Pial collaterals limit stroke progression and metabolic stress in hypoperfused tissue: An MRI perfusion and mq-BOLD study.

BACKGROUND AND PURPOSE: In acute ischemic stroke (AIS) due to large-vessel occlusion (LVO), the relationship between cerebral oxygen extraction fraction (OEF) as the hallmark of the ischemic penumbra and leptomeningeal collateral supply is not well established. We aimed to investigate the relationship between pial collateralization and tissue oxygen extraction in patients with LVO using magnetic resonance imaging (MRI). METHODS: Data from 14 patients with anterior circulation LVO who underwent MRI before acute stroke treatment were analyzed. In addition to diffusion-weighted imaging and perfusion-weighted imaging (PWI), the protocol comprised sequences for multiparametric quantitative blood-oxygen-level-dependent imaging for the calculation of relative OEF (rOEF). Pial collateral supply was quantitatively assessed by analyzing the signal variance in T2*-weighted PWI time series. Relationships between collateral supply, infarct volume, rOEF in peri-infarct hypoperfused tissue, and clinical stroke severity were assessed. RESULTS: The PWI-based parameter quantifying collateral supply was negatively correlated with baseline ischemic core volume and rOEF in the hypoperfused peri-infarct area (p < .01). Both reduced collateral supply and increased rOEF correlated significantly with higher scores on the National Institutes of Health Stroke Scale (p < .05). Increased rOEF within hypoperfused tissue was associated with higher baseline (p = .043) and follow-up infarct volume (p = .009). CONCLUSIONS: Signal variance-based mapping of collaterals with PWI depicts pial collateral supply, which is closely tied to tissue pathophysiology and clinical and imaging outcomes. Magnetic-resonance-derived mapping of cerebral rOEF reveals penumbral characteristics of hypoperfused tissue and might provide a promising imaging biomarker in AIS.

Macro- and microvascular contributions to cerebral structural alterations in patients with asymptomatic carotid artery stenosis.

Atherosclerosis can underly internal carotid artery stenosis (ICAS), a major risk factor for ischemic stroke, as well as small vessel disease (SVD). This study aimed to investigate hemodynamics and structural alterations associated with SVD in ICAS patients. 28 patients with unilateral asymptomatic ICAS and 30 age-matched controls underwent structural (T1-/T2-weighted and diffusion tensor imaging [DTI]) and hemodynamic (pseudo-continuous arterial spin labeling and dynamic susceptibility contrast) magnetic resonance imaging. SVD-related alterations were assessed using free water (FW), FW-corrected DTI, and peak-width of skeletonized mean diffusivity (PSMD). Furthermore, cortical thickness, cerebral blood flow (CBF), and capillary transit time heterogeneity (CTH) were analyzed. Ipsilateral to the stenosis, cortical thickness was significantly decreased in the posterior dorsal cingulate cortex (p = 0.024) and temporal pole (p = 0.028). ICAS patients exhibited elevated PSMD (p = 0.005), FW (p < 0.001), and contralateral alterations in FW-corrected DTI metrics. We found significantly lateralized CBF (p = 0.011) and a tendency for lateralized CTH (p = 0.067) in the white matter (WM) related to ICAS. Elevated PSMD and FW may indicate a link between SVD and WM changes. Contralateral alterations were seen in FW-corrected DTI, whereas hemodynamic and cortical changes were mainly ipsilateral, suggesting SVD might influence global brain changes concurrent with ICAS-related hemodynamic alterations.

Deep Learning for Retrospective Motion Correction in MRI: A Comprehensive Review.

Motion represents one of the major challenges in magnetic resonance imaging (MRI). Since the MR signal is acquired in frequency space, any motion of the imaged object leads to complex artefacts in the reconstructed image in addition to other MR imaging artefacts. Deep learning has been frequently proposed for motion correction at several stages of the reconstruction process. The wide range of MR acquisition sequences, anatomies and pathologies of interest, and motion patterns (rigid vs. deformable and random vs. regular) makes a comprehensive solution unlikely. To facilitate the transfer of ideas between different applications, this review provides a detailed overview of proposed methods for learning-based motion correction in MRI together with their common challenges and potentials. This review identifies differences and synergies in underlying data usage, architectures, training and evaluation strategies. We critically discuss general trends and outline future directions, with the aim to enhance interaction between different application areas and research fields.

An energy costly architecture of neuromodulators for human brain evolution and cognition.

In comparison to other species, the human brain exhibits one of the highest energy demands relative to body metabolism. It remains unclear whether this heightened energy demand uniformly supports an enlarged brain or if specific signaling mechanisms necessitate greater energy. We hypothesized that the regional distribution of energy demands will reveal signaling strategies that have contributed to human cognitive development. We measured the energy distribution within the brain functional connectome using multimodal brain imaging and found that signaling pathways in evolutionarily expanded regions have up to 67% higher energetic costs than those in sensory-motor regions. Additionally, histology, transcriptomic data, and molecular imaging independently reveal an up-regulation of signaling at G-protein-coupled receptors in energy-demanding regions. Our findings indicate that neuromodulator activity is predominantly involved in cognitive functions, such as reading or memory processing. This study suggests that an up-regulation of neuromodulator activity, alongside increased brain size, is a crucial aspect of human brain evolution.

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.

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.

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.

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.

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.

Hemodynamic MRI parameters to predict asymptomatic unilateral carotid artery stenosis with random forest machine learning.

Background: Internal carotid artery stenosis (ICAS) can cause stroke and cognitive decline. Associated hemodynamic impairments, which are most pronounced within individual watershed areas (iWSA) between vascular territories, can be assessed with hemodynamic-oxygenation-sensitive MRI and may help to detect severely affected patients. We aimed to identify the most sensitive parameters and volumes of interest (VOI) to predict high-grade ICAS with random forest machine learning. We hypothesized an increased predictive ability considering iWSAs and a decreased cognitive performance in correctly classified patients. Materials and methods: Twenty-four patients with asymptomatic, unilateral, high-grade carotid artery stenosis and 24 age-matched healthy controls underwent MRI comprising pseudo-continuous arterial spin labeling (pCASL), breath-holding functional MRI (BH-fMRI), dynamic susceptibility contrast (DSC), T2 and T2* mapping, MPRAGE and FLAIR. Quantitative maps of eight perfusion, oxygenation and microvascular parameters were obtained. Mean values of respective parameters within and outside of iWSAs split into gray (GM) and white matter (WM) were calculated for both hemispheres and for interhemispheric differences resulting in 96 features. Random forest classifiers were trained on whole GM/WM VOIs, VOIs considering iWSAs and with additional feature selection, respectively. Results: The most sensitive features in decreasing order were time-to-peak (TTP), cerebral blood flow (CBF) and cerebral vascular reactivity (CVR), all of these inside of iWSAs. Applying iWSAs combined with feature selection yielded significantly higher receiver operating characteristics areas under the curve (AUC) than whole GM/WM VOIs (AUC: 0.84 vs. 0.90, p = 0.039). Correctly predicted patients presented with worse cognitive performances than frequently misclassified patients (Trail-making-test B: 152.5s vs. 94.4s, p = 0.034). Conclusion: Random forest classifiers trained on multiparametric MRI data allow identification of the most relevant parameters and VOIs to predict ICAS, which may improve personalized treatments.

Imaging effective oxygen diffusivity in the human brain with multiparametric magnetic resonance imaging.

Cerebrovascular diseases can impair blood circulation and oxygen extraction from the blood. The effective oxygen diffusivity (EOD) of the capillary bed is a potential biomarker of microvascular function that has gained increasing interest, both for clinical diagnosis and for elucidating oxygen transport mechanisms. Models of capillary oxygen transport link EOD to measurable oxygen extraction fraction (OEF) and cerebral blood flow (CBF). In this work, we confirm that two well established mathematical models of oxygen transport yield nearly equivalent EOD maps. Furthermore, we propose an easy-to-implement and clinically applicable multiparametric magnetic resonance imaging (MRI) protocol for quantitative EOD mapping. Our approach is based on imaging OEF and CBF with multiparametric quantitative blood oxygenation level dependent (mq-BOLD) MRI and pseudo-continuous arterial spin labeling (pCASL), respectively. We evaluated the imaging protocol by comparing MRI-EOD maps of 12 young healthy volunteers to PET data from a published study in different individuals. Our results show comparably good correlation between MRI- and PET-derived cortical EOD, OEF and CBF. Importantly, absolute values of MRI and PET showed high accordance for all three parameters. In conclusion, our data indicates feasibility of the proposed MRI protocol for EOD mapping, rendering the method promising for future clinical evaluation of patients with cerebrovascular diseases.

Visualizing cellularity and angiogenesis in newly-diagnosed glioblastoma with diffusion and perfusion MRI and FET-PET imaging.

PURPOSE: Combining imaging modalities has become an essential tool for assessment of tumor biology in glioblastoma (GBM) patients. Aim of this study is to understand how tumor cellularity and neovascularization are reflected in O-(2-[18F]fluoroethyl)-L-tyrosine positron emission tomography ([18F] FET PET) and magnetic resonance imaging (MRI) parameters, including cerebral blood volume (CBV), fractional anisotropy (FA) and mean diffusivity (MD). METHODS: In this prospective cohort, 162 targeted biopsies of 43 patients with therapy-naïve, isocitrate dehydrogenase (IDH) wildtype GBM were obtained after defining areas of interest based on imaging parameters [18F] FET PET, CBV, FA and MD. Histopathological analysis of cellularity and neovascularization was conducted and results correlated to imaging data. RESULTS: ANOVA analysis showed a significant increase of CBV in areas with high neovascularization. For diffusion metrics, and in particular FA, a trend for inverse association with neovascularization was found. [18F] FET PET showed a significant positive correlation to cellularity, while CBV also showed a trend towards correlation with cellularity, not reaching significant levels. In contrast, MD and FA were negatively associated with cellularity. CONCLUSION: Our study confirms that amino acid PET and MR imaging parameters are indicative of histological tumor properties in glioblastoma and highlights the ability of multimodal imaging to assess tumor biology non-invasively.

Migraine attacks as a result of hypothalamic loss of control.

Migraine is a complex neurological disorder affecting approximately 12% of the population. The pathophysiology is not yet fully understood, however the clinical features of the disease, such as the cyclic behaviour of attacks and vegetative symptoms, suggest a prominent role of the hypothalamus. Previous research has observed neuronal alterations at different time points during the migraine interval, specifically just before the headache is initiated. We therefore aimed to assess the trajectory of migraineurs' brain activity over an entire migraine cycle. Using functional magnetic resonance imaging (fMRI) with pseudo-continuous arterial spin labelling (ASL), we designed a longitudinal intra-individual study to detect the rhythmicity of (1) the cerebral perfusion and (2) the hypothalamic connectivity over an entire migraine cycle. Twelve episodic migraine patients were examined in 82 sessions during spontaneous headache attacks with follow-up recordings towards the next attack. We detected cyclic changes of brain perfusion in the limbic circuit (insula and nucleus accumbens), with the highest perfusion during the headache attack. In addition, we found an increase of hypothalamic connectivity to the limbic system over the interictal interval towards the attack, then collapsing during the headache phase. The present data provide strong evidence for the predominant role of the hypothalamus in generating migraine attacks. Due to a genetically-determined cortical hyperexcitability, migraineurs are most likely characterised by an increased susceptibility of limbic neurons to the known migraine trigger. The hypothalamus as a metronome of internal processes is suggested to control these limbic circuits: migraine attacks may occur as a result of the hypothalamus losing control over the limbic system. Repetitive psychosocial stress, one of the leading trigger factors reported by patients, might make the limbic system even more vulnerable and lead to a premature triggering of a migraine attack. Potential therapeutic interventions are therefore suggested to strengthen limbic circuits with dedicated medication or psychological approaches.

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.

Hemodynamic impairments within individual watershed areas in asymptomatic carotid artery stenosis by multimodal MRI.

Improved understanding of complex hemodynamic impairments in asymptomatic internal carotid artery stenosis (ICAS) is crucial to better assess stroke risks. Multimodal MRI is ideal for measuring brain hemodynamics and has the potential to improve diagnostics and treatment selections. We applied MRI-based perfusion and oxygenation-sensitive imaging in ICAS with the hypothesis that the sensitivity to hemodynamic impairments will improve within individual watershed areas (iWSA). We studied cerebral blood flow (CBF), cerebrovascular reactivity (CVR), relative cerebral blood volume (rCBV), relative oxygen extraction fraction (rOEF), oxygen extraction capacity (OEC) and capillary transit-time heterogeneity (CTH) in 29 patients with asymptomatic, unilateral ICAS (age 70.3 ± 7.0 y) and 30 age-matched healthy controls. In ICAS, we found significant impairments of CBF, CVR, rCBV, OEC, and CTH (strongest lateralization ΔCVR = -24%), but not of rOEF. Although the spatial overlap of compromised hemodynamic parameters within each patient varied in a complex manner, most pronounced changes of CBF, CVR and rCBV were detected within iWSAs (strongest effect ΔCVR = +117%). At the same time, CTH impairments were iWSA independent, indicating widespread dysfunction of capillary-level oxygen diffusivity. In summary, complementary MRI-based perfusion and oxygenation parameters offer deeper perspectives on complex microvascular impairments in individual patients. Furthermore, knowledge about iWSAs improves the sensitivity to hemodynamic impairments.

Reduced apparent fiber density in the white matter of premature-born adults.

Premature-born adults exhibit lasting white matter alterations as demonstrated by widespread reduction in fractional anisotropy (FA) based on diffusion-weighted imaging (DWI). FA reduction, however, is non-specific for microscopic underpinnings such as aberrant myelination or fiber density (FD). Using recent advances in DWI, we tested the hypothesis of reduced FD in premature-born adults and investigated its link with the degree of prematurity and cognition. 73 premature- and 89 mature-born adults aged 25-27 years underwent single-shell DWI, from which a FD measure was derived using convex optimization modeling for microstructure informed tractography (COMMIT). Premature-born adults exhibited lower FD in numerous tracts including the corpus callosum and corona radiata compared to mature-born adults. These FD alterations were associated with both the degree of prematurity, as assessed via gestational age and birth weight, as well as with reduced cognition as measured by full-scale IQ. Finally, lower FD overlapped with lower FA, suggesting lower FD underlie unspecific FA reductions. Results provide evidence that premature birth leads to lower FD in adulthood which links with lower full-scale IQ. Data suggest that lower FD partly underpins FA reductions of premature birth but that other processes such as hypomyelination might also take place.

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.

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.