State-Dependent Biomechanical Behavior of Oropharyngeal Structures in Apneics and Controls: A Proof-of-Concept Study.

Rationale: Apneics have reduced airway caliber during sleep. The biomechanical changes in upper airway anatomy contributing to this airway narrowing are largely unknown. Objectives: To investigate the state-dependent (wake vs. sleep) biomechanical behavior of the upper airway soft-tissue and craniofacial structures. Methods: Upper airway magnetic resonance imaging was performed in 15 sleep-deprived controls (AHI<5; 0.3±0.5 events/hour) and 12 sleep-deprived apneics (AHI≥5; 35.2±18.1 events/hour) during wake and sleep and analyzed for airway measures and soft-tissue/mandibular movement. Results: In the retropalatal region, controls showed sleep-dependent reductions (p≤0.037) in average cross-sectional airway area (CSA), minimum CSA, anteroposterior, and lateral dimensions. Apneics showed sleep-dependent reductions (p≤0.002) in average CSA, minimum CSA, anteroposterior and lateral dimensions. In the retroglossal region, controls had no sleep-dependent airway reductions. However, apneics had sleep-dependent reductions in minimal CSA (p=0.001) and lateral dimensions (p=0.014). Controls only showed sleep-dependent posterior movement of the anterior-inferior tongue octant (p=0.039), while apneics showed posterior movement of the soft palate (p=0.006) and all tongue octants (p≤0.012). Sleep-dependent medial movement of the lateral walls was seen at the retropalatal minimum level (p=0.013) in controls and the retropalatal and retroglossal minimum levels (p≤0.017) in apneics. There was posterior movement of the mandible in apneics (p≤0.017). Conclusion: During sleep, controls and apneics showed reductions in retropalatal airway caliber; only apneics showed retroglossal airway narrowing. Reductions in anteroposterior and lateral airway dimensions were primarily due to posterior soft palate, tongue and mandibular movement and medial lateral walls movement. These data provide important initial insights into obstructive sleep apnea pathogenesis.

Sleep-stage-dependent alterations in cerebral oxygen metabolism quantified by magnetic resonance.

A key function of sleep is to provide a regular period of reduced brain metabolism, which is critical for maintenance of healthy brain function. The purpose of this work was to quantify the sleep-stage-dependent changes in brain energetics in terms of cerebral metabolic rate of oxygen (CMRO2 ) as a function of sleep stage using quantitative magnetic resonance imaging (MRI) with concurrent electroencephalography (EEG) during sleep in the scanner. Twenty-two young and older subjects with regular sleep hygiene and Pittsburgh Sleep Quality Index (PSQI) in the normal range were recruited for the study. Cerebral blood flow (CBF) and venous oxygen saturation (SvO2 ) were obtained simultaneously at 3 Tesla field strength and 2.7-s temporal resolution during an 80-min time series using OxFlow, an in-house developed imaging sequence. The method yields whole-brain CMRO2 in absolute physiologic units via Fick's Principle. Nineteen subjects yielded evaluable data free of subject motion artifacts. Among these subjects, 10 achieved slow-wave (N3) sleep, 16 achieved N2 sleep, and 19 achieved N1 sleep while undergoing the MRI protocol during scanning. Mean CMRO2 was 98 ± 7(µmol min-1 )/100 g awake, declining progressively toward deepest sleep stage: 94 ± 10.8 (N1), 91 ± 11.4 (N2), and 76 ± 9.0 µmol min-1 /100 g (N3), with each level differing significantly from the wake state. The technology described is able to quantify cerebral oxygen metabolism in absolute physiologic units along with non-REM sleep stage, indicating brain oxygen consumption to be closely associated with depth of sleep, with deeper sleep stages exhibiting progressively lower CMRO2 levels.

Quantification of neurovascular compliance with retrospectively gated phase-contrast MRI.

OBJECTIVE: Neurovascular compliance (NVC) is the change in the brain's arterial tree blood volume, ΔV, divided by the change in intra-vascular blood pressure, ΔP, during the cardiac cycle. The primary aim of this work was to evaluate the performance of MRI measurement of NVC obtained from time-resolved measurements of internal carotid artery (ICA) and vertebral artery (VA) flow rates. A secondary aim was to explore whether NVC could be estimated from common carotid (CCA) flow in conjunction with prior knowledge of mean ICA and VA fractional flow rates, given the small cross-section of ICA and VA in some populations, in particular small children. METHODS: ΔV was quantified from the blood flow rate measured at the ICA and VA for actual NVC derivation. It was further estimated from individually measured CCA flow rate and mean flow fractions ICA/CCA and VA/CCA (which could alternatively be obtained from literature data), to yield estimated NVC. Time-resolved blood flow rate in CCA, ICA and VA was obtained via retrospectively-gated 2D PC-MRI at 1.5 T in healthy subjects (N = 16, 8 women, mean age 36 ± 13 years). ΔP was determined via a brachial pressure measurement. RESULTS: Actual and estimated mean NVC were 27 ± 15 and 38 ± 15 µL/mmHg, respectively, and the two measurements were strongly correlated (r = 0.80; p = 0.0002) with test-retest intra-class correlation coefficients of 0.964 and 0.899. CONCLUSION: Both methods yielded excellent retest precision. In spite of a large bias, actual and estimated NVC were strongly correlated.

Validation of a new 3D quantitative BOLD based cerebral oxygen extraction mapping.

Quantitative BOLD (qBOLD) MRI allows evaluation of oxidative metabolism of the brain based purely on an endogenous contrast mechanism. The method quantifies deoxygenated blood volume (DBV) and hemoglobin oxygen saturation level of venous blood (Yv), yielding oxygen extraction fraction (OEF), and along with a separate measurement of cerebral blood flow, cerebral metabolic rate of oxygen (CMRO2) maps. Here, we evaluated our recently reported 3D qBOLD method that rectifies a number of deficiencies in prior qBOLD approaches in terms of repeat reproducibility and sensitivity to hypercapnia on the metabolic parameters, and in comparison to dual-gas calibrated BOLD (cBOLD) MRI for determining resting-state oxygen metabolism. Results suggested no significant difference between test-retest qBOLD scans in either DBV and OEF. Exposure to hypercapnia yielded group averages of 38 and 28% for OEF and 151 and 146 µmol/min/100 g for CMRO2 in gray matter at baseline and hypercapnia, respectively. The decrease of OEF during hypercapnia was significant (p ≪ 0.01), whereas CMRO2 did not change significantly (p = 0.25). Finally, baseline OEF (37 vs. 39%) and CMRO2 (153 vs. 145 µmol/min/100 g) in gray matter using qBOLD and dual-gas cBOLD were found to be in good agreement with literature values, and were not significantly different from each other (p > 0.1).

Cranial bone imaging using ultrashort echo-time bone-selective MRI as an alternative to gradient-echo based "black-bone" techniques.

OBJECTIVES: CT is the clinical standard for surgical planning of craniofacial abnormalities in pediatric patients. This study evaluated three MRI cranial bone imaging techniques for their strengths and limitations as a radiation-free alternative to CT. METHODS: Ten healthy adults were scanned at 3 T with three MRI sequences: dual-radiofrequency and dual-echo ultrashort echo time sequence (DURANDE), zero echo time (ZTE), and gradient-echo (GRE). DURANDE bright-bone images were generated by exploiting bone signal intensity dependence on RF pulse duration and echo time, while ZTE bright-bone images were obtained via logarithmic inversion. Three skull segmentations were derived, and the overlap of the binary masks was quantified using dice similarity coefficient. Craniometric distances were measured, and their agreement was quantified. RESULTS: There was good overlap of the three masks and excellent agreement among craniometric distances. DURANDE and ZTE showed superior air-bone contrast (i.e., sinuses) and soft-tissue suppression compared to GRE. DISCUSSIONS: ZTE has low levels of acoustic noise, however, ZTE images had lower contrast near facial bones (e.g., zygomatic) and require effective bias-field correction to separate bone from air and soft-tissue. DURANDE utilizes a dual-echo subtraction post-processing approach to yield bone-specific images, but the sequence is not currently manufacturer-supported and requires scanner-specific gradient-delay corrections.

Quantification of whole-organ individual and bilateral renal metabolic rate of oxygen.

PURPOSE: Renal metabolic rate of oxygen (rMRO2 ) is a potentially important biomarker of kidney function. The key parameters for rMRO2 quantification include blood flow rate (BFR) and venous oxygen saturation (SvO2 ) in a draining vessel. Previous approaches to quantify renal metabolism have focused on the single organ. Here, both kidneys are considered as one unit to quantify bilateral rMRO2 . A pulse sequence to facilitate bilateral rMRO2 quantification is introduced. METHODS: To quantify bilateral rMRO2 , measurements of BFR and SvO2 are made along the inferior vena cava (IVC) at suprarenal and infrarenal locations. From the continuity equation, these four parameters can be related to derive an expression for bilateral rMRO2 . The recently reported K-MOTIVE pulse sequence was implemented at four locations: left kidney, right kidney, suprarenal IVC, and infrarenal IVC. A dual-band variant of K-MOTIVE (db-K-MOTIVE) was developed by incorporating simultaneous-multi-slice imaging principles. The sequence simultaneously measures BFR and SvO2 at suprarenal and infrarenal locations in a single pass of 21 s, yielding bilateral rMRO2 . RESULTS: SvO2 and BFR are higher in suprarenal versus infrarenal IVC, and the renal veins are highly oxygenated (SvO2 >90%). Bilateral rMRO2 quantified in 10 healthy subjects (8 M, 30 ± 8 y) was found to be 291 ± 247 and 349 ± 300 (µmolO2 /min)/100 g, derived from K-MOTIVE and db-K-MOTIVE, respectively. In comparison, total rMRO2 from combining left and right was 329 ± 273 (µmolO2 /min)/100 g. CONCLUSION: The present work demonstrates that bilateral rMRO2 quantification is feasible with fair reproducibility and physiological plausibility. The indirect method is a promising approach to compute bilateral rMRO2 when individual rMRO2 quantification is difficult.

MRI-based quantification of whole-organ renal metabolic rate of oxygen.

During the early stages of diabetes, kidney oxygen utilization increases. The mismatch between oxygen demand and supply contributes to tissue hypoxia, a key driver of chronic kidney disease. Thus, whole-organ renal metabolic rate of oxygen (rMRO2 ) is a potentially valuable biomarker of kidney function. The key parameters required to determine rMRO2 include the renal blood flow rate (RBF) in the feeding artery and oxygen saturation in the draining renal vein (SvO2 ). However, there is currently no noninvasive method to quantify rMRO2 in absolute physiologic units. Here, a new MRI pulse sequence, Kidney Metabolism of Oxygen via T2 and Interleaved Velocity Encoding (K-MOTIVE), is described, along with evaluation of its performance in the human kidney in vivo. K-MOTIVE interleaves a phase-contrast module before a background-suppressed T2 -prepared balanced steady-state-free-precession (bSSFP) readout to measure RBF and SvO2 in a single breath-hold period of 22 s, yielding rMRO2 via Fick's principle. Variants of K-MOTIVE to evaluate alternative bSSFP readout strategies were studied. Kidney mass was manually determined from multislice gradient recalled echo images. Healthy subjects were recruited to quantify rMRO2 of the left kidney at 3-T field strength (N = 15). Assessments of repeat reproducibility and comparisons with individual measurements of RBF and SvO2 were performed, and the method's sensitivity was evaluated with a high-protein meal challenge (N = 8). K-MOTIVE yielded the following metabolic parameters: T2  = 157 ± 19 ms; SvO2  = 92% ± 6%; RBF = 400 ± 110 mL/min; and rMRO2  = 114 ± 117(µmol O2 /min)/100 g tissue. Reproducibility studies of T2 and RBF (parameters directly measured by K-MOTIVE) resulted in coefficients of variation less than 10% and intraclass correlation coefficients more than 0.75. The high-protein meal elicited an increase in rMRO2 , which was corroborated by serum biomarkers. The K-MOTIVE sequence measures SvO2 and RBF, the parameters necessary to quantify whole-organ rMRO2 , in a single breath-hold. The present work demonstrates that rMRO2 quantification is feasible with good reproducibility. rMRO2 is a potentially valuable physiological biomarker.

Six-minute, in vivo MRI quantification of proximal femur trabecular bone 3D microstructure.

BACKGROUND: Assessment of proximal femur trabecular bone microstructure in vivo by magnetic resonance imaging has recently been validated for acquiring information independent of bone mineral density in osteoporotic patients. However, the requisite signal-to-noise ratio (SNR) and resolution for interrogation of the trabecular microstructure at this anatomical location prolongs the scan duration and renders the imaging protocol clinically infeasible. Parallel imaging and compressed sensing (PICS) techniques can reduce the scan duration of the imaging protocol without substantially compromising image quality. The present work investigates the limits of acceleration for a commonly used PICS technique, ℓ1-ESPIRiT, for the purpose of quantifying measures of trabecular bone microarchitecture. Based on a desired error tolerance, a six-minute, prospectively accelerated variant of the imaging protocol was developed and assessed for intersession reproducibility and agreement with the longer reference scan. PURPOSE: To investigate the limits of acceleration for MRI-based trabecular bone quantification by parallel imaging and compressed sensing reconstruction, and to develop a prototypical imaging protocol for assessing the proximal femur microstructure in a clinically practical scan time. METHODS: Healthy participants (n = 11) were scanned by a 3D balanced steady-state free precession (bSSFP) sequence satisfying the Nyquist criterion with a scan duration of about 18 min. The raw data were retrospectively undersampled and reconstructed to mimic various acceleration factors ranging from 2 to 6. Trabecular volumes-of-interest in four major femoral regions (greater trochanter, intertrochanteric region, femoral neck, and femoral head) were analyzed and six relevant measures of trabecular bone microarchitecture (bone volume fraction, surface-to-curve ratio, erosion index, elastic modulus, trabecular thickness, plates-to-rods ratio) were obtained for images of all accelerations. To assess agreement, median percent error and intraclass correlation coefficients (ICCs) were computed using the fully-sampled data as reference. Based on this analysis, a prospectively 3-fold accelerated sequence with a duration of about 6 min was developed and the analysis was repeated. RESULTS: A prospective acceleration factor of 3 demonstrated comparable performance in reproducibility and absolute agreement to the fully-sampled scan. The median CoV over all image-derived metrics was generally <6 % and ICCs >0.70. Also, measurements from prospectively 3-fold accelerated scans demonstrated in general median percent errors of <7 % and ICCs >0.70. CONCLUSION: The present work proposes a method to make in vivo quantitative assessment of proximal femur trabecular microstructure with a clinically practical scan duration of about 6 min.

Automated, calibration-free quantification of cortical bone porosity and geometry in postmenopausal osteoporosis from ultrashort echo time MRI and deep learning.

BACKGROUND: Assessment of cortical bone porosity and geometry by imaging in vivo can provide useful information about bone quality that is independent of bone mineral density (BMD). Ultrashort echo time (UTE) MRI techniques of measuring cortical bone porosity and geometry have been extensively validated in preclinical studies and have recently been shown to detect impaired bone quality in vivo in patients with osteoporosis. However, these techniques rely on laborious image segmentation, which is clinically impractical. Additionally, UTE MRI porosity techniques typically require long scan times or external calibration samples and elaborate physics processing, which limit their translatability. To this end, the UTE MRI-derived Suppression Ratio has been proposed as a simple-to-calculate, reference-free biomarker of porosity which can be acquired in clinically feasible acquisition times. PURPOSE: To explore whether a deep learning method can automate cortical bone segmentation and the corresponding analysis of cortical bone imaging biomarkers, and to investigate the Suppression Ratio as a fast, simple, and reference-free biomarker of cortical bone porosity. METHODS: In this retrospective study, a deep learning 2D U-Net was trained to segment the tibial cortex from 48 individual image sets comprised of 46 slices each, corresponding to 2208 training slices. Network performance was validated through an external test dataset comprised of 28 scans from 3 groups: (1) 10 healthy, young participants, (2) 9 postmenopausal, non-osteoporotic women, and (3) 9 postmenopausal, osteoporotic women. The accuracy of automated porosity and geometry quantifications were assessed with the coefficient of determination and the intraclass correlation coefficient (ICC). Furthermore, automated MRI biomarkers were compared between groups and to dual energy X-ray absorptiometry (DXA)- and peripheral quantitative CT (pQCT)-derived BMD. Additionally, the Suppression Ratio was compared to UTE porosity techniques based on calibration samples. RESULTS: The deep learning model provided accurate labeling (Dice score 0.93, intersection-over-union 0.88) and similar results to manual segmentation in quantifying cortical porosity (R2 ≥ 0.97, ICC ≥ 0.98) and geometry (R2 ≥ 0.82, ICC ≥ 0.75) parameters in vivo. Furthermore, the Suppression Ratio was validated compared to established porosity protocols (R2 ≥ 0.78). Automated parameters detected age- and osteoporosis-related impairments in cortical bone porosity (P ≤ .002) and geometry (P values ranging from <0.001 to 0.08). Finally, automated porosity markers showed strong, inverse Pearson's correlations with BMD measured by pQCT (|R| ≥ 0.88) and DXA (|R| ≥ 0.76) in postmenopausal women, confirming that lower mineral density corresponds to greater porosity. CONCLUSION: This study demonstrated feasibility of a simple, automated, and ionizing-radiation-free protocol for quantifying cortical bone porosity and geometry in vivo from UTE MRI and deep learning.

Superior sagittal sinus flow as a proxy for tracking global cerebral blood flow dynamics during wakefulness and sleep.

Sleep, a state of reduced consciousness, affects brain oxygen metabolism and lowers cerebral metabolic rate of oxygen (CMRO2). Previously, we quantified CMRO2 during sleep via Fick's Principle, with a single-band MRI sequence measuring both hemoglobin O2 saturation (SvO2) and superior sagittal sinus (SSS) blood flow, which was upscaled to obtain total cerebral blood flow (tCBF). The procedure involves a brief initial calibration scan to determine the upscaling factor (fc), assumed state-invariant. Here, we used a dual-band sequence to simultaneously provide SvO2 in SSS and tCBF in the neck every 16 seconds, allowing quantification of fc dynamically. Ten healthy subjects were scanned by MRI with simultaneous EEG for 80 minutes, yielding 300 temporal image frames per subject. Four volunteers achieved slow-wave sleep (SWS), as evidenced by increased δ-wave activity (per American Academy of Sleep Medicine criteria). SWS was maintained for 13.5 ± 7.0 minutes, with CMRO2 28.6 ± 5.5% lower than pre-sleep wakefulness. Importantly, there was negligible bias between tCBF obtained by upscaling SSS-blood flow, and tCBF measured directly in the inflowing arteries of the neck (intra-class correlation 0.95 ± 0.04, averaged across all subjects), showing that the single-band approach is a valid substitute for quantifying tCBF, simplifying image data collection and analysis without sacrificing accuracy.

