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The medial temporal lobe (MTL) is a key area implicated in many brain diseases, such as Alzheimer's disease. As a functional biomarker, the oxygen extraction fraction (OEF) of MTL may be more sensitive than structural atrophy of MTL, especially at the early stages of diseases. However, there is a lack of non-invasive techniques to measure MTL-OEF in humans. The goal of this work is to develop an MRI technique to assess MTL-OEF in a clinically practical time without using contrast agents. The proposed method measures venous oxygenation (Y

PURPOSEAccumulating evidence from recent studies has indicated the importance of studying the interaction between the microvascular and lymphatic systems in the brain. To date, most imaging methods can only measure blood or lymphatic vessels separately, such as dynamic-susceptibility-contrast (DSC) MRI for blood vessels and DSC MRI in the CSF (cDSC MRI) for lymphatic vessels. An approach that can measure both blood and lymphatic vessels in a single scan will offer the advantages such as halved scan time and contrast dosage. Based on previous works on DSC and cDSC MRI, this study proposes an MRI approach for concurrent measurement of perfusion parameters related to small blood and lymphatic vessels in the brain within one single scan.METHODSBloch simulations were performed to optimize a dual-echo sequence for the measurement of gadolinium(Gd)-induced blood and CSF signal changes using a short and a long echo time, respectively. MRI experiments were performed in healthy subjects to evaluate the dual-echo approach by comparing it with existing separate methods.RESULTSThe proposed method showed consistent results in human brains as previous studies using separate methods. Signal changes from small blood vessels occurred faster than lymphatic vessels after intravenous Gd-injection.CONCLUSIONGd-induced signal changes in blood and CSF can be detected simultaneously in healthy subjects with the proposed sequence. To the best of our knowledge, this may be the first study in which the temporal difference in Gd-induced signal changes from small blood and lymphatic vessels after intravenous Gd-injection was measured in the same human subjects.

Objective Blood-brain barrier (BBB) breakdown has been suggested to be an early biomarker in human cognitive impairment. However, the relationship between BBB breakdown and brain pathology, most commonly Alzheimer disease (AD) and vascular disease, is still poorly understood. The present study measured human BBB function in mild cognitive impairment (MCI) patients on 2 molecular scales, specifically BBB's permeability to water and albumin molecules. Methods Fifty-five elderly participants were enrolled, including 33 MCI patients and 22 controls. BBB permeability to water was measured with a new magnetic resonance imaging technique, water extraction with phase contrast arterial spin tagging. BBB permeability to albumin was determined using cerebrospinal fluid (CSF)/serum albumin ratio. Cognitive performance was assessed by domain-specific composite scores. AD pathology (including CSF Aβ and ptau) and vascular risk factors were examined. Results Compared to cognitively normal subjects, BBB in MCI patients manifested an increased permeability to small molecules such as water but was no more permeable to large molecules such as albumin. BBB permeability to water was found to be related to AD markers of CSF Aβ and ptau. On the other hand, BBB permeability to albumin was found to be related to vascular risk factors, especially hypercholesterolemia, but was not related to AD pathology. BBB permeability to small molecules, but not to large molecules, was found to be predictive of cognitive function. Interpretation These findings provide early evidence that BBB breakdown is related to both AD and vascular risks, but their effects can be differentiated by spatial scales. BBB permeability to small molecules has a greater impact on cognitive performance. ANN NEUROL 2021;90:227-238.

When planning for brain tumor resection, a balance between maximizing resection and minimizing injury to eloquent brain parenchyma is paramount. The advent of blood oxygenation level-dependent functional magnetic resonance (fMR) imaging has allowed researchers and clinicians to reliably measure physiologic fluctuations in brain oxygenation related to neuronal activity with good spatial resolution. fMR imaging can offer a unique insight into preoperative planning for brain tumors by identifying eloquent areas of the brain affected or spared by the neoplasm. This article discusses the fMR imaging techniques and their applications in neurosurgical planning.

Neurovascular uncoupling (NVU) is one of the most important confounds of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMR imaging) in the setting of focal brain lesions such as brain tumors. This article reviews the assessment of NVU related to focal brain lesions with emphasis on the use of cerebrovascular reactivity mapping measurement methods and resting state BOLD fMR imaging metrics in the detection of NVU, as well as the use of amplitude of low-frequency fluctuation metrics to mitigate the effects of NVU on clinical fMR imaging activation.

We developed multiple histogram-based CBF indices and evaluated their association with histopathologic grade in de novo brain tumor patients. Furthermore, the associations between these advanced CBF indices and molecular markers, including IDH1 mutation, ATRX loss, and 1p/19q co-deletion were also investigated. Thirteen de novo brain tumor patients (age 21–68 years, 9 M/4F) who were enrolled in our prospective study were scanned on 3 T MRI using a pCASL perfusion sequence following IRB-approved written informed consent. All patients have since undergone surgical intervention with tissue sampling for histopathologic tumor grading and molecular marker assessment. Tumor region of interest (ROI) were manually delineated on FLAIR images including the full extent of the tumor and peritumoral edema. Fourteen rCBF indices were derived from the histogram of the voxels with the ROI. Multi-linear regression was then used to compare rCBF indices with histopathologic tumor grade and molecular markers. Averaged rCBF in top 10 and top 20 voxels (p

