Using dual-calibrated functional MRI to map brain oxygen supply and consumption in multiple sclerosis

Evidence suggests that cerebrovascular function and oxygen consumption are altered in multiple sclerosis (MS). Here, we quantified the vascular and oxygen metabolic MRI burden in patients with MS (PwMS) and assessed the relationship between these MRI measures of and metrics of damage and disability. In PwMS and in matched healthy volunteers, we applied a newly developed dual-calibrated fMRI method of acquisition and analysis to map grