (QSM) is a promising non-invasive method for obtaining information relating to oxygen metabolism. However, the optimal acquisition sequence and QSM reconstruction method for reliable venous susceptibility measurements are unknown. Full flow compensation is generally recommended to correct for the influence of venous blood flow, although the effect of flow compensation on the accuracy of venous susceptibility values has not been systematically evaluated. In this study, we investigated the effect of different acquisition sequences, including different flow compensation schemes, and different QSM reconstruction methods on venous susceptibilities. Ten healthy subjects were scanned with five or six distinct QSM sequence designs using monopolar readout gradients and different flow compensation schemes. All data sets were processed using six different QSM pipelines and venous blood susceptibility was evaluated in whole-brain segmentations of the venous vasculature and single veins. The quality of vein segmentations and the accuracy of venous susceptibility values were analyzed and compared between all combinations of sequences and reconstruction methods. The influence of the QSM reconstruction method on average venous susceptibility values was found to be 2.7-11.6 times greater than the influence of the acquisition sequence, including flow compensation. The majority of the investigated QSM reconstruction methods tended to underestimate venous susceptibility values in the vein segmentations that were obtained. In summary, we found that multi-echo gradient-echo acquisition sequences without full flow compensation yielded venous susceptibility values comparable to sequences with full flow compensation. However, the QSM reconstruction method had a great influence on susceptibility values and thus needs to be selected carefully for accurate venous QSM.

Decreasing Spatial Variability of Individual Watershed Areas by Revascularization Therapy in Patients With High-Grade Carotid Artery Stenosis.

BACKGROUND: Carotid artery stenosis can impair cerebral hemodynamics especially within watershed areas (WSAs) between vascular territories. WSAs can shift because of collateral flow, which may be an indicator for increased hemodynamic implications and hence higher risk for ischemic stroke. However, whether revascularization treatment can reverse the spatial displacement of individual WSAs (iWSAs) and impaired hemodynamics remains unknown. HYPOTHESIS: That iWSAs spatially normalize because of hemodynamic improvement resulting from revascularization treatment. STUDY TYPE: Prospective. POPULATION: Sixteen patients with unilateral, high-grade carotid artery stenosis confirmed by duplex ultrasonography and 17 healthy controls. FIELD STRENGTH/SEQUENCES: A 3 T-magnetization-prepared rapid acquisition gradient echo (MPRAGE), gradient-echo echo planar dynamic susceptibility contrast (DSC), and fluid-attenuated inversion recovery (FLAIR) sequences. Additionally, contrast-enhanced 3D gradient echo magnetic resonance angiography (MRA) and diffusion-tensor imaging (DTI) spin-echo echo planar imaging were performed. ASSESSMENT: iWSAs were delineated by a recently proposed procedure based on time-to-peak maps from DSC perfusion MRI, which were also used to evaluate perfusion delay. We spatially compared iWSAs and perfusion delay before and after treatment (endarterectomy or stenting). Additionally, the Circle of Willis collateralization status was evaluated, and basic cognitive testing was conducted. STATISTICAL TESTS: Statistical tests included two-sample t-tests and Chi-squared tests. A P value < 0.05 was considered to be statistically significant. RESULTS: After revascularization, patients showed a significant spatial shift of iWSAs and significantly reduced perfusion delay ipsilateral to the stenosis. Spatial shift of iWSA (P = 0.007) and cognitive improvement (P = 0.013) were more pronounced in patients with poor pre-existing collateralization. Controls demonstrated stable spatial extent of iWSAs (P = 0.437) and symmetric perfusion delays between hemispheres over time (P = 0.773). DATA CONCLUSION: These results demonstrate the normalization of iWSA and impaired hemodynamics after revascularization in patients with high-grade carotid artery stenosis. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Modeling the impact of neurovascular coupling impairments on BOLD-based functional connectivity at rest.

Functional magnetic resonance imaging (fMRI) of blood oxygenation level dependent (BOLD) signals during the resting-state is widely used to study functional connectivity (FC) of slowly fluctuating ongoing brain activity (BOLD-FC) in humans with and without brain diseases. While physiological impairments, e.g. aberrant perfusion or vascular reactivity, are common in neurological and psychiatric disorders, their impact on BOLD-FC is widely unknown and ignored. The aim of our simulation study, therefore, was to investigate the influence of impaired neurovascular coupling on resting-state BOLD-FC. Simulated BOLD signals comprising intra- and extravascular contributions were derived from an adjusted balloon model, which allows for independent definitions of cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) responses, being elicited by a synthetic oscillatory input signal with low frequency (0.05 â€‹Hz) amplitude modulations. BOLD-FC was then defined by correlations between physiological reference BOLD time curves (seeds of seed-based BOLD-FC) and the test BOLD time curves (targets of BOLD-FC) featuring altered physiological variables (CMRO2, CBF, cerebral blood volume (CBV)). Impact of impaired neurovascular coupling on BOLD-FC was investigated for three different scenarios with independent changes in (1) CBF and CMRO2amplitudes, (2) CBF and CMRO2delays, and (3) coupling between CBF and CBV. For scenario 1, we found 'linear' influences of CMRO2 and CBF amplitudes on BOLD-FC: for a given CMRO2 amplitude, BOLD-FC changes from negative to positive FC with increasing CBF amplitude, and increasing CMRO2 amplitude simply shifts this dependence linearly. For scenario 2, CMRO2 and CBF delays had a complex 'non-linear' effect on BOLD-FC: for small CMRO2 delays, we found that BOLD-FC changes from positive to negative BOLD-FC with increasing CBF delays, but for large CMRO2 delays positive BOLD-FC simply diminishes with increasing CBF delay. For scenario 3, changes in CBF-CBV coupling have almost no effect on BOLD-FC. All these changes were not critically influenced by both signal-to-noise-ratio and temporal resolution modulations. Our results demonstrate the importance of alterations in neurovascular coupling for aberrant resting-state BOLD-FC. Based on our data, we suggest to complement BOLD-FC studies, at least of at-risk patient populations, with perfusion and oxygenation sensitive MRI. In cases where this is not available, we recommend careful interpretation of BOLD-FC results considering previous findings about hemodynamic-metabolic changes. In the future, accurate modeling of the hemodynamic-metabolic context might improve both our understanding of the crucial interplay between vascular-hemodynamic-neuronal components of intrinsic BOLD-FC and the evaluation of aberrant BOLD-FC in brain diseases with vascular-hemodynamic impairments.

Oxygen extraction fraction mapping with multi-parametric quantitative BOLD MRI: Reduced transverse relaxation bias using 3D-GraSE imaging.

Magnetic resonance imaging (MRI)-based quantification of the blood-oxygenation-level-dependent (BOLD) effect allows oxygen extraction fraction (OEF) mapping. The multi-parametric quantitative BOLD (mq-BOLD) technique facilitates relative OEF (rOEF) measurements with whole brain coverage in clinically applicable scan times. Mq-BOLD requires three separate scans of cerebral blood volume and transverse relaxation rates measured by gradient-echo (1/T2∗) and spin-echo (1/T2). Although the current method is of clinical merit in patients with stroke, glioma and internal carotid artery stenosis (ICAS), there are relaxation measurement artefacts that impede the sensitivity of mq-BOLD and artificially elevate reported rOEF values. We posited that T2-related biases caused by slice refocusing imperfections during rapid 2D-GraSE (Gradient and Spin Echo) imaging can be reduced by applying 3D-GraSE imaging sequences, because the latter requires no slice selective pulses. The removal of T2-related biases would decrease overestimated rOEF values measured by mq-BOLD. We characterized effects of T2-related bias in mq-BOLD by comparing the initially employed 2D-GraSE and two proposed 3D-GraSE sequences to multiple single spin-echo reference measurements, both in vitro and in vivo. A phantom and 25 participants, including young and elderly healthy controls as well as ICAS-patients, were scanned. We additionally proposed a procedure to reliably identify and exclude artefact affected voxels. In the phantom, 3D-GraSE derived T2 values had 57% lower deviation from the reference. For in vivo scans, the formerly overestimated rOEF was reduced by -27% (p â€‹< â€‹0.001). We obtained rOEF â€‹= â€‹0.51, which is much closer to literature values from positron emission tomography (PET) measurements. Furthermore, increased sensitivity to a focal rOEF elevation in an ICAS-patient was demonstrated. In summary, the application of 3D-GraSE improves the mq-BOLD-based rOEF quantification while maintaining clinically feasible scan times. Thus, mq-BOLD with non-slice selective T2 imaging is highly promising to improve clinical diagnostics of cerebrovascular diseases such as ICAS.

18F-Fluoroethyl-tyrosine uptake is correlated with amino acid transport and neovascularization in treatment-naive glioblastomas.

PURPOSE: To investigate the in vivo correlation between 18F-fluoroethyl-tyrosine (18F-FET) uptake and amino acid transporter expression and vascularization in treatment-naive glioblastomas. METHODS: A total of 43 stereotactic biopsies were obtained from 13 patients with suspected glioblastoma prior to therapy. All patients underwent a dynamic 18F-FET PET/MRI scan before biopsy. Immunohistochemistry was performed using antibodies against SLC7A5 (amino acid transporter), MIB-1 (Ki67, proliferation), CD31 (vascularization) and CA-IX (hypoxia). The intensity of staining was correlated with 18F-FET uptake and the dynamic 18F-FET uptake slope at the biopsy target point. RESULTS: In all patients, the final diagnosis was IDH-wildtype glioblastoma, WHO grade IV. Static 18F-FET uptake was significantly correlated with SLC7A5 staining (r = 0.494, p = 0.001). While the dynamic 18F-FET uptake slope did not show a significant correlation with amino acid transporter expression, it was significantly correlated with the number of CD31-positive vessels (r = -0.350, p = 0.031), which is line with earlier results linking 18F-FET kinetics with vascularization and perfusion. Besides, static 18F-FET uptake also showed correlations with CA-IX staining (r = 0.394, p = 0.009) and CD31 positivity (r = 0.410, p = 0.006). While the correlation between static 18F-FET uptake and SLC7A5 staining was confirmed as significant in multivariate analysis, this was not the case for the correlation with CD31 positivity, most likely because of the lower effect size and the relatively low number of samples. No significant correlation between 18F-FET uptake and Ki67 proliferation index was observed in our cohort. CONCLUSION: Our results support the findings of preclinical studies suggesting that specific 18F-FET uptake in glioblastomas is mediated by amino acid transporters. As proposed previously, dynamic 18F-FET parameters might be more influenced by perfusion and therefore related to properties of the tumour neovascularization.

Wavelet-based reconstruction of dynamic susceptibility MR-perfusion: a new method to visualize hypervascular brain tumors.

OBJECTIVES: Parameter maps based on wavelet-transform post-processing of dynamic perfusion data offer an innovative way of visualizing blood vessels in a fully automated, user-independent way. The aims of this study were (i) a proof of concept regarding wavelet-based analysis of dynamic susceptibility contrast (DSC) MRI data and (ii) to demonstrate advantages of wavelet-based measures compared to standard cerebral blood volume (CBV) maps in patients with the initial diagnosis of glioblastoma (GBM). METHODS: Consecutive 3-T DSC MRI datasets of 46 subjects with GBM (mean age 63.0 ± 13.1 years, 28 m) were retrospectively included in this feasibility study. Vessel-specific wavelet magnetic resonance perfusion (wavelet-MRP) maps were calculated using the wavelet transform (Paul wavelet, order 1) of each voxel time course. Five different aspects of image quality and tumor delineation were each qualitatively rated on a 5-point Likert scale. Quantitative analysis included image contrast and contrast-to-noise ratio. RESULTS: Vessel-specific wavelet-MRP maps could be calculated within a mean time of 2:27 min. Wavelet-MRP achieved higher scores compared to CBV in all qualitative ratings: tumor depiction (4.02 vs. 2.33), contrast enhancement (3.93 vs. 2.23), central necrosis (3.86 vs. 2.40), morphologic correlation (3.87 vs. 2.24), and overall impression (4.00 vs. 2.41); all p < .001. Quantitative image analysis showed a better image contrast and higher contrast-to-noise ratios for wavelet-MRP compared to conventional perfusion maps (all p < .001). CONCLUSIONS: wavelet-MRP is a fast and fully automated post-processing technique that yields reproducible perfusion maps with a clearer vascular depiction of GBM compared to standard CBV maps. KEY POINTS: • Wavelet-MRP offers high-contrast perfusion maps with a clear delineation of focal perfusion alterations. • Both image contrast and visual image quality were beneficial for wavelet-MRP compared to standard perfusion maps like CBV. • Wavelet-MRP can be automatically calculated from existing dynamic susceptibility contrast (DSC) perfusion data.

Consistency of normalized cerebral blood volume values in glioblastoma using different leakage correction algorithms on dynamic susceptibility contrast magnetic resonance imaging data without and with preload.

BACKGROUND AND PURPOSE: Several leakage correction algorithms for dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI)-based cerebral blood volume (CBV) measurement have been proposed, and combination with a preload of contrast agent is generally recommended. A single bolus application scheme would largely simplify and facilitate standardized clinical applications, while reducing contrast agent (CA) dose. The aim of this study was, therefore, to investigate whether appropriate leakage correction redundantizes prebolus application by comparing normalized DSC-based CBV (nCBV) measures of two consecutive CA boli. MATERIALS AND METHODS: Twenty-seven patients with suspected glioblastoma (WHO-grade-IV) underwent DSC-MRI during two consecutive boli of Gd-based CA. Four variants of two post-processing leakage correction techniques were compared with respect to nCBV in contrast enhancing tumor tissue. First, a reference curve approach with first pass and full integration of corrected ΔR2*(t), and second, a deconvolution-based approach using singular value decomposition (SVD) with a standard noise-dependent cutoff or Tikhonov regularization. RESULTS: Compared to respective uncorrected values, all leakage correction techniques increased nCBV for data acquired without prebolus, while there was no consistent trend for data acquired with prebolus. The best agreement between corrected nCBV values in contrast enhancing tumor, obtained in the same patients without and with prebolus, respectively, was obtained for the reference curve-based correction approach with either first pass or full integration. CONCLUSION: The reference curve-based leakage correction approach with integration-based nCBV calculation yielded a high accordance between nCBV values without and with prebolus, respectively. Thus, it appears possible to obtain valid nCBV in glioblastoma with a single CA injection.

Alzheimer Disease and Mild Cognitive Impairment: Integrated Pulsed Arterial Spin-Labeling MRI and 18F-FDG PET.

Purpose To compare PET/MR hypoperfusion and hypometabolism in patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) compared with healthy control (HC) participants. Materials and Methods Maps of cerebral blood flow (CBF; pulsed arterial spin-labeling [ASL] MRI), glucose metabolism (fluorine 18 [18F] fluorodeoxyglucose [FDG] PET), and gray matter (GM) volume (structural T1-weighted MRI) were calculated from integrated PET/MR data in 45 patients with AD (mean age, 69 years ± 9 [standard deviation]; age range, 51-89 years), 20 patients with MCI (mean age, 64 years ± 10; age range, 45-82 years), and 11 HC participants (mean age, 65 years ± 8; age range, 54-80 years) between 2011 and 2014. After preprocessing, voxel-wise analyses of variance, volume of interest, and independent component analyses were performed for comparisons of CBF and glucose metabolism. Results Analyses revealed high overlap between components, regional and quantitative hypoperfusion, and hypometabolism in patients with AD compared with HC participants in precuneus, parietal, temporal, and occipital cortex. In patients with MCI compared with HC participants, FDG PET exclusively demonstrated quantitative hypometabolism and a component in the precuneus. Volume-of-interest analysis in global GM in patients with AD compared with HC participants showed lower CBF (42 mL/100 g per minute ± 8 vs 49 mL/100 g per minute ± 7, respectively; P = .035) and lower FDG uptake (0.8 ± 0.1 vs 1 ± 0.1, respectively; P < .001). Conclusion In patients with AD, pulsed ASL MRI revealed regional and quantitative abnormalities and components similar to 18F-FDG PET with a reduced extent. In patients with MCI, 18F-FDG PET exclusively demonstrated quantitative hypometabolism and a component in the precuneus, indicating higher sensitivity to detect preclinical AD compared with the currently used pulsed ASL MRI sequence.

Increased variability of watershed areas in patients with high-grade carotid stenosis.

PURPOSE: Watershed areas (WSAs) of the brain are most susceptible to acute hypoperfusion due to their peripheral location between vascular territories. Additionally, chronic WSA-related vascular processes underlie cognitive decline especially in patients with cerebral hemodynamic compromise. Despite of high relevance for both clinical diagnostics and research, individual in vivo WSA definition is fairly limited to date. Thus, this study proposes a standardized segmentation approach to delineate individual WSAs by use of time-to-peak (TTP) maps and investigates spatial variability of individual WSAs. METHODS: We defined individual watershed masks based on relative TTP increases in 30 healthy elderly persons and 28 patients with unilateral, high-grade carotid stenosis, being at risk for watershed-related hemodynamic impairment. Determined WSA location was confirmed by an arterial transit time atlas and individual super-selective arterial spin labeling. We compared spatial variability of WSA probability maps between groups and assessed TTP differences between hemispheres in individual and group-average watershed locations. RESULTS: Patients showed significantly higher spatial variability of WSAs than healthy controls. Perfusion on the side of the stenosis was delayed within individual watershed masks as compared to a watershed template derived from controls, being independent from the grade of the stenosis and collateralization status of the circle of Willis. CONCLUSION: Results demonstrate feasibility of individual WSA delineation by TTP maps in healthy elderly and carotid stenosis patients. Data indicate necessity of individual segmentation approaches especially in patients with hemodynamic compromise to detect critical regions of impaired hemodynamics.

Characterizing hypoxia in human glioma: A simultaneous multimodal MRI and PET study.

Hypoxia plays an important role for the prognosis and therapy response of cancer. Thus, hypoxia imaging would be a valuable tool for pre-therapeutic assessment of tumor malignancy. However, there is no standard validated technique for clinical application available yet. Therefore, we performed a study in 12 patients with high-grade glioma, where we directly compared the two currently most promising techniques, namely the MR-based relative oxygen extraction fraction (MR-rOEF) and the PET hypoxia marker H-1-(3-[18 F]-fluoro-2-hydroxypropyl)-2-nitroimidazole ([18 F]-FMISO). MR-rOEF was determined from separate measurements of T2 , T2 * and relative cerebral blood volume (rCBV) employing a multi-parametric approach for quantification of the blood-oxygenation-level-dependent (BOLD) effect. With respect to [18 F]-FMISO-PET, besides the commonly used late uptake between 120 and 130 min ([18 F]-FMISO120-130 min ), we also analyzed the hypoxia specific uptake rate [18 F]-FMISO-k3 , as obtained by pharmacokinetic modeling of dynamic uptake data. Since pharmacokinetic modeling of partially acquired dynamic [18 F]-FMISO data was sensitive to a low signal-to-noise-ratio, analysis was restricted to high-uptake tumor regions. Individual spatial analyses of deoxygenation and hypoxia-related parameter maps revealed that high MR-rOEF values clustered in (edematous) peritumoral tissue, while areas with high [18 F]-FMISO120-130 min concentrated in and around active tumor with disrupted blood-brain barrier, i.e. contrast enhancement in T1 -weighted MRI. Volume-of-interest-based correlations between MR-rOEF and [18 F]-FMISO120-130 min as well as [18 F]-FMISO-k3 , and voxel-wise analyses in individual patients, yielded limited correlations, supporting the notion that [18 F]-FMISO uptake, even after 2 h, might still be influenced by perfusion while [18 F]-FMISO-k3 was severely hampered by noise. According to these results, vascular deoxygenation, as measured by MR-rOEF, and severe tissue hypoxia, as measured by [18 F]-FMISO, show a poor spatial correspondence. Overall, the two methods appear to rather provide complementary than redundant information about high-grade glioma biology.

Intra-lesional spatial correlation of static and dynamic FET-PET parameters with MRI-based cerebral blood volume in patients with untreated glioma.

PURPOSE: 18F-fluorethyltyrosine-(FET)-PET and MRI-based relative cerebral blood volume (rCBV) have both been used to characterize gliomas. Recently, inter-individual correlations between peak static FET-uptake and rCBV have been reported. Herein, we assess the local intra-lesional relation between FET-PET parameters and rCBV. METHODS: Thirty untreated glioma patients (27 high-grade) underwent simultaneous PET/MRI on a 3 T hybrid scanner obtaining structural and dynamic susceptibility contrast sequences. Static FET-uptake and dynamic FET-slope were correlated with rCBV within tumour hotspots across patients and intra-lesionally using a mixed-effects model to account for inter-individual variation. Furthermore, maximal congruency of tumour volumes defined by FET-uptake and rCBV was determined. RESULTS: While the inter-individual relationship between peak static FET-uptake and rCBV could be confirmed, our intra-lesional, voxel-wise analysis revealed significant positive correlations (median r = 0.374, p < 0.0001). Similarly, significant inter- and intra-individual correlations were observed between FET-slope and rCBV. However, rCBV explained only 12% of the static and 5% of the dynamic FET-PET variance and maximal overlap of respective tumour volumes was 37% on average. CONCLUSIONS: Our results show that the relation between peak values of MR-based rCBV and static FET-uptake can also be observed intra-individually on a voxel basis and also applies to a dynamic FET parameter, possibly determining hotspots of higher biological malignancy. However, just a small part of the FET-PET signal variance is explained by rCBV and tumour volumes determined by the two modalities showed only moderate overlap. These findings indicate that FET-PET and MR-based rCBV provide both congruent and complimentary information on glioma biology.

Intra- and interscanner variability of magnetic resonance imaging based volumetry in multiple sclerosis.

Brain volumetric measurements in multiple sclerosis (MS) reflect not only disease-specific processes but also other sources of variability. The latter has to be considered especially in multicenter and longitudinal studies. Here, we compare data generated by three different 3-Tesla magnetic resonance scanners (Philips Achieva; Siemens Verio; GE Signa MR750). We scanned two patients diagnosed with relapsing remitting MS six times per scanner within three weeks (T1w and FLAIR, 3D). We assessed T2-hyperintense lesions by an automated lesion segmentation tool and determined volumes of grey matter (GM), white matter (WM) and whole brain (GM+WM) from the lesion-filled T1-weighted images using voxel-based morphometry (SPM8/VBM8) and SIENAX (FSL). We measured cortical thickness using FreeSurfer from both, lesion-filled and original T1-weighted images. We quantified brain volume changes with SIENA. In both patients, we found significant differences in total lesion volume, global brain tissue volumes and cortical thickness measures between the scanners. Morphometric measures varied remarkably between repeated scans at each scanner, independent of the brain imaging software tool used. We conclude that for cross-sectional multicenter studies, the effect of different scanners has to be taken into account. For longitudinal monocentric studies, the expected effect size should exceed the size of false positive findings observed in this study. Assuming a physiological loss of brain volume of about 0.3% per year in healthy adult subjects (Good et al., 2001), which may double in MS (De Stefano et al., 2010; De Stefano et al., 2015), with current tools reliable estimation of brain atrophy in individual patients is only possible over periods of several years.

Neural Correlates of Sevoflurane-induced Unconsciousness Identified by Simultaneous Functional Magnetic Resonance Imaging and Electroencephalography.

BACKGROUND: The neural correlates of anesthetic-induced unconsciousness have yet to be fully elucidated. Sedative and anesthetic states induced by propofol have been studied extensively, consistently revealing a decrease of frontoparietal and thalamocortical connectivity. There is, however, less understanding of the effects of halogenated ethers on functional brain networks. METHODS: The authors recorded simultaneous resting-state functional magnetic resonance imaging and electroencephalography in 16 artificially ventilated volunteers during sevoflurane anesthesia at burst suppression and 3 and 2 vol% steady-state concentrations for 700 s each to assess functional connectivity changes compared to wakefulness. Electroencephalographic data were analyzed using symbolic transfer entropy (surrogate of information transfer) and permutation entropy (surrogate of cortical information processing). Functional magnetic resonance imaging data were analyzed by an independent component analysis and a region-of-interest-based analysis. RESULTS: Electroencephalographic analysis showed a significant reduction of anterior-to-posterior symbolic transfer entropy and global permutation entropy. At 2 vol% sevoflurane concentrations, frontal and thalamic networks identified by independent component analysis showed significantly reduced within-network connectivity. Primary sensory networks did not show a significant change. At burst suppression, all cortical networks showed significantly reduced functional connectivity. Region-of-interest-based thalamic connectivity at 2 vol% was significantly reduced to frontoparietal and posterior cingulate cortices but not to sensory areas. CONCLUSIONS: Sevoflurane decreased frontal and thalamocortical connectivity. The changes in blood oxygenation level dependent connectivity were consistent with reduced anterior-to-posterior directed connectivity and reduced cortical information processing. These data advance the understanding of sevoflurane-induced unconsciousness and contribute to a neural basis of electroencephalographic measures that hold promise for intraoperative anesthesia monitoring.