ObjectiveTo determine whether MRI-based cerebrovascular reactivity (CVR) can predict cognitive performance independently of Alzheimer pathologic markers, we studied the relationship between cognition, CVR, and CSF-derived β-amyloid42 (Aβ42) and tau in a group of elderly individuals with mixed Alzheimer and vascular cognitive impairment and dementia.MethodsThis was a cross-sectional study of 72 participants 69 ± 8 years of age consisting of individuals with normal cognition (n = 28) and cognitive impairment (n = 44) (including 36 with mild cognitive impairment [MCI] and 8 with mild dementia). CVR was measured with hypercapnia-MRI. Whole-brain CVR (percent blood oxygen level–dependent per 1 mm Hg Etco2) was used to estimate vasodilatory capacity. Montreal Cognitive Assessment (MoCA) scores, cognitive domains scores, and a global composite cognitive score were obtained. AD biomarkers included CSF assays of Aβ42 and tau.ResultsWhole-brain CVR was lower in the impaired (mean ± SE, 0.132 ± 0.006%/mm Hg) compared to the normal (0.151 ± 0.007%/mm Hg) group (β = −0.02%/mm Hg; 95% confidence interval [CI] −0.038 to −0.001). After adjustment for CSF Aβ42 and tau, higher whole-brain CVR was associated with better performance on the MoCA (β = 29.64, 95% CI 9.94–49.34) and with a global composite cognitive score (β = 4.32, 95% CI 0.05–8.58). When the CVR marker was compared with the Fazekas score based on white matter hyperintensities and vascular risk-score in a single regression model predicting the MoCA score, only CVR revealed a significant effect (β = 28.09, 95% CI 6.14–50.04), while the other 2 measures were not significant.ConclusionsCVR was significantly associated with cognitive performance independently of AD pathology. Whole-brain CVR may be a useful biomarker for evaluating cognitive impairment related to vascular disease in older individuals.Classification of evidenceThis study provides Class II evidence that CVR was significantly associated with cognitive performance independent of AD pathology.

Background Alzheimer's disease and vascular cognitive impairment (VCI), as well as their concurrence, represent the most common types of cognitive dysfunction. Treatment strategies for these two conditions are quite different; however, there exists a considerable overlap in their clinical manifestations, and most biomarkers reveal similar abnormalities between these two conditions. Purpose To evaluate the potential of cerebral oxygen extraction fraction (OEF) as a biomarker for differential diagnosis of Alzheimer's disease and VCI. We hypothesized that in Alzheimer's disease OEF will be reduced (decreased oxygen consumption due to decreased neural activity), while in vascular diseases OEF will be elevated (increased oxygen extraction due to abnormally decreased blood flow). Study type Prospective cross-sectional. Population Sixty-five subjects aged 52-89 years, including 33 mild cognitive impairment (MCI), 7 dementia, and 25 cognitively normal subjects. Field strength/sequence 3T T2 -relaxation-under-spin-tagging (TRUST) and fluid-attenuated inversion recovery imaging (FLAIR). Assessment OEF, consensus diagnoses of cognitive impairment, vascular risk factors (such as hypertension, hypercholesterolemia, diabetes, smoking, and obesity), cognitive assessments, and cerebrospinal fluid concentration of amyloid and tau were assessed. Statistical tests Multiple linear regression analyses of OEF with diagnostic category (normal, MCI, or dementia), vascular risks, cognitive performance, amyloid and tau pathology. Results When evaluating the entire group, OEF was found to be lower with more severe cognitive impairment (β = -2.70 ± 1.15, T = -2.34, P = 0.02), but was higher with greater vascular risk factors (β = 1.36 ± 0.55, T = 2.48, P = 0.02). Further investigation of the subgroup of participants with low vascular risks (N = 44) revealed that lower OEF was associated with worse cognitive performance (β = 0.04 ± 0.01, T = 3.27, P = 0.002) and greater amyloid burden (β = 92.12 ± 41.23, T = 2.23, P = 0.03). Among cognitively impaired individuals (N = 40), higher OEF was associated with greater vascular risk factors (β = 2.19 ± 0.71, T = 3.08, P = 0.004). Data conclusion These findings suggest that OEF is differentially affected by Alzheimer's disease and VCI pathology and may be useful in etiology-based diagnosis of cognitive impairment. Level of evidence 1 TECHNICAL EFFICACY: Stage 3 J. MAGN. RESON. IMAGING 2020;52:1829-1837.

BACKGROUND AND PURPOSE: Accurate differentiation between glioblastoma and solitary brain metastasis is of vital importance clinically. This study aimed to investigate the potential value of the inflow-based vascular-space-occupancy MR imaging technique, which has no need for an exogenous contrast agent, in differentiating glioblastoma and solitary brain metastasis and to compare it with DSC MR imaging. MATERIALS AND METHODS: Twenty patients with glioblastoma and 22 patients with solitary brain metastasis underwent inflow-based vascular-space-occupancy and DSC MR imaging with a 3T clinical scanner. Two neuroradiologists independently measured the maximum inflow-based vascular-space-occupancy–derived arteriolar CBV and DSC-derived CBV values in intratumoral regions and peritumoral T2-hyperintense regions, which were normalized to the contralateral white matter (relative arteriolar CBV and relative CBV, inflow-based vascular-space-occupancy relative arteriolar CBV, and DSC-relative CBV). The intraclass correlation coefficient, Student t test, or Mann-Whitney U test and receiver operating characteristic analysis were performed. RESULTS: All parameters of both regions had good or excellent interobserver reliability (0.74∼0.89). In peritumoral T2-hyperintese regions, DSC-relative CBV (P < .001), inflow-based vascular-space-occupancy arteriolar CBV (P = .001), and relative arteriolar CBV (P = .005) were significantly higher in glioblastoma than in solitary brain metastasis, with areas under the curve of 0.94, 0.83, and 0.72 for discrimination, respectively. In the intratumoral region, both inflow-based vascular-space-occupancy arteriolar CBV and relative arteriolar CBV were significantly higher in glioblastoma than in solitary brain metastasis (both P < .001), with areas under the curve of 0.91 and 0.90, respectively. Intratumoral DSC-relative CBV showed no significant difference (P = .616) between the 2 groups. CONCLUSIONS: Inflow-based vascular-space-occupancy has the potential to discriminate glioblastoma from solitary brain metastasis, especially in the intratumoral region.