MRI Quantification of Cortical Bone Porosity, Mineralization, and Morphologic Structure in Postmenopausal Osteoporosis.

Background Preclinical studies have suggested that solid-state MRI markers of cortical bone porosity, morphologic structure, mineralization, and osteoid density are useful measures of bone health. Purpose To explore whether MRI markers of cortical bone porosity, morphologic structure, mineralization, and osteoid density are affected in postmenopausal osteoporosis (OP) and to examine associations between MRI markers and bone mineral density (BMD) in postmenopausal women. Materials and Methods In this single-center study, postmenopausal women were prospectively recruited from January 2019 to October 2020 into two groups: participants with OP who had not undergone treatment, defined as having any dual-energy x-ray absorptiometry (DXA) T-score of -2.5 or less, and age-matched control participants without OP (hereafter, non-OP). Participants underwent MRI in the midtibia, along with DXA in the hip and spine, and peripheral quantitative CT in the midtibia. Specifically, MRI measures of cortical bone porosity (pore water and total water), osteoid density (bound water [BW]), morphologic structure (cortical bone thickness), and mineralization (phosphorous [P] density [31P] and 31P-to-BW concentration ratio) were quantified at 3.0 T. MRI measures were compared between OP and non-OP groups and correlations with BMD were assessed. Results Fifteen participants with OP (mean age, 63 years ± 5 [SD]) and 19 participants without OP (mean age, 65 years ± 6) were evaluated. The OP group had elevated pore water (11.6 mol/L vs 9.5 mol/L; P = .007) and total water densities (21.2 mol/L vs 19.7 mol/L; P = .03), and had lower cortical bone thickness (4.8 mm vs 5.6 mm; P < .001) and 31P density (6.4 mol/L vs 7.5 mol/L; P = .01) than the non-OP group, respectively, although there was no evidence of a difference in BW or 31P-to-BW concentration ratio. Pore and total water densities were inversely associated with DXA and peripheral quantitative CT BMD (P < .001), whereas cortical bone thickness and 31P density were positively associated with DXA and peripheral quantitative CT BMD (P = .01). BW, 31P density, and 31P-to-BW concentration ratio were positively associated with DXA (P < .05), but not with peripheral quantitative CT. Conclusion Solid-state MRI of cortical bone was able to help detect potential impairments in parameters reflecting porosity, morphologic structure, and mineralization in postmenopausal osteoporosis. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Bae in this issue.

Metabolite patterns associated with individual response to supervised exercise therapy in patients with intermittent claudication.

Objective: Supervised exercise therapy (SET) is the first line treatment for intermittent claudication owing to peripheral arterial disease. Despite multiple randomized controlled trials proving the efficacy of SET, there are large differences in individual patient's responses. We used plasma metabolomics to identify potential metabolic influences on the individual response to SET. Methods: Primary metabolites, complex lipids, and lipid mediators were measured on plasma samples taken at before and after Gardner graded treadmill walking tests that were administered before and after 12 weeks of SET. We used an ensemble modeling approach to identify metabolites or changes in metabolites at specific time points that associated with interindividual variability in the functional response to SET. Specific time points analyzed included baseline metabolite levels before SET, dynamic metabolomics changes before SET, the difference in pre- and post-SET baseline metabolomics, and the difference (pre- and post-SET) of the dynamic (pre- and post-treadmill). Results: High levels of baseline anandamide levels pre- and post-SET were associated with a worse response to SET. Increased arachidonic acid (AA) and decreased levels of the AA precursor dihomo-γ-linolenic acid across SET were associated with a worse response to SET. Participants who were able to tolerate large increases in AA during acute exercise had longer, or better, walking times both before and after SET. Conclusions: We identified two pathways of relevance to individual response to SET that warrant further study: anandamide synthesis may activate endocannabinoid receptors, resulting in worse treadmill test performance. SET may train patients to withstand higher levels of AA, and inflammatory signaling, resulting in longer walking times. Clinical Relevance: This manuscript describes the use of metabolomic techniques to measure the interindividual effects of SET in patients with peripheral artery disease (PAD). We identified high levels of AEA are linked to CB1 signaling and activation of inflammatory pathways. This alters energy expenditure in myoblasts by decreasing glucose uptake and may induce an acquired skeletal muscle myopathy. SET may also help participants tolerate increased levels of AA and inflammation produced during exercise, resulting in longer walking times. This data will enhance understanding of the pathophysiology of PAD and the mechanism by which SET improves walking intolerance.

Cerebral hemodynamic and metabolic dysregulation in the postradiation brain.

Technological advances in the delivery of radiation and other novel cancer therapies have significantly improved the 5-year survival rates over the last few decades. Although recent developments have helped to better manage the acute effects of radiation, the late effects such as impairment in cognition continue to remain of concern. Accruing data in the literature have implicated derangements in hemodynamic parameters and metabolic activity of the irradiated normal brain as predictive of cognitive impairment. Multiparametric imaging modalities have allowed us to precisely quantify functional and metabolic information, enhancing the anatomic and morphologic data provided by conventional MRI sequences, thereby contributing as noninvasive imaging-based biomarkers of radiation-induced brain injury. In this review, we have elaborated on the mechanisms of radiation-induced brain injury and discussed several novel imaging modalities, including MR spectroscopy, MR perfusion imaging, functional MR, SPECT, and PET that provide pathophysiological and functional insights into the postradiation brain, and its correlation with radiation dose as well as clinical neurocognitive outcomes. Additionally, we explored some innovative imaging modalities, such as quantitative blood oxygenation level-dependent imaging, susceptibility-based oxygenation measurement, and T2-based oxygenation measurement, that hold promise in delineating the potential mechanisms underlying deleterious neurocognitive changes seen in the postradiation setting. We aim that this comprehensive review of a range of imaging modalities will help elucidate the hemodynamic and metabolic injury mechanisms underlying cognitive impairment in the irradiated normal brain in order to optimize treatment regimens and improve the quality of life for these patients.

Impact of supervised exercise on skeletal muscle blood flow and vascular function measured with MRI in patients with peripheral artery disease.

Supervised exercise is a common therapeutic intervention for patients with peripheral artery disease (PAD), however, the mechanism underlying the improvement in claudication symptomatology is not completely understood. The hypothesis that exercise improves microvascular blood flow is herein tested via temporally resolved magnetic resonance imaging (MRI) measurement of blood flow and oxygenation dynamics during reactive hyperemia in the leg with the lower ankle-brachial index. One hundred and forty-eight subjects with PAD were prospectively assigned to standard medical care or 3 mo of supervised exercise therapy. Before and after the intervention period, subjects performed a graded treadmill walking test, and MRI data were collected with Perfusion, Intravascular Venous Oxygen saturation, and T2* (PIVOT), a method that simultaneously quantifies microvascular perfusion, as well as relative oxygenation changes in skeletal muscle and venous oxygen saturation in a large draining vein. The 3-mo exercise intervention was associated with an improvement in peak walking time (64% greater in those randomized to the exercise group at follow-up, P < 0.001). Significant differences were not observed in the MRI measures between the subjects randomized to exercise therapy versus standard medical care based on an intention-to-treat analysis. However, the peak postischemia perfusion averaged across the leg between baseline and follow-up visits increased by 10% (P = 0.021) in participants that were adherent to the exercise protocol (completed >80% of prescribed exercise visits). In this cohort of adherent exercisers, there was no difference in the time to peak perfusion or oxygenation metrics, suggesting that there was no improvement in microvascular function nor changes in tissue metabolism in response to the 3-mo exercise intervention.NEW & NOTEWORTHY Supervised exercise interventions can improve symptomatology in patients with peripheral artery disease, but the underlying mechanism remains unclear. Here, MRI was used to evaluate perfusion, relative tissue oxygenation, and venous oxygen saturation in response to cuff-induced ischemia. Reactive hyperemia responses were measured before and after 3 mo of randomized supervised exercise therapy or standard medical care. Those participants who were adherent to the exercise regimen had a significant improvement in peak perfusion.

Metabolism of oxygen via T2 and interleaved velocity encoding: A rapid method to quantify whole-brain cerebral metabolic rate of oxygen.

PURPOSE: Cerebral metabolic rate of oxygen (CMRO2 ) is an important biomarker of brain function. Key physiological parameters required to quantify CMRO2 include blood flow rate in the feeding arteries and venous oxygen saturation (SvO2 ) in the draining vein. Here, a pulse sequence, metabolism of oxygen via T2 and interleaved velocity encoding (MOTIVE), was developed to measure both parameters simultaneously and enable CMRO2 quantification in a single pass. METHODS: The MOTIVE sequence interleaves a phase-contrast module between a nonselective saturation and a background-suppressed T2 -prepared EPI readout (BGS-EPI) to measure T2 of blood water protons and cerebral blood flow in 20 s or less. The MOTIVE and standalone BGS-EPI sequences were compared against TRUST ("T2 relaxation under spin tagging") in the brain in healthy subjects (N = 24). Variants of MOTIVE to enhance resolution or shorten scan time were explored. Intrasession and intersession reproducibility studies were performed. RESULTS: MOTIVE experiments yielded an average SvO2 of 61 ± 6% in the superior sagittal sinus of the brain and an average cerebral blood flow of 56 ± 10 ml/min/100 g. The bias in SvO2 of MOTIVE and BGS-EPI to TRUST was +2 ± 4% and +1 ± 3%, respectively. The bias in cerebral blood flow of MOTIVE to Cartesian phase-contrast reference was +1 ± 6 ml/min/100 g. CONCLUSIONS: The MOTIVE sequence is an advance over existing T2 -based oximetric methods. It does not require a control image and simultaneously measures SvO2 and flow velocity. The measurements agree well with TRUST and reference phase-contrast sequences. This noninvasive technique enables CMRO2 quantification in under 20 s and is reproducible for in vivo applications.

A flow-diffusion model of oxygen transport for quantitative mapping of cerebral metabolic rate of oxygen (CMRO2) with single gas calibrated fMRI.

One promising approach for mapping CMRO2 is dual-calibrated functional MRI (dc-fMRI). This method exploits the Fick Principle to combine estimates of CBF from ASL, and OEF derived from BOLD-ASL measurements during arterial O2 and CO2 modulations. Multiple gas modulations are required to decouple OEF and deoxyhemoglobin-sensitive blood volume. We propose an alternative single gas calibrated fMRI framework, integrating a model of oxygen transport, that links blood volume and CBF to OEF and creates a mapping between the maximum BOLD signal, CBF and OEF (and CMRO2). Simulations demonstrated the method's viability within physiological ranges of mitochondrial oxygen pressure, PmO2, and mean capillary transit time. A dc-fMRI experiment, performed on 20 healthy subjects using O2 and CO2 challenges, was used to validate the approach. The validation conveyed expected estimates of model parameters (e.g., low PmO2), with spatially uniform OEF maps (grey matter, GM, OEF spatial standard deviation ≈ 0.13). GM OEF estimates obtained with hypercapnia calibrated fMRI correlated with dc-fMRI (r = 0.65, p = 2·10-3). For 12 subjects, OEF measured with dc-fMRI and the single gas calibration method were correlated with whole-brain OEF derived from phase measures in the superior sagittal sinus (r = 0.58, p = 0.048; r = 0.64, p = 0.025 respectively). Simplified calibrated fMRI using hypercapnia holds promise for clinical application.

MRI evaluation of cerebral metabolic rate of oxygen (CMRO2) in obstructive sleep apnea.

Patients with obstructive sleep apnea (OSA) are at elevated risk of developing systemic vascular disease and cognitive dysfunction. Here, cerebral oxygen metabolism was assessed in patients with OSA by means of a magnetic resonance-based method involving simultaneous measurements of cerebral blood flow rate and venous oxygen saturation in the superior sagittal sinus for a period of 10 minutes at an effective temporal resolution of 1.3 seconds before, during, and after repeated 24-second breath-holds mimicking spontaneous apneas, yielding, along with pulse oximetry-derived arterial saturation, whole-brain CMRO2 via Fick's Principle. Enrolled subjects were classified based on their apnea-hypopnea indices into OSA (N = 31) and non-sleep apnea reference subjects (NSA = 21), and further compared with young healthy subjects (YH, N = 10). OSA and NSA subjects were matched for age and body mass index. CMRO2 was lower in OSA than in the YH group during normal breathing (105.6 ± 14.1 versus 123.7 ± 22.8 µmol O2/min/100g, P = 0.01). Further, the fractional change in CMRO2 in response to a breath-hold challenge was larger in OSA than in the YH group (15.2 ± 9.2 versus 8.5 ± 3.4%, P = 0.04). However, there was no significant difference in CMRO2 between OSA and NSA subjects. The data suggest altered brain oxygen metabolism in OSA and possibly in NSA as well.

Whole-brain 3D mapping of oxygen metabolism using constrained quantitative BOLD.

Quantitative BOLD (qBOLD) MRI permits noninvasive evaluation of hemodynamic and metabolic states of the brain by quantifying parametric maps of deoxygenated blood volume (DBV) and hemoglobin oxygen saturation level of venous blood (Yv), and along with a measurement of cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2). The method, thus should have potential to provide important information on many neurological disorders as well as normal cerebral physiology. One major challenge in qBOLD is to separate deoxyhemoglobin's contribution to R2' from other sources modulating the voxel signal, for instance, R2, R2' from non-heme iron (R'2,nh), and macroscopic magnetic field variations. Further, even with successful separation of the several confounders, it is still challenging to extract DBV and Yv from the heme-originated R2' because of limited sensitivity of the qBOLD model. These issues, which have not been fully addressed in currently practiced qBOLD methods, have so far precluded 3D whole-brain implementation of qBOLD. Thus, the purpose of this work was to develop a new 3D MRI oximetry technique that enables robust qBOLD parameter mapping across the entire brain. To achieve this goal, we employed a rapid, R2'-sensitive, steady-state 3D pulse sequence (termed 'AUSFIDE') for data acquisition, and implemented a prior-constrained qBOLD processing pipeline that exploits a plurality of preliminary parameters obtained via AUSFIDE, along with additionally measured cerebral venous blood volume. Numerical simulations and in vivo studies at 3 T were performed to evaluate the performance of the proposed, constrained qBOLD mapping in comparison to the parent qBOLD method. Measured parameters (Yv, DBV, R'2,nh, nonblood magnetic susceptibility) in ten healthy subjects demonstrate the expected contrast across brain territories, while yielding group-averages of 64.0 ± 2.3 % and 62.2 ± 3.1 % for Yv and 2.8 ± 0.5 % and 1.8 ± 0.4 % for DBV in cortical gray and white matter, respectively. Given the Yv measurements, additionally quantified CBF in seven of the ten study subjects enabled whole-brain 3D CMRO2 mapping, yielding group averages of 134.2 ± 21.1 and 79.4 ± 12.6 µmol/100 g/min for cortical gray and white matter, in good agreement with literature values. The results suggest feasibility of the proposed method as a practical and reliable means for measuring neurometabolic parameters over an extended brain coverage.

