Blood Oxygen Level-dependent MRI Research Articles

Assessment of Hypoxia in Breast Cancer: Emerging Functional MR Imaging and Spectroscopy Techniques and Clinical Applications.

Breast cancer is one of the most prevalent forms of cancer affecting women worldwide. Hypoxia, a condition characterized by insufficient oxygen supply in tumor tissues, is closely associated with tumor aggressiveness, resistance to therapy, and poor clinical outcomes. Accurate assessment of tumor hypoxia can guide treatment decisions, predict therapy response, and contribute to the development of targeted therapeutic interventions. Over the years, functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) techniques have emerged as promising noninvasive imaging options for evaluating hypoxia in cancer. Such techniques include blood oxygen level-dependent (BOLD) MRI, oxygen-enhanced MRI (OE) MRI, chemical exchange saturation transfer (CEST) MRI, and proton MRS (1H-MRS). These may help overcome the limitations of the routinely used dynamic contrast-enhanced (DCE) MRI and diffusion-weighted imaging (DWI) techniques, contributing to better diagnosis and understanding of the biological features of breast cancer. This review aims to provide a comprehensive overview of the emerging functional MRI and MRS techniques for assessing hypoxia in breast cancer, along with their evolving clinical applications. The integration of these techniques in clinical practice holds promising implications for breast cancer management. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 1.

Test-retest reliability and time-of-day variations of perfusion imaging at rest and during a vigilance task.

Arterial spin-labeled perfusion and blood oxygenation level-dependent functional MRI are indispensable tools for noninvasive human brain imaging in clinical and cognitive neuroscience, yet concerns persist regarding the reliability and reproducibility of functional MRI findings. The circadian rhythm is known to play a significant role in physiological and psychological responses, leading to variability in brain function at different times of the day. Despite this, test-retest reliability of brain function across different times of the day remains poorly understood. This study examined the test-retest reliability of six repeated cerebral blood flow measurements using arterial spin-labeled perfusion imaging both at resting-state and during the psychomotor vigilance test, as well as task-induced cerebral blood flow changes in a cohort of 38 healthy participants over a full day. The results demonstrated excellent test-retest reliability for absolute cerebral blood flow measurements at rest and during the psychomotor vigilance test throughout the day. However, task-induced cerebral blood flow changes exhibited poor reliability across various brain regions and networks. Furthermore, reliability declined over longer time intervals within the day, particularly during nighttime scans compared to daytime scans. These findings highlight the superior reliability of absolute cerebral blood flow compared to task-induced cerebral blood flow changes and emphasize the importance of controlling time-of-day effects to enhance the reliability and reproducibility of future brain imaging studies.

Denoising of the gradient artifact present in simultaneous studies of muscle blood oxygen level dependent (BOLD) signal and electromyography (EMG)

The MR-induced gradient artifact affects EMG recordings during simultaneous muscle BOLD/EMG acquisitions. However, no dedicated hardware can remove the gradient artifact easily, and alternative methods are expensive and time-consuming. This study aimed to develop three denoising methods requiring different processing levels and MR-compatible hardware.At two time points, surface EMG was recorded from the lower leg of 6 participants (50:50 sex ratio, age = 26.24.6 yrs., height = 173.59.2 cm, weight = 71.511.4 kg) using a plantar flexion-based block design consisting of 30s of rest followed by 30s of flexion for 5 min, under three conditions: inside the MRI bore, with and without a BOLD sequence (3 T, BOLD sequence, GRE EPI, 10 slices, 6464 matrix, 2 mm thickness, and TE/TR/flip = 35/3000 ms/70), and outside the MRI environment. Simultaneous BOLD/EMG recordings were denoised using average artifact subtraction with three methods of artifact template creation, each having varying timing and hardware requirements. Method M1 builds the artifact template by recording the scanner triggers coming from the MRI; M2 creates the artifact template with a constant artifact period computed as TR/[number of slices]; M3 estimates the artifact template by looking at the periodicity of the gradient artifact located in the EMG recordings. Following postprocessing, SNR analysis was performed, comparing rest-to-flexion periods, to assess the efficacy of denoising methods and to compare differences between conditions.Linear mixed-effects models showed no significant differences in the mean SNR between denoising methods (p = 0.656). Furthermore, EMG SNR measurements were significantly affected by the magnetic environment (p < 0.05) but not by muscle fatigue over time (p = 0.975).EMG recordings contaminated with gradient artifacts during simultaneous BOLD/EMG can be efficiently denoised using all proposed methods, with two methods requiring no extra hardware. With minimal post-processing, EMG can easily be performed during muscle BOLD MRI studies.

Intensity Score of Vessel Wall Contrast Enhancement in MRI Allows Prediction of Disease Progression in Moyamoya Angiopathy.

The underlying pathophysiological cause of moyamoya angiopathy (MMA) is still unclear. High-resolution vessel wall imaging has become a useful tool. The aim was to study vessel wall contrast-enhancement (VW-CE) as an imaging marker to predict disease progression in MMA. Patients with MMA, who had undergone serial contrast-enhanced high-resolution MRI with concomitant and follow-up digital subtraction angiography, were analyzed retrospectively. VW-CE was semiquantified by measurement of the signal intensity of the vessel wall in in contrast-enhanced high-resolution MRI. A comparative quotient with the contrast-intensity of the pituitary stalk was calculated and graded accordingly from grade 1 to 5. VW-CE status was correlated with disease status, stroke, cerebrovascular reactivity in CO2-triggered blood-oxygen level-dependent MRI, angiographic disease progression, revascularization surgery, and follow-up imaging. Forty eight patients met the inclusion criteria. N = 56 MRI and digital subtraction angiography time-intervals were evaluated for 12 vessel sections per hemisphere each (N = 1344). N = 38 (79%) patients showed VW-CE and N = 10 (21%) did not. VW-CE was only observed in the terminal internal carotid artery and the proximal circle of Willis (N = 96/1344). Notably, patients with VW-CE significantly more often presented with acute infarction in the concomitant MRI. The incidence of angiographically proven disease progression was significantly associated with the incidence of VW-CE, and time to disease progression was earlier in higher grades of VW-CE compared with lower grades. VW-CE is a semiquantifiable marker for disease activity in patients with MMA and associated with disease progression and increased risk of stroke. VW-CE analysis can be routinely performed in patients with MMA to estimate the risk for disease progression and stroke.

Linking renal hypoxia and oxidative stress in chronic kidney disease: Based on clinical subjects and animal models.

This study aims to explore the relationships between renal function, hypoxia, and oxidative stress in chronic kidney disease (CKD). Seventy-six non-dialysis patients with CKD stages 1-5 and eight healthy subjects were included in the clinical research. They were divided into three groups: healthy subjects, CKD stages 1-3, and CKD stages 4-5. In the animal study, 16 rat models of CKD were established through 5/6 renal ablation/infarction (A/I) surgery, and 8 normal rats were split into 3 groups: Sham, CKD, and losartan groups. Blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) was used to measure cortical and medullary T2* values (COT2* and MET2*) in all subjects and rats to evaluate renal oxygenation. Biochemical indicators were used to assess renal function and antioxidant capacity. Furthermore, the effects of losartan on renal fibrosis, hypoxia, and oxidative stress were examined using immunoblotting, colorimetric, and fluorometric assays. The results demonstrated significant positive associations between COT2* and MET2* with estimated glomerular filtration rate (eGFR). Patients with CKD stages 4-5 showed significantly lower serum superoxide dismutase (SOD) levels, which also had positive correlations with eGFR, COT2*, and MET2*. Furthermore, losartan treatment resulted in improved renal function and fibrosis, leading to increased levels of COT2*, MET2*, and SOD levels in 5/6 A/I rats. This was accompanied by reduced levels of hypoxia-inducible factor-1 alpha (HIF-1α) and malondialdehyde. Furthermore, losartan restored the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and suppressed the expression of Kelch-like ECH-associated protein 1 (Keap1) in 5/6 A/I kidneys. The study indicates that decline in renal oxygenation and antioxidant capacity is associated with the severity of renal failure in CKD. Losartan can potentially alleviate renal hypoxia and oxidative stress in the treatment of CKD via Keap1-Nrf2/HO-1 pathway.

Non-invasive in-utero quantification of vascular reactivity in human placenta.

Placental vascular reactivity (PlVR) indicates the ability of the placental vasculature to match blood supply to fetal demand. Many pregnancy disorders alter the characteristics of PlVR, resulting in suboptimal oxygen delivery, although current understanding is limited by the lack of non-invasive, repeatable methods to measure PlVR in utero. Our objective was to quantify PlVR by measuring the placental response to transient changes in maternal carbon dioxide (CO2) using blood-oxygen-level-dependent (BOLD) magnetic resonance imaging (MRI). We hypothesized that PlVR will increase with gestational age to meet the changing demands of a growing fetus, and that PlVR will be driven by a maternal response to changes in CO2 concentration. This was a cross-sectional study of 35 women with a healthy singleton pregnancy, of whom 31 were included in the analysis. The median gestational age was 32.6 (range, 22.6-38.4) weeks. Pregnant women were instructed to follow audiovisual breathing cues during a MRI scan. Maternal end-tidal CO2 (EtCO2) was measured concurrently with resting placental BOLD MRI for a total of 7-8 min. Preprocessing of magnetic resonance images consisted of manual delineation of placental anatomy and motion correction. In each placental voxel, vascular reactivity was computed using a coherence-weighted general linear model between MRI signal and EtCO2 stimulus. Global PlVR was computed as the mean of voxel-wise PlVR values across the placenta. PlVR, quantified by the placental response to induced, transient changes in maternal CO2, was consistently measured in utero using BOLD MRI. PlVR increased non-linearly with advancing gestational age (P < 0.001) and was higher on the fetal side of the placenta. PlVR was associated positively with fetal brain volume after accounting for gestational age. PlVR did not show any significant associations with maternal characteristics. We present, for the first time, a non-invasive paradigm to quantify PlVR in ongoing human pregnancies without the use of exogenous gases or contrast agents. Our findings suggest that PlVR is driven by a fetal response to changes in maternal CO2. Ease of translation to the clinical setting makes PlVR a promising biomarker for the identification and management of high-risk pregnancies. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Magnetic resonance imaging-based approaches for detecting the efficacy of combining therapy following VEGFR-2 and PD-1 blockade in a colon cancer model

BackgroundAngiogenesis inhibitors have been identified to improve the efficacy of immunotherapy in recent studies. However, the delayed therapeutic effect of immunotherapy poses challenges in treatment planning. Therefore, this study aims to explore the potential of non-invasive imaging techniques, specifically intravoxel-incoherent-motion diffusion-weighted imaging (IVIM-DWI) and blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI), in detecting the anti-tumor response to the combination therapy involving immune checkpoint blockade therapy and anti-angiogenesis therapy in a tumor-bearing animal model.MethodsThe C57BL/6 mice were implanted with murine MC-38 cells to establish colon cancer xenograft model, and randomly divided into the control group, anti-PD-1 therapy group, and combination therapy group (VEGFR-2 inhibitor combined with anti-PD-1 antibody treatment). All mice were imaged before and, on the 3rd, 6th, 9th, and 12th day after administration, and pathological examinations were conducted at the same time points.ResultsThe combination therapy group effectively suppressed tumor growth, exhibiting a significantly higher tumor inhibition rate of 69.96% compared to the anti-PD-1 group (56.71%). The f value and D* value of IVIM-DWI exhibit advantages in reflecting tumor angiogenesis. The D* value showed the highest correlation with CD31 (r = 0.702, P = 0.001), and the f value demonstrated the closest correlation with vessel maturity (r = 0.693, P = 0.001). While the BOLD-MRI parameter, R2* value, shows the highest correlation with Hif-1α(r = 0.778, P < 0.001), indicating the capability of BOLD-MRI to evaluate tumor hypoxia. In addition, the D value of IVIM-DWI is closely related to tumor cell proliferation, apoptosis, and infiltration of lymphocytes. The D value was highly correlated with Ki-67 (r = − 0.792, P < 0.001), TUNEL (r = 0.910, P < 0.001) and CD8a (r = 0.918, P < 0.001).ConclusionsThe combination of VEGFR-2 inhibitors with PD-1 immunotherapy shows a synergistic anti-tumor effect on the mouse colon cancer model. IVIM-DWI and BOLD-MRI are expected to be used as non-invasive approaches to provide imaging-based evidence for tumor response detection and efficacy evaluation.

Non-Contrast-Enhanced Multiparametric MRI of the Hypoxic Tumor Microenvironment Allows Molecular Subtyping of Breast Cancer: A Pilot Study.

Tumor neoangiogenesis is an important hallmark of cancer progression, triggered by alternating selective pressures from the hypoxic tumor microenvironment. Non-invasive, non-contrast-enhanced multiparametric MRI combining blood-oxygen-level-dependent (BOLD) MRI, which depicts blood oxygen saturation, and intravoxel-incoherent-motion (IVIM) MRI, which captures intravascular and extravascular diffusion, can provide insights into tumor oxygenation and neovascularization simultaneously. Our objective was to identify imaging markers that can predict hypoxia-induced angiogenesis and to validate our findings using multiplexed immunohistochemical analyses. We present an in vivo study involving 36 female athymic nude mice inoculated with luminal A, Her2+, and triple-negative breast cancer cells. We used a high-field 9.4-tesla MRI system for imaging and subsequently analyzed the tumors using multiplex immunohistochemistry for CD-31, PDGFR-β, and Hif1-α. We found that the hyperoxic-BOLD-MRI-derived parameter ΔR2* discriminated luminal A from Her2+ and triple-negative breast cancers, while the IVIM-derived parameter fIVIM discriminated luminal A and Her2+ from triple-negative breast cancers. A comprehensive analysis using principal-component analysis of both multiparametric MRI- and mpIHC-derived data highlighted the differences between triple-negative and luminal A breast cancers. We conclude that multiparametric MRI combining hyperoxic BOLD MRI and IVIM MRI, without the need for contrast agents, offers promising non-invasive markers for evaluating hypoxia-induced angiogenesis.

Value of blood oxygenation level-dependent magnetic resonance imaging in early evaluation of the response and prognosis of esophageal squamous cell carcinoma treated with definitive chemoradiotherapy: a preliminary study

BackgroundTo find a useful hypoxia non-invasive biomarker for evaluating early treatment response and prognosis to definitive chemoradiotherapy (dCRT) in patients with esophageal squamous cell carcinoma (ESCC), using blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI).MethodsThe R2* values were obtained pre- and 2–3 weeks post-dCRT in 28 patients with ESCC using BOLD MRI. Independent samples t-test (normality) or Mann-Whitney U test (non-normality) was used to compare the differences of R2*-related parameters between the complete response (CR) and the non-CR groups. Diagnostic performance of parameters in predicting response was tested with receiver operating characteristic (ROC) curve analysis. The 3-year overall survival (OS) was evaluated using Kaplan Meier curve, log rank test, and Cox proportional hazards regression analysis.ResultsThe post-R2*, ∆R2*, and ∆%R2* in the CR group were significantly higher than those in the non-CR group (P = 0.002, 0.003, and 0.006, respectively). The R2*-related parameters showed good prediction of tumor response, with AUC ranging from 0.813 to 0.829. The 3-year OS rate in patients with ∆R2* >-7.54 s− 1 or CR were significantly longer than those with ∆R2* ≤ -7.54 s− 1 (72.37% vs. 0.00%; Hazard ratio, HR = 0.196; 95% confidence interval, 95% CI = 0.047–0.807; P = 0.024) or non-CR (76.47% vs. 29.27%; HR = 0.238, 95% CI = 0.059–0.963; P = 0.044).ConclusionsThe preliminary results demonstrated that the R2* value might be a useful hypoxia non-invasive biomarker for assessing response and prognosis of ESCC treated with dCRT. BOLD MRI might be used as a potential tool for evaluating tumor oxygenation metabolism, which is routinely applied in clinical practice and beneficial to clinical decision-making. A large sample size was needed for further follow-up studies to confirm the findings.

Pathological Factors Affecting the R2* Values of the Kidney in Blood Oxygenation Level-dependent MR Imaging: A Retrospective Study.

Despite the usefulness of blood oxygenation level-dependent (BOLD) MRI in assessing glomerulonephritis activity, its relationship with histological findings remains unclear. Because glomerulonephritis presents multiple complex injury patterns, analysis of each pattern is essential. We aimed to elucidate the relationship between the histological findings of the kidney and BOLD MRI findings in mesangial proliferative glomerulonephritis. Children under 16 years of age diagnosed with mesangial proliferative glomerulonephritis by kidney biopsy at our university hospital between January 2013 and September 2022 were included in this study. Cortical and medullary spin relaxation rate (R2*) values were measured using BOLD MRI at 3T within two weeks before and after the kidney biopsy. The R2* values, including the fluctuations with low-dose oxygen administration, were retrospectively examined in relation to the cortical (mesangial proliferation, endothelial cell proliferation, crescent, sclerosis, and fibrosis) and medullary findings (fibrosis). Sixteen times kidney biopsies were performed for glomerulonephritis during the study period, and one patient was excluded because of comorbidities; the remaining 14 patients included six boys with a mean age of 11.9 ± 3.5 years at the BOLD examination. None of the patients had medullary fibrosis. Among the kidney tissue parameters, only sclerosis showed a significant correlation with R2* values: medulla with R2* values under atmospheric pressure (r = 0.53, P < 0.05) and cortex with the rate of change in R2* values with low-dose oxygen administration (r = -0.57, P < 0.03). In the multiple regression analysis, only sclerosis was an independent contributor to the change in R2* values with oxygen administration in the cortex (regression coefficient -0.109, P < 0.05). Since the R2* values reflect histological changes in the kidney, BOLD MRI may facilitate the evaluation of mesangial proliferative glomerulonephritis, potentially reducing the patient burden.

Patterns of cortical oxygenation may predict the response to stenting in subjects with renal artery stenosis: A radiomics-based model.

Percutaneous-transluminal renal angioplasty (PTRA) and stenting aim to halt the progression of kidney disease in patients with renal artery stenosis (RAS), but its outcome is often suboptimal. We hypothesized that a model incorporating markers of renal function and oxygenation extracted using radiomics analysis of blood oxygenation-level dependent (BOLD)-MRI images may predict renal response to PTRA in swine RAS. Twenty domestic pigs with RAS were scanned with CT and BOLD MRI before and 4 weeks after PTRA. Stenotic (STK) and contralateral (CLK) kidney volume, blood flow (RBF), and glomerular filtration rate (GFR) were determined, and BOLD-MRI R2*maps were generated before and after administration of furosemide, a tubular reabsorption inhibitor. Radiomics features were extracted from pre-PTRA BOLD maps and Robust features were determined by Intraclass correlation coefficients (ICC). Prognostic models were developed to predict post-PTRA renal function based on the baseline functional and BOLD-radiomics features, using Lasso-regression for training, and testing with resampling. Twenty-six radiomics features passed the robustness test. STK oxygenation distribution pattern did not respond to furosemide, whereas in the CLK radiomics features sensitive to oxygenation heterogeneity declined. Radiomics-based model predictions of post-PTRA GFR (r=0.58, p=0.007) and RBF (r=0.68; p=0.001) correlated with actual measurements with sensitivity and specificity of 92% and 67%, respectively. Models were unsuccessful in predicting post-PTRA systemic measures of renal function. Several radiomics features are sensitive to cortical oxygenation patterns and permit estimation of post-PTRA renal function, thereby distinguishing subjects likely to respond to PTRA and stenting.

Functional MRI evaluation of blood oxygen dependent (BOLD) in renal allograft dysfunction: a prospective study.

Blood oxygen level dependent-magnetic resonance imaging (BOLD-MRI) is a non-invasive functional imaging technique that can be used to assess renal allograft dysfunction. To evaluate the diagnostic performance of BOLD-MRI using a 3-T scanner in discriminating causes of renal allograft dysfunction in the post-transplant period. This prospective study was conducted on 112 live donor-renal allograft recipients: 53 with normal graft function, as controls; 18 with biopsy-proven acute rejection (AR); and 41 with biopsy-proven acute tubular necrosis (ATN). Multiple fast-field echo sequences were performed to obtain T2*-weighted images. Cortical R2* (CR2*) level, medullary R2* (MR2*) level, and medullary over cortical R2* ratio (MCR) were measured in all participants. The mean MR2* level was significantly lower in the AR group (20.8 ± 2.8/s) compared to the normal group (24 ± 2.4/s, P <0.001) and ATN group (27.4 ± 1.7/s, P <0.001). The MCR was higher in ATN group (1.47 ± 0.18) compared to the AR group (1.18 ± 0.17) and normal functioning group (1.34 ± 0.2). Both MR2* (area under the curve [AUC] = 0.837, P <0.001) and MCR (AUC = 0.727, P = 0.003) can accurately discriminate ATN from AR, however CR2* (AUC = 0.590, P = 0.237) showed no significant difference between both groups. In early post-transplant renal dysfunction, BOLD-MRI is a valuable non-invasive diagnostic technique that can differentiate between AR and ATN by measuring changes in intra-renal tissue oxygenation.

Assessment of Cerebrovascular Reactivity Using CO2 -BOLD MRI: A 15-Year, Single Center Experience.

Cerebrovascular reactivity (CVR) is a measure of the change in cerebral blood flow (CBF) in response to a vasoactive challenge. It is a useful indicator of the brain's vascular health. To evaluate the factors that influence successful and unsuccessful CVR examinations using precise arterial and end-tidal partial pressure of CO2 control during blood oxygen level-dependent (BOLD) MRI. Retrospective. Patients that underwent a CVR between October 2005 and May 2021 were studied (total of 1162 CVR examinations). The mean (±SD) age was 46.1 (±18.8) years, and 352 patients (43%) were female. 3 T; T1-weighted images, T2*-weighed two-dimensional gradient-echo sequence with standard echo-planar readout. Measurements were obtained following precise hypercapnic stimuli using BOLD MRI as a surrogate of CBF. Successful CVR examinations were defined as those where: 1) patients were able to complete CVR testing, and 2) a clinically useful CVR map was generated. Unsuccessful examinations were defined as those where patients were not able to complete the CVR examination or the CVR maps were judged to be unreliable due to, for example, excessive head motion, and poor PET CO2 targeting. Successful and unsuccessful CVR examinations between hypercapnic stimuli, and between different patterns of stimulus were compared with Chi-Square tests. Interobserver variability was determined by using the intraclass correlation coefficient (P < 0.05 is significant). In total 1115CVR tests in 662 patients were included in the final analysis. The success rate of generating CVR maps was 90.8% (1012 of 1115). Among the different hypercapnic stimuli, those containing a step plus a ramp protocol was the most successful (95.18%). Among the unsuccessful examinations (9.23%), most were patient related (89.3%), the most common of which was difficulty breathing. CO2 -BOLD MRI CVR studies are well tolerated with a high success rate. 4 TECHNICAL EFFICACY: Stage 3.

The MANGO study: a prospective investigation of oxygen enhanced and blood-oxygen level dependent MRI as imaging biomarkers of hypoxia in glioblastoma.

Glioblastoma (GBM) is the most aggressive type of brain cancer, with a 5-year survival rate of ~5% and most tumours recurring locally within months of first-line treatment. Hypoxia is associated with worse clinical outcomes in GBM, as it leads to localized resistance to radiotherapy and subsequent tumour recurrence. Current standard of care treatment does not account for tumour hypoxia, due to the challenges of mapping tumour hypoxia in routine clinical practice. In this clinical study, we aim to investigate the role of oxygen enhanced (OE) and blood-oxygen level dependent (BOLD) MRI as non-invasive imaging biomarkers of hypoxia in GBM, and to evaluate their potential role in dose-painting radiotherapy planning and treatment response assessment. The primary endpoint is to evaluate the quantitative and spatial correlation between OE and BOLD MRI measurements and [18F]MISO values of uptake in the tumour. The secondary endpoints are to evaluate the repeatability of MRI biomarkers of hypoxia in a test-retest study, to estimate the potential clinical benefits of using MRI biomarkers of hypoxia to guide dose-painting radiotherapy, and to evaluate the ability of MRI biomarkers of hypoxia to assess treatment response. Twenty newly diagnosed GBM patients will be enrolled in this study. Patients will undergo standard of care treatment while receiving additional OE/BOLD MRI and [18F]MISO PET scans at several timepoints during treatment. The ability of OE/BOLD MRI to map hypoxic tumour regions will be evaluated by assessing spatial and quantitative correlations with areas of hypoxic tumour identified via [18F]MISO PET imaging. MANGO (Magnetic resonance imaging of hypoxia for radiation treatment guidance in glioblastoma multiforme) is a diagnostic/prognostic study investigating the role of imaging biomarkers of hypoxia in GBM management. The study will generate a large amount of longitudinal multimodal MRI and PET imaging data that could be used to unveil dynamic changes in tumour physiology that currently limit treatment efficacy, thereby providing a means to develop more effective and personalised treatments.

In search of a marker of altered cerebrovascular function in hypertension: Analysis of the fractional amplitude of low-frequency fluctuations in UK Biobank resting state fMRI data

The selfish brain mechanism proposes that in some patients with impaired cerebral blood flow (CBF) or cerebrovascular function, hypertension may develop as a compensatory mechanism that aims to maintain CBF by increasing systemic blood pressure through an increase in cardiovascular sympathetic tone. The amplitude of low frequency fluctuations (ALFF) in the resting state blood oxygenation level dependent (BOLD) functional MRI signal has been previously posited as an index of cerebrovascular reactivity.We investigated whether regional fractional ALFF (fALFF) differs between 2054 hypertensives and 1724 normotensives using data from the UK Biobank dataset. Our primary hypothesis was that cerebrovascular function in the medulla and other regions involved in sympathetic regulation differs between hypertensives and normotensives, and that this is reflected by regional variations in fALFF.There is a significant regional variation in fALFF (F(14) =1126.17, p < 2 × 10−16, partial η2 = 0.22), but this regional variation does not differ between hypertensives and normotensives (F(14) = 0.23, p = 0.99, partial η2 = 8 × 10−5).Prospective longitudinal studies of cerebral haemodynamics in hypertensives and normotensives are required to further investigate the selfish brain mechanism.

Focal tDCS of auditory cortex in chronic tinnitus: A randomized controlled mechanistic trial

ObjectiveThe goal of this pilot study was to understand how focal transcranial direct current stimulation (tDCS) targeting auditory cortex changes brain function in chronic tinnitus using magnetic resonance imaging (MRI). MethodsPeople with chronic tinnitus were randomized to active or sham tDCS on five consecutive days in this mechanistic trial (n = 10/group). Focal 4x1 tDCS (central anode, surround cathodes) targeted left auditory cortex, with single-blind 2 mA current during twenty-minute sessions. Arterial spin-labeled and blood oxygenation level dependent MRI occurred immediately before and after the first tDCS session, and tinnitus symptoms were measured starting one week before the first tDCS session and through four weeks after the final session. ResultsAcute increases in cerebral blood flow and functional connectivity were noted in auditory cortex after the first active tDCS session. Reduced tinnitus loudness ratings after the final tDCS session correlated with acute change in functional connectivity between an auditory network and mediodorsal thalamus and prefrontal cortex. Reduced tinnitus intrusiveness also correlated with acute change in connectivity between precuneus and an auditory network. ConclusionsFocal auditory-cortex tDCS can influence function in thalamus, auditory, and prefrontal cortex, which may associate with improved tinnitus. SignificanceWith future refinement, tDCS targeting auditory cortex could become a viable intervention for tinnitus.

Shape-aware Segmentation of the Placenta in BOLD Fetal MRI Time Series

Blood oxygen level dependent (BOLD) MRI time series with maternal hyperoxia can assess placental oxygenation and function. Measuring precise BOLD changes in the placenta requires accurate temporal placental segmentation and is confounded by fetal and maternal motion, contractions, and hyperoxia-induced intensity changes. Current BOLD placenta segmentation methods warp a manually annotated subject-specific template to the entire time series. However, as the placenta is a thin, elongated, and highly non-rigid organ subject to large deformations and obfuscated edges, existing work cannot accurately segment the placental shape, especially near boundaries. In this work, we propose a machine learning segmentation framework for placental BOLD MRI and apply it to segmenting each volume in a time series. We use a placental-boundary weighted loss formulation and perform a comprehensive evaluation across several popular segmentation objectives. Our model is trained and tested on a cohort of (91) subjects containing healthy fetuses, fetuses with fetal growth restriction, and mothers with high BMI. Biomedically, our model performs reliably in segmenting volumes in both normoxic and hyperoxic points in the BOLD time series. We further find that boundary-weighting increases placental segmentation performance by 8.3% and 6.0% Dice coefficient for the cross-entropy and Signed Distance Transform objectives, respectively.

Effects of Canagliflozin on Renal Oxygenation Evaluated Using Blood Oxygenation Level-Dependent MRI in Patients with Type 2 Diabetes

Effects of Canagliflozin on Renal Oxygenation Evaluated Using Blood Oxygenation Level-Dependent MRI in Patients with Type 2 Diabetes

GABA, glutamatergic dynamics and BOLD contrast assessed concurrently using functional MRS during a cognitive task.

A recurring issue in functional neuroimaging is how to link task-driven haemodynamic blood oxygen level dependent functional MRI (BOLD-fMRI) responses to underlying neurochemistry at the synaptic level. Glutamate and γ-aminobutyric acid (GABA), the major excitatory and inhibitory neurotransmitters respectively, are typically measured with MRS sequences separately from fMRI, in the absence of a task. The present study aims to resolve this disconnect, developing acquisition and processing techniques to simultaneously assess GABA, glutamate and glutamine (Glx) and BOLD in relation to a cognitive task, at 3 T. Healthy subjects (N = 81) performed a cognitive task (Eriksen flanker), which was presented visually in a task-OFF, task-ON block design, with individual event onset timing jittered with respect to the MRS readout. fMRS data were acquired from the medial anterior cingulate cortex during task performance, using an adapted MEGA-PRESS implementation incorporating unsuppressed water-reference signals at a regular interval. These allowed for continuous assessment of BOLD activation, through T2 *-related changes in water linewidth. BOLD-fMRI data were additionally acquired. A novel linear model was used to extract modelled metabolite spectra associated with discrete functional stimuli, building on well established processing and quantification tools. Behavioural outcomes from the flanker task, and activation patterns from the BOLD-fMRI sequence, were as expected from the literature. BOLD response assessed through fMRS showed a significant correlation with fMRI, specific to the fMRS-targeted region of interest; fMRS-assessed BOLD additionally correlated with lengthening of response time in the incongruent flanker condition. While no significant task-related changes were observed for GABA+, a significant increase in measured Glx levels (~8.8%) was found between task-OFF and task-ON periods. These findings verify the efficacy of our protocol and analysis pipelines for the simultaneous assessment of metabolite dynamics and BOLD. As well as establishing a robust basis for further work using these techniques, we also identify a number of clear directions for further refinement in future studies.

Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial

Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease. We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated. Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10-4%/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10-4%/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10-4%/mm Hg [19·6; -45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10-4%/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10-4%/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10-4%/mm Hg [27·5; -77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10-4%/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10-4%/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake. 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research. EU Horizon 2020 programme.