The high-level relationships that form complex networks within tumors and between surrounding tissue is challenging and not fully understood. To better understand these tumoral networks, we developed a tumor connectomics framework (TCF) based on graph theory with machine learning to model the complex interactions within and around the tumor microenvironment that are detectable on imaging. The TCF characterization model was tested with independent datasets of breast, brain, and prostate lesions with corresponding validation datasets in breast and brain cancer. The TCF network connections were modeled using graph metrics of centrality, average path length (APL), and clustering from multiparametric MRI with IsoSVM. The Matthews Correlation Coefficient (MCC), Area Under the Curve-ROC, and Precision-Recall (AUC-ROC and AUC-PR) were used for statistical analysis. The TCF classified the breast and brain tumor cohorts with an IsoSVM AUC-PR and MCC of 0.86, 0.63 and 0.85, 0.65, respectively. The TCF benign breast lesions had a significantly higher clustering coefficient and degree centrality than malignant TCFs. Grade 2 brain tumors demonstrated higher connectivity compared to Grade 4 tumors with increased degree centrality and clustering coefficients. Gleason 7 prostate lesions had increased betweenness centrality and APL compared to Gleason 6 lesions with AUC-PR and MCC ranging from 0.90 to 0.99 and 0.73 to 0.87, respectively. These TCF findings were similar in the validation breast and brain datasets. In conclusion, we present a new method for tumor characterization and visualization that results in a better understanding of the global and regional connections within the lesion and surrounding tissue.

We assessed the utility of apparent diffusion coefficients (ADCs) derived from diffusion-weighted imaging to differentiate benign and malignant orbital tumours by oculoplastic surgeons in the clinical setting and sought to validate observed ADC cut-off values.Retrospective review of patients with benign or malignant biopsy-confirmed orbital tumours.Blinded graders including 2 oculoplastic surgeons, 1 neuroradiologist, and 1 medical student located and measured orbital tumour ADCs (10Nonradiologist measurements were compared with each other to assess reliability and with an expert neuroradiologist measurement and final pathology to assess accuracy.Twenty-nine orbital tumours met inclusion criteria, consisting of 6 benign tumours and 23 malignant tumours. Mean ADC values for benign orbital tumours were 1430.59 ± 254.81 and 798.68 ± 309.12 mmOur ADC cut-off of 1120.84 × 10

Objective Mental activation has been reported to modify the occurrence of epileptiform activity. We studied its effect on afterdischarges. Method In 15 patients with implanted electrodes we presented cognitive tasks when afterdischarges occurred. We developed a wavelet cross-coherence function to analyze the electrocorticography before and after the tasks and compared findings when cognitive tasks did or did not result in afterdischarge termination. Six patients returned for functional MRI (fMRI) testing, using similar tasks. Results Cognitive tasks often could terminate afterdischarges when direct abortive stimulation could not. Wavelet cross-coherence analysis showed that, when afterdischarges stopped, there was decreased coherence throughout the brain in the 7.13–22.53 Hz frequency ranges (p values 0.008–0.034). This occurred a) regardless of whether an area activated on fMRI and b) regardless of whether there were afterdischarges in the area. Conclusions It is known that cognitive tasks can alter localized or network synchronization. Our results show that they can change activity throughout the brain. These changes in turn can terminate localized epileptiform activity. Significance Cognitive tasks result in diffuse brain changes that can modify focal brain activity. Combined with a seizure detection device, cognitive activation might provide a non-invasive method of terminating or modifying seizures.

Background Apolipoprotein E4 (APOE4) is a major genetic risk factor for late-onset Alzheimer disease. However, the mechanisms by which APOE4 affects the brain, underpinning this risk, have not been fully elucidated. Purpose To investigate the influence of APOE4 on global cerebral oxygen extraction fraction (OEF) and possible mediation through amyloid burden by using MRI-based brain oxygen extraction technique. Materials and Methods Participants were enrolled from a longitudinal prospective study, the Biomarkers for Older Controls at Risk for Dementia study (data collected from January 2015 to December 2017), of whom 35% (50 of 143 participants) were APOE4 carriers. OEF was measured by using a T2-relaxation-under-spin-tagging MRI technique with a 3.0-T MRI system. PET acquired with carbon 11-labeled Pittsburgh compound B tracer was available in 119 participants to measure amyloid burden. Cognitive performance was assessed by using domain-specific composite scores including executive function, episodic memory, visual-spatial processing, and language. Linear regression analysis was performed to investigate the relationship between APOE4, OEF, and amyloid burden. The association between OEF and cognitive function was studied for the entire study cohort and separately for the APOE4 carriers and noncarriers. Results A total of 143 cognitively healthy individuals (mean age 6 standard deviation, 69.1 years 6 8.2; 57 men and 86 women) were studied. APOE4 genetic status was associated with lower OEF (noncarriers, 41.1% 6 5.8; one E4 allele, 40.1% 6 4.9; two E4 alleles, 36.7% 6 4.5; P = .03). Furthermore, among APOE4 carriers, lower OEF correlated with lower executive function scores (b = 0.079 z score for each percent change in OEF; P = .03). Amyloid burden and OEF were independently associated with APOE4 but were not associated with one another, suggesting that the effect of APOE4 on OEF is not mediated by amyloid. Conclusion MRI-based brain oxygen extraction shows that cognitively healthy carriers of the apolipoprotein E4 gene manifest diminished brain oxygen extraction capacity independent of amyloid burden. ©RSNA, 2019 Online supplemental material is available for this article.

The goal of this study was to demonstrate that a novel resting state BOLD ALFF (amplitude of low frequency fluctuations)-based correction method can substantially enhance the detectability of motor task activation in the presence of tumor-induced neurovascular uncoupling (NVU). Twelve de novo brain tumor patients who underwent comprehensive clinical BOLD fMRI exams including task fMRI and resting state fMRI (rsfMRI) were evaluated. Each patient displayed decreased/absent task fMRI activation in the ipsilesional primary motor cortex in the absence of corresponding motor deficit or suboptimal task performance, consistent with NVU. Z-score maps for the motor tasks were obtained from general linear model (GLM) analysis (reflecting motor activation vs. rest). ALFF maps were calculated from rsfMRI data. Precentral and postcentral gyri in contralesional (CL) and ipsilesional (IL) hemispheres were parcellated using an Automated Anatomical Labeling (AAL) template for each patient. A novel ALFF-based correction method was used to identify the NVU affected voxels in the ipsilesional primary motor cortex (PMC), and a correction factor was applied to normalize the baseline Z-scores for these voxels. In all cases, substantially greater activation was seen on post-ALFF correction motor activation maps within the ipsilesional precentral gyri than in the pre-ALFF correction activation maps. We have demonstrated the feasibility of a new resting state ALFF-based technique for effective correction of brain tumor-related NVU in the primary motor cortex.

PURPOSE The ability to measure cerebral vascular compliance (VC) is important in the evaluation of vascular diseases. Additionally, quantification of arterial wall pulsation in the brain may be useful for understanding the driving force of the recently discovered glymphatic system. Our goal is to develop an MRI technique to measure VC and arterial wall pulsation in major intracranial vessels. METHODS A total of 17 healthy subjects were studied on a 3T MRI system. The technique, called VaCom-PCASL, uses pseudo-continuous arterial spin labeling (PCASL) to obtain pure blood vessel signal, uses a 3D radial acquisition, and applies a golden-angle radial sparse parallel (GRASP) algorithm for image reconstruction. The k-space data were retrospectively sorted into different cardiac phases. The GRASP algorithm allows the reconstruction of 5D (three spatial dimensions, one control/label dimension, and one cardiac-phase dimension) data simultaneously. The proposed technique was optimized in terms of reconstruction parameters and labeling duration. Intracranial VC was compared with aortic pulse wave velocity measured with phase-contrast MRI. Age differences in VC were studied. RESULTS The VaCom-PCASL technique using 10 cardiac phases and GRASP sparsity constraints of λlabel/control = 0.05 and λcardiac = 0.05 provided the highest contrast-to-noise ratio. A labeling duration of 800 ms was found to yield signals comparable to those of longer duration (P > .2), whereas 400 ms yielded significant overestimation (P < .005). A significant correlation was observed between intracranial VC and aortic pulse wave velocity (r = -0.73, P = .038, N = 8). Vascular compliance in the older group was lower than that in the younger group. CONCLUSION The VaCom-PCASL-MRI technique represents a promising approach for noninvasive assessment of arterial stiffness and pulsatility.

Purpose Assessment of the blood-brain barrier (BBB) permeability without the need for contrast agent is desirable, and the ability to measure the permeability to small molecules such as water may further increase the sensitivity in detecting diseases. This study proposed a time-efficient, noncontrast method to measure BBB permeability to water, evaluated its test-retest reproducibility, and compared it with a contrast agent-based method. Methods A single-delay water extraction with phase-contrast arterial spin tagging (WEPCAST) method was devised in which spatial profile of the signal along the superior sagittal sinus was used to estimate bolus arrival time, and the WEPCAST signal at the corresponding location was used to compute water extraction fraction, which was combined with global cerebral blood flow to estimate BBB permeability surface area product to water. The reliability of WEPCAST sequence was examined in terms of intrasession, intersession, and inter-vendor (Philips [Ingenia, Best, the Netherlands] and Siemens [Prisma, Erlangen, Germany]) reproducibility. Finally, we compared this new technique to a contrast agent-based method. Results Single-delay WEPCAST reduced the scan duration from approximately 20 min to 5 min. Extract fraction values estimated from single-delay WEPCAST showed good consistency with the multi-delay method (R = 0.82, P = .004). Group-averaged permeability surface area product values were found to be 137.5 ± 9.3 mL/100 g/min. Intrasession, intersession, and inter-vendor coefficient of variation of the permeability surface area product values were 6.6 ± 4.5%, 6.9 ± 3.7%, and 8.9 ± 3.0%, respectively. Finally, permeability surface area product obtained from WEPCAST MRI showed a significant correlation with that from the contrast-based method (R = .73, P = .02). Conclusion Single-delay WEPCAST MRI can measure BBB permeability to water within 5 min with an intrasession, intersession, and inter-vendor test-retest reproducibility of 6% to 9%. This method may provide a useful marker of BBB breakdown in clinical studies.

Dynamic functional connectivity adds another dimension to resting-state functional MR imaging analysis. In recent years, dynamic functional connectivity has been increasingly used in resting-state functional MR imaging, and several studies have demonstrated that dynamic functional connectivity patterns correlate with different physiologic and pathologic brain states. In fact, evidence suggests that dynamic functional connectivity is a more sensitive marker than static functional connectivity; therefore, it might be a promising tool to add to clinical functional neuroimaging. This article provides a broad overview of dynamic functional connectivity and reviews its general principles, techniques, and potential clinical applications.

The L-type calcium channel gene, CACNA1C, is a validated risk gene for schizophrenia and the target of calcium channel blockers. Carriers of the risk-associated genotype (rs1006737 A allele) have increased frontal cortical activity during working memory and higher CACNA1C mRNA expression in the prefrontal cortex. The aim of this study was to determine how the brain-penetrant calcium channel blocker, nimodipine, changes brain activity during working memory and other cognitive and emotional processes. We conducted a double-blind randomized cross-over pharmacoMRI study of a single 60 mg dose of oral nimodipine solution and matching placebo in healthy men, prospectively genotyped for rs1006737. With performance unchanged, nimodipine significantly decreased frontal cortical activity by 39.1% and parietal cortical activity by 42.8% during the N-back task (2-back > 0-back contrast; PFWE n = 28). Higher peripheral nimodipine concentrations were correlated with a greater decrease in activation in the frontal cortex. Carriers of the risk-associated allele, A (n = 14), had a greater decrease in frontal cortical activation during working memory compared to non-risk allele carriers. No differences in brain activation were found between nimodipine and placebo for other tasks. Future studies should be conducted to test if the decreased cortical brain activity after nimodipine is associated with improved working memory performance in patients with schizophrenia, particularly those who carry the risk-associated genotype. Furthermore, changes in cortical activity during working memory may be a useful biomarker in future trials of L-type calcium channel blockers.

We developed multiple histogram-based CBF indices and evaluated their association with histopathologic grade in de novo brain tumor patients. Furthermore, the associations between these advanced CBF indices and molecular markers, including IDH1 mutation, ATRX loss, and 1p/19q co-deletion were also investigated.Thirteen de novo brain tumor patients (age 21-68 years, 9 M/4F) who were enrolled in our prospective study were scanned on 3 T MRI using a pCASL perfusion sequence following IRB-approved written informed consent. All patients have since undergone surgical intervention with tissue sampling for histopathologic tumor grading and molecular marker assessment. Tumor region of interest (ROI) were manually delineated on FLAIR images including the full extent of the tumor and peritumoral edema. Fourteen rCBF indices were derived from the histogram of the voxels with the ROI. Multi-linear regression was then used to compare rCBF indices with histopathologic tumor grade and molecular markers.Averaged rCBF in top 10 and top 20 voxels (p 0.004), but not the entire tumor ROI, was positively associated with WHO tumor grade. After accounting for tumor grade, the presence of 1p/19q co-deletion was associated with higher rCBF in top voxels, as well as with standard deviation of rCBF in the tumor ROI (p 0.001). ATRX retention was related to higher rCBF, and this effect appears to be present in both higher-perfusion (p 0.004) and low-perfusion (p 0.05) voxels. IDH mutation was not significantly associated with any of the CBF indices investigated.ASL MRI may provide useful supplemental noninvasive imaging assessment of brain tumor grade and molecular marker status.

The aim of the study is to assess the diagnostic performance of inflow-based vascular-space-occupancy (iVASO) MR imaging for differentiating glioblastomas (grade IV, GBM) and lower-grade diffuse gliomas (grade II and III, LGG) and its potential to predict IDH mutation status.One hundred and two patients with diffuse cerebral glioma (56 males; median age, 43.5 years) underwent iVASO and dynamic susceptibility contrast (DSC) MR imaging. The iVASO-derived arteriolar cerebral blood volume (CBVa), relative CBVa (rCBVa), and the DSC-derived relative cerebral blood volume (rCBV) were obtained, and these measurements were compared between the GBM group (n = 43) and the LGG group (n = 59) and between the IDH-mutation group (n = 54) and the IDH-wild group (n = 48).Significant correlation was observed between rCBV and CBVa (P 0.001) or rCBVa (P 0.001). Both CBVa (P 0.001) and rCBVa (P 0.001) were higher in the GBM group. Both CBVa (P 0.001) and rCBVa (P 0.001) were lower in the IDH-mutation group compared to the IDH-wild group. Receiver operating characteristic analyses showed the area under curve (AUC) of 0.95 with CBVa and 0.97 with rCBVa in differentiating GBM from LGG. The AUCs were 0.82 and 0.85 for CBVa and rCBVa in predicting IDH gene status, respectively, which were lower than that of rCBV (AUC = 0.90). Combined rCBV and rCBVa significantly improved the diagnostic performance (AUC = 0.95).iVASO MR imaging has the potential to predict IDH mutation and grade in glioma.

PURPOSE: The circulation of cerebrospinal fluid (CSF) is closely associated with many aspects of brain physiology. When gadolinium(Gd)-based contrast is administered intravenously, pre- and post-contrast MR signal changes can often be observed in the CSF at certain locations within the intra-cranial space, mainly due to the lack of a blood-brain barrier in the dural blood vessels. This study aims to develop and systemically optimize MRI sequences that can detect dynamic signal changes in the CSF after Gd administration with a sub-millimeter spatial resolution, a temporal resolution of

We present a novel deep learning framework that uses dynamic functional connectivity to simultaneously localize the language and motor areas of the eloquent cortex in brain tumor patients. Our method leverages convolutional layers to extract graph-based features from the dynamic connectivity matrices and a long-short term memory (LSTM) attention network to weight the relevant time points during classification. The final stage of our model employs multi-task learning to identify different eloquent subsystems. Our unique training strategy finds a shared representation between the cognitive networks of interest, which enables us to handle missing patient data. We evaluate our method on resting-state fMRI data from 56 brain tumor patients while using task fMRI activations as surrogate ground-truth labels for training and testing. Our model achieves higher localization accuracies than conventional deep learning approaches and can identify bilateral language areas even when trained on left-hemisphere lateralized cases. Hence, our method may ultimately be useful for preoperative mapping in tumor patients.

Purpose Arterial-Spin-Labeling (ASL) MRI is intrinsically a low SNR technique. This study aims to enhance its sensitivity by quantifying physiological noise attributed to cardiac pulsation and devising an improved sequence, cardiac-triggered ASL, to minimize this noise. Methods A total of 16 healthy subjects were studied on a 3T MRI system. The influence of cardiac pulsation on pseudo-continuous ASL (pCASL) signal was first investigated by performing a regular pCASL sequence while the cardiac phase of the image acquisition was recorded by a pulse oximeter. We then designed a new sequence, cardiac-triggered pCASL, to align the cardiac phases of the control and labeled scans. The performance of the new sequence was evaluated in the context of single-shot 3D GraSE acquisition, multi-shot 3D spiral acquisition, and hypercapnia-induced CBF changes. Results In regular pCASL, the signal intensities of both control and labeled images were strongly modulated by the cardiac phase. In single-shot acquisitions, this results in signal instability in regions near large vessels. In segmented acquisitions, it results in ghosting artifacts in the image and, furthermore, the signal fluctuation is smeared along the segmentation direction to affect more brain regions. Cardiac-triggered pCASL enhanced the temporal SNR by 94% and 28% in single-shot and segmented 3D acquisition, respectively. When applied to detect CBF changes, the triggered sequence revealed a greater statistical power in terms of both the number of significant voxels and t-score histograms. Conclusion Cardiac-triggered pCASL represents a potential scheme to enhance the reliability of ASL signal.

Localizing the eloquent cortex is a crucial part of presurgical planning. While invasive mapping is the gold standard, there is increasing interest in using noninvasive fMRI to shorten and improve the process. However, many surgical patients cannot adequately perform task-based fMRI protocols. Resting-state fMRI has emerged as an alternative modality, but automated eloquent cortex localization remains an open challenge. In this paper, we develop a novel deep learning architecture to simultaneously identify language and primary motor cortex from rs-fMRI connectivity. Our approach uses the representational power of convolutional neural networks alongside the generalization power of multi-task learning to find a shared representation between the eloquent subnetworks. We validate our method on data from the publicly available Human Connectome Project and on a brain tumor dataset acquired at the Johns Hopkins Hospital. We compare our method against feature-based machine learning approaches and a fully-connected deep learning model that does not account for the shared network organization of the data. Our model achieves significantly better performance than competing baselines. We also assess the generalizability and robustness of our method. Our results clearly demonstrate the advantages of our graph convolution architecture combined with multi-task learning and highlight the promise of using rs-fMRI as a presurgical mapping tool.

Functional connectivity in resting-state functional magnetic resonance imaging (rs-fMRI) has received substantial attention since the initial findings of Biswal et al. Traditional network correlation metrics assume that the functional connectivity in the brain remains stationary over time. However, recent studies have shown that robust temporal fluctuations of functional connectivity among as well as within functional networks exist, challenging this assumption. In this study, these dynamic correlation differences were investigated between the dorsal and ventral sensorimotor networks by applying the dynamic conditional correlation model to rs-fMRI data of 20 healthy subjects. k-Means clustering was used to determine an optimal number of discrete connectivity states (k = 10) of the sensorimotor system across all subjects. Our analysis confirms the existence of differences in dynamic correlation between the dorsal and ventral networks, with highest connectivity found within the ventral motor network.

Sarcopenia is an important prognostic consideration in surgical oncology that has received relatively little attention in brain tumor patients. Temporal muscle thickness (TMT) has recently been proposed as a novel radiographic marker of sarcopenia that can be efficiently obtained within existing workflows. We investigated the prognostic value of TMT in primary and progressive glioblastoma.TMT measurements were performed on magnetic resonance images of 384 patients undergoing 541 surgeries for glioblastoma. Relationships between TMT and clinical characteristics were examined on bivariate analysis. Optimal TMT cutpoints were established using maximally selected rank statistics. Predictive value of TMT upon postoperative survival (PS) was assessed using Cox proportional hazards regression adjusted for age, sex, Karnofsky performance status (KPS), Stupp protocol completion, extent of resection, and tumor molecular markers.Average TMT for the primary and progressive glioblastoma cohorts was 9.55 mm and 9.40 mm, respectively. TMT was associated with age (r = -0.14, p = 0.0008), BMI (r = 0.29, p 0.0001), albumin (r = 0.11, p = 0.0239), and KPS (r = 0.11, p = 0.0101). Optimal TMT cutpoints for the primary and progressive cohorts were ≤ 7.15 mm and ≤ 7.10 mm, respectively. High TMT was associated with increased Stupp protocol completion (p = 0.001). On Cox proportional hazards regression, high TMT predicted increased PS in progressive [HR 0.47 (95% confidence interval (CI)) 0.25-0.90), p = 0.023] but not primary [HR 0.99 (95% CI 0.64-1.51), p = 0.949] glioblastoma.TMT correlates with important prognostic variables in glioblastoma and predicts PS in patients with progressive, but not primary, disease. TMT may represent a pragmatic neurosurgical biomarker in glioblastoma that could inform treatment planning and perioperative optimization.

Methods of image acquisition and analysis for resting-state functional MR imaging (rsfMR imaging) are still evolving. Neurovascular uncoupling and susceptibility artifact are important confounds of rsfMR imaging in the setting of focal brain lesions such as brain tumors. This article reviews the detection of these confounds using rsfMR imaging metrics in the setting of focal brain lesions. In the near future, with the wide range of ongoing research in rsfMR imaging, these issues likely will be overcome and will open new windows into brain function and connectivity.

Resting state functional MR imaging (rs-fMR imaging) has become an indispensable tool for examining brain function. The greatest opportunity to translate rs-fMR imaging from the research domain into clinical use is as a tool for examining intrinsic brain networks for preoperative planning. Many studies have demonstrated concordance of intrinsic motor networks from rs-fMR imaging data with task-fMR imaging and direct cortical stimulation. Earlier reports show concordance of language networks as well, although more recent studies with larger numbers of subjects demonstrate subject-level variability that needs to be further investigated and addressed before widespread implementation of rs-fMR imaging for preoperative planning.

INTRODUCTION: Functional MR imaging is increasingly being used for presurgical language assessment in the treatment of patients with brain tumors, epilepsy, vascular malformations, and other conditions. The inherent complexity of fMRI, which includes numerous processing steps and selective analyses, is compounded by institution-unique approaches to patient training, paradigm choice, and an eclectic array of postprocessing options from various vendors. Consequently, institutions perform fMRI in such markedly different manners that data sharing, comparison, and generalization of results are difficult. The American Society of Functional Neuroradiology proposes widespread adoption of common fMRI language paradigms as the first step in countering this lost opportunity to advance our knowledge and improve patient care. LANGUAGE PARADIGM REVIEW PROCESS: A taskforce of American Society of Functional Neuroradiology members from multiple institutions used a broad literature review, member polls, and expert opinion to converge on 2 sets of standard language paradigms that strike a balance between ease of application and clinical usefulness. ASFNR RECOMMENDATIONS: The taskforce generated an adult language paradigm algorithm for presurgical language assessment including the following tasks: Sentence Completion, Silent Word Generation, Rhyming, Object Naming, and/or Passive Story Listening. The pediatric algorithm includes the following tasks: Sentence Completion, Rhyming, Antonym Generation, or Passive Story Listening. DISCUSSION: Convergence of fMRI language paradigms across institutions offers the first step in providing a “Rosetta Stone” that provides a common reference point with which to compare and contrast the usefulness and reliability of fMRI data. From this common language task battery, future refinements and improvements are anticipated, particularly as objective measures of reliability become available. Some commonality of practice is a necessary first step to develop a foundation on which to improve the clinical utility of this field.

Purpose Cerebral venous oxygenation (Yv) is an important biomarker for brain diseases. This study aims to develop an R2*-based MR oximetry that can measure cerebral Yv in 3D. Methods This technique separates blood signal from tissue by velocity-encoding phase contrast and measures the R2* of pure blood by multi-gradient-echo acquisition. The blood R2* was converted to Yv using an R2*-versus-oxygenation (Y) calibration curve, which was obtained by in vitro bovine blood experiments. Reproducibility, sensitivity, validity, and resolution dependence of the technique were evaluated. Results In vitro R2*-Y calibration plot revealed a strong dependence of blood R2* on oxygenation, with additional dependence on hematocrit. In vivo results demonstrated that the technique can provide a 3D venous oxygenation map that depicts both large sinuses and smaller cortical veins, with venous oxygenation ranging from 57 to 72%. Intrasession coefficient of variation of the measurement was 3.0%. The technique detected an average Yv increase of 10.8% as a result of hyperoxia, which was validated by global oxygenation measurement from T2-Relaxation-Under-Spin-Tagging (TRUST) MRI. Two spatial resolutions, one with an isotropic voxel dimension and the other with a nonisotropic dimension, were tested for full brain coverage. Conclusions This study demonstrated the feasibility of 3D brain oxygenation mapping without using contrast agent. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Functional magnetic resonance imaging (fMRI) serves as a critical tool for presurgical mapping of eloquent cortex and changes in neurological function in patients diagnosed with brain tumors. However, the blood-oxygen-level-dependent (BOLD) contrast mechanism underlying fMRI assumes that neurovascular coupling remains intact during brain tumor progression, and that measured changes in cerebral blood flow (CBF) are correlated with neuronal function. Recent preclinical and clinical studies have demonstrated that even low-grade brain tumors can exhibit neurovascular uncoupling (NVU), which can confound interpretation of fMRI data. Therefore, to avoid neurosurgical complications, it is crucial to understand the biophysical basis of NVU and its impact on fMRI. Here we review the physiology of the neurovascular unit, how it is remodeled, and functionally altered by brain cancer cells. We first discuss the latest findings about the components of the neurovascular unit. Next, we synthesize results from preclinical and clinical studies to illustrate how brain tumor induced NVU affects fMRI data interpretation. We examine advances in functional imaging methods that permit the clinical evaluation of brain tumors with NVU. Finally, we discuss how the suppression of anomalous tumor blood vessel formation with antiangiogenic therapies can “normalize” the brain tumor vasculature, and potentially restore neurovascular coupling.

The aim of this study is to determine whether regional homogeneity (ReHo) of resting-state blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (rsfMRI) data based on Kendall's coefficient of concordance (KCC-ReHo) and coherence (Cohe-ReHo) metrics may allow detection of brain tumor-induced neurovascular uncoupling (NVU) in the sensorimotor network similar to findings in standard motor task-based BOLD fMRI (tbfMRI) activation. Twelve de novo brain tumor patients undergoing clinical fMRI exams (tbfMRI and rsfMRI) were included in this Institutional Review Board (IRB)-approved study. Each patient displayed decreased/absent tbfMRI activation in the primary ipsilesional sensorimotor cortex in the absence of corresponding motor deficit or suboptimal task performance, consistent with NVU. Z-score maps for motor tasks were obtained from the general linear model (GLM) analysis (reflecting motor activation vs. rest). KCC-ReHo and Cohe-ReHo maps were calculated from rsfMRI data. Precentral and postcentral gyri in contralesional (CL) and ipsilesional (IL) hemispheres were parcellated using an automated anatomical labeling (AAL) template for each patient. Similar region of interest (ROI) analysis was performed on tbfMRI, KCC-ReHo, and Cohe-ReHo maps to allow direct comparison of results. Voxel values in CL and IL ROIs of each map were divided by the corresponding global mean of KCC-ReHo and Cohe-ReHo in bihemispheric cortical brain tissue. Group analysis revealed significantly decreased IL mean KCC-ReHo (p = 0.02) and Cohe-ReHo (p = 0.04) metrics compared with respective values in the CL ROIs, consistent with similar findings of significantly decreased ipsilesional BOLD signal for tbfMRI (p = 0.0005). Ipsilesional abnormalities in ReHo derived from rsfMRI may serve as potential indicators of NVU in patients with brain tumors and other resectable brain lesions; as such, ReHo findings may complement findings on tbfMRI used for presurgical planning.

BACKGROUND AND PURPOSE: Resting-state fMRI readily identifies the dorsal but less consistently the ventral somatomotor network. Our aim was to assess the relative utility of resting-state fMRI in the identification of the ventral somatomotor network via comparison with task-based fMRI in patients with brain tumor. MATERIALS AND METHODS: We identified 26 surgically naive patients referred for presurgical fMRI brain mapping who had undergone both satisfactory ventral motor activation tasks and resting-state fMRI. Following standard preprocessing for task-based fMRI and resting-state fMRI, general linear model analysis of the ventral motor tasks and independent component analysis of resting-state fMRI were performed with the number of components set to 20, 30, 40, and 50. Visual overlap of task-based fMRI and resting-state fMRI at different component levels was assessed and categorized as full match, partial match, or no match. Rest-versus-task-fMRI concordance was calculated with Dice coefficients across varying fMRI thresholds before and after noise removal. Multithresholded Dice coefficient volume under the surface was calculated. RESULTS: The ventral somatomotor network was identified in 81% of patients. At the subject level, better matches between resting-state fMRI and task-based fMRI were seen with an increasing order of components (53% of cases for 20 components versus 73% for 50 components). Noise-removed group-mean volume under the surface improved as component numbers increased from 20 to 50, though ANOVA demonstrated no statistically significant difference among the 4 groups. CONCLUSIONS: In most patients, the ventral somatomotor network can be identified with an increase in the probability of a better match at a higher component number. There is variable concordance of the ventral somatomotor network at the single-subject level between resting-state and task-based fMRI.

Objective The aim of this study is to evaluate the correlation between resting state functional MRI (RS-fMRI) activity and motor and cognitive impairment in spinocerebellar ataxia type 6 (SCA6). Methods Twelve patients with genetically confirmed SCA6 and 14 age matched healthy controls were imaged with RS-fMRI. Whole brain gray matter was automatically parcellated into 1000 regions of interest (ROIs). For each ROI, the first eigenvariate of voxel time courses was extracted. For each patient, Pearson correlation coefficients between each pair of ROI time courses were calculated across the 1000 ROIs. The set of average control correlation coefficients were fed as an undirected weighted adjacency matrix into the Rubinov and Sporns (2010) modularity algorithm. The intranetwork global efficiency of the thresholded adjacency sub-matrix was calculated and correlated with ataxia scores and cognitive performance. Results SCA6 patients showed mild cognitive impairments in executive function and visual-motor processing compared to control subjects. These neuropsychological impairments were correlated with decreased RS functional connectivity (FC) in the attention network. Conclusions Mild cognitive executive functions and visual-motor coordination impairments seen in SCA6 patients correlate with decreased resting-state connectivity in the attention network, suggesting a possible metric for the study of cognitive dysfunction in cerebellar disease. Hum Brain Mapp 38:3001–3010, 2017. © 2017 Wiley Periodicals, Inc.

BACKGROUND: MRI performed with echo-planar imaging (EPI) sequences is sensitive to susceptibility artifacts in the presence of metallic objects, which presents a substantial barrier for performing functional MRI and diffusion tensor imaging (DTI) in patients with metallic orthodontic material and other head implants. PURPOSE: To evaluate the ability to reduce susceptibility artifacts in healthy human participants wearing metallic orthodontic braces for two alternative approaches: T2-prepared functional MRI and diffusion-prepared DTI with three-dimensional fast gradient-echo readout. MATERIALS AND METHODS: In this prospective study conducted from February to September 2018, T2-prepared functional MRI and diffusion-prepared DTI were performed in healthy human participants. Removable dental braces with bonding trays were used so that MRI could be performed with braces and without braces in the same participants. Results were evaluated in regions with strong (EPI dropout regions for functional MRI and the inferior fronto-occipital fasciculus for DTI) and minimal (motor cortex for functional MRI and the posterior limb of internal capsule for DTI) susceptibility artifacts. Signal-to-noise ratio (SNR), contrast-to-noise ratio for functional MRI, apparent diffusion coefficient and fractional anisotropy for DTI, and degree of distortion (quantified with the Jaccard index, which measures the similarity of geometric shapes) were compared in regions with strong or minimal susceptibility effects between the current standard EPI sequences and the proposed alternatives by using paired t test. RESULTS: Six participants were evaluated (mean age ± standard deviation, 40 years ± 6; three women). In brain regions with strong susceptibility effects from the metallic braces, T2-prepared functional MRI showed significantly higher SNR (37.8 ± 2.4 vs 15.5 ± 5.3; P < .001) and contrast-to-noise ratio (0.83 ± 0.16 vs 0.29 ± 0.10; P < .001), whereas diffusion-prepared DTI showed higher SNR (5.8 ± 1.5 vs 3.8 ± 0.7; P = .03) than did conventional EPI methods. Apparent diffusion coefficient and fractional anisotropy were consistent with the literature. Geometric distortion was substantially reduced throughout the brain with the proposed methods (significantly higher Jaccard index, 0.95 ± 0.12 vs 0.81 ± 0.61; P < .001). CONCLUSION: T2-prepared functional MRI and diffusion-prepared diffusion tensor imaging can acquire functional and diffusion MRI, respectively, in healthy human participants wearing metallic dental braces with less susceptibility artifacts and geometric distortion than with conventional echo-planar imaging. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Dietrich in this issue.

MR Fingerprinting (MRF)-based Arterial-Spin-Labeling (ASL) has the potential to measure multiple parameters such as cerebral blood flow (CBF), bolus arrival time (BAT), and tissue T(1) in a single scan. However, the previous reports have only demonstrated a proof-of-principle of the technique but have not examined the performance of the sequence in the context of key imaging parameters. Furthermore, there has not been a study to directly compare the technique to clinically used perfusion method of dynamic-susceptibility-contrast (DSC) MRI. The present report consists of two studies. In the first study (N = 8), we examined the dependence of MRF-ASL sequence onTR time pattern. Ten different TR patterns with a range of temporal characteristics were examined by both simulations and experiments. The results revealed that there was a significance dependence of the sequence performance on TR pattern (p < 0.001), although there was not a single pattern that provided dramatically improvements. Among the TR patterns tested, a sinusoidal pattern with a period of 125 TRs provided an overall best estimation in terms of spatial consistency. These experimental observations were consistent with those of numerical simulations. In the second study (N = 8), we compared MRF-ASL results with those of DSC MRI. It was found that MRF-ASL and DSC MRI provided highly comparable maps of cerebral blood flow (CBF) and bolus-arrival-time (BAT), with spatial correlation coefficients of 0.79 and 0.91, respectively. However, in terms of quantitative values, BAT obtained with MRF-ASL was considerably lower than that from DSC (p < 0.001), presumably because of the differences in tracer characteristics in terms of diffusible versus intravascular tracers. Test–retest assessment of MRF-ASL MRI revealed that the spatial correlations of parametric maps were 0.997, 0.962, 0.746 and 0.863 for B(1)(+), T(1), CBF, and BAT, respectively. MRF-ASL is a promising technique for assessing multiple perfusion parameters simultaneously without contrast agent.

Clinical use of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) is a relatively new phenomenon, with only about 3 decades of collective experience. Nevertheless, task-based BOLD fMRI has been widely accepted for presurgical planning, over traditional methods, which are invasive and at times perilous. Many studies have demonstrated the ability of BOLD fMRI to make substantial clinical impact with respect to surgical planning and preoperative risk assessment, especially to localize the eloquent motor and visual areas. Reproducibility and repeatability of language fMRI are important in the assessment of its clinical usefulness. There are national efforts currently underway to standardize language fMRI. The American Society of Functional Neuroradiology (ASFNR) has recently provided guidelines on fMRI paradigm algorithms for presurgical language assessment for language lateralization and localization. In this review article, we provide a comprehensive overview of current standards of language fMRI mapping and its reproducibility.