Automatic Segmentation of Bone Selective MR Images for Visualization and Craniometry of the Cranial Vault.

RATIONALE AND OBJECTIVES: Solid-state MRI has been shown to provide a radiation-free alternative imaging strategy to CT. However, manual image segmentation to produce bone-selective MR-based 3D renderings is time and labor intensive, thereby acting as a bottleneck in clinical practice. The objective of this study was to evaluate an automatic multi-atlas segmentation pipeline for use on cranial vault images entirely circumventing prior manual intervention, and to assess concordance of craniometric measurements between pipeline produced MRI and CT-based 3D skull renderings. MATERIALS AND METHODS: Dual-RF, dual-echo, 3D UTE pulse sequence MR data were obtained at 3T on 30 healthy subjects along with low-dose CT images between December 2018 to January 2020 for this prospective study. The four-point MRI datasets (two RF pulse widths and two echo times) were combined to produce bone-specific images. CT images were thresholded and manually corrected to segment the cranial vault. CT images were then rigidly registered to MRI using mutual information. The corresponding cranial vault segmentations were then transformed to MRI. The "ground truth" segmentations served as reference for the MR images. Subsequently, an automated multi-atlas pipeline was used to segment the bone-selective images. To compare manually and automatically segmented MR images, the Dice similarity coefficient (DSC) and Hausdorff distance (HD) were computed, and craniometric measurements between CT and automated-pipeline MRI-based segmentations were examined via Lin's concordance coefficient (LCC). RESULTS: Automated segmentation reduced the need for an expert to obtain segmentation. Average DSC was 90.86 ± 1.94%, and average 95th percentile HD was 1.65 ± 0.44 mm between ground truth and automated segmentations. MR-based measurements differed from CT-based measurements by 0.73-1.2 mm on key craniometric measurements. LCC for distances between CT and MR-based landmarks were vertex-basion: 0.906, left-right frontozygomatic suture: 0.780, and glabella-opisthocranium: 0.956 for the three measurements. CONCLUSION: Good agreement between CT and automated MR-based 3D cranial vault renderings has been achieved, thereby eliminating the laborious manual segmentation process. Target applications comprise craniofacial surgery as well as imaging of traumatic injuries and masses involving both bone and soft tissue.

Magnetic susceptibility and R2* of myocardial reperfusion injury at 3T and 7T.

PURPOSE: Magnetic susceptibility (Δχ) alterations have shown association with myocardial infarction (MI) iron deposition, yet there remains limited understanding of the relationship between relaxation rates and susceptibility or the effect of magnetic field strength. Hence, Δχ and R2∗ in MI were compared at 3T and 7T. METHODS: Subacute MI was induced by coronary artery ligation in male Yorkshire swine. 3D multiecho gradient echo imaging was performed at 1-week postinfarction at 3T and 7T. Quantitative susceptibility mapping images were reconstructed using a morphology-enabled dipole inversion. R2∗ maps and quantitative susceptibility mapping were generated to assess the relationship between R2∗ , Δχ, and field strength. Infarct histopathology was investigated. RESULTS: Magnetic susceptibility was not significantly different across field strengths (7T: 126.8 ± 41.7 ppb; 3T: 110.2 ± 21.0 ppb, P = NS), unlike R2∗ (7T: 247.0 ± 14.8 Hz; 3T: 106.1 ± 6.5 Hz, P < .001). Additionally, infarct Δχ and R2∗ were significantly higher than remote myocardium. Magnetic susceptibility at 7T versus 3T had a significant association (ß = 1.02, R2 = 0.82, P < .001), as did R2∗ (ß = 2.35, R2 = 0.98, P < .001). Infarct pathophysiology and iron deposition were detected through histology and compared with imaging findings. CONCLUSION: R2∗ showed dependence and Δχ showed independence of field strength. Histology validated the presence of iron and supported imaging findings.