Mapping of cerebral metabolic rate of oxygen using dynamic susceptibility contrast and blood oxygen level dependent MR imaging in acute ischemic stroke.

INTRODUCTION: MR-derived cerebral metabolic rate of oxygen utilization (CMRO(2)) has been suggested to be analogous to PET-derived CMRO(2) and therefore may be used for detection of viable tissue at risk for infarction. The purpose of this study was to evaluate MR-derived CMRO(2) mapping in acute ischemic stroke in relation to established diffusion- and perfusion-weighted imaging. METHODS: In 23 patients (mean age 63 ± 18.7 years, 11 women) with imaging findings for acute ischemic stroke, relative oxygen extraction fraction was calculated from quantitative transverse relaxation times (T2, T2*) and relative cerebral blood volume using a quantitative blood oxygenation level dependent (BOLD) approach in order to detect a local increase of deoxyhemoglobin. Relative CMRO(2) (rCMRO(2)) maps were calculated by multiplying relative oxygen extraction fraction (rOEF) by cerebral blood flow, derived from PWI. After co-registration, rCMRO(2) maps were evaluated in comparison with apparent diffusion coefficient (ADC) and time-to-peak (TTP) maps. Mean rCMRO(2) values in areas with diffusion-restriction or TTP/ADC mismatch were compared with rCMRO(2) values in the contralateral tissue. RESULTS: In tissue with diffusion restriction, mean rCMRO(2) values were significantly decreased compared to perfusion-impaired (17.9 [95 % confidence interval 10.3, 25.0] vs. 58.1 [95 % confidence interval 50.1, 70.3]; P < 0.001) and tissue in the contralateral hemisphere (68.2 [95 % confidence interval 61.4, 75.0]; P < 0.001). rCMRO(2) in perfusion-impaired tissue showed no significant change compared to tissue in the contralateral hemisphere (58.1 [95 % confidence interval 50.1, 70.3] vs. 66.7 [95 % confidence interval 53.4, 73.4]; P = 0.34). CONCLUSION: MR-derived CMRO(2) was decreased within diffusion-restricted tissue and stable within perfusion-impaired tissue, suggesting that this technique may be adequate to reveal different pathophysiological stages in acute stroke.

Technical considerations on the validity of blood oxygenation level-dependent-based MR assessment of vascular deoxygenation.

A blood oxygenation level-dependent (BOLD)-based apparent relative oxygen extraction fraction (rOEF) as a semi-quantitative marker of vascular deoxygenation has recently been introduced in clinical studies of patients with glioma and stroke, yielding promising results. These rOEF measurements are based on independent quantification of the transverse relaxation times T2 and T2* and relative cerebral blood volume (rCBV). Simulations demonstrate that small errors in any of the underlying measures may result in a large deviation of the calculated rOEF. Therefore, we investigated the validity of such measurements. For this, we evaluated the quantitative measurements of T2 and T2* at 3 T in a gel phantom, in healthy subjects and in healthy tissue of patients with brain tumors. We calculated rOEF maps covering large portions of the brain from T2, T2* and rCBV [routinely measured in patients using dynamic susceptibility contrast (DSC)], and obtained rOEF values of 0.63 ± 0.16 and 0.90 ± 0.21 in healthy-appearing gray matter (GM) and white matter (WM), respectively; values of about 0.4 are usually reported. Quantitative T2 mapping using the fast, clinically feasible, multi-echo gradient spin echo (GRASE) approach yields significantly higher values than much slower multiple single spin echo (SE) experiments. Although T2* mapping is reliable in magnetically homogeneous tissues, uncorrectable macroscopic background gradients and other effects (e.g. iron deposition) shorten T2*. Cerebral blood volume (CBV) measurement using DSC and normalization to WM yields robust estimates of rCBV in healthy-appearing brain tissue; absolute quantification of the venous fraction of CBV, however, is difficult to achieve. Our study demonstrates that quantitative measurements of rOEF are currently biased by inherent difficulties in T2 and CBV quantification, but also by inadequacies of the underlying model. We argue, however, that standardized, reproducible measurements of apparent T2, T2* and rCBV may still allow the estimation of a meaningful apparent rOEF, which requires further validation in clinical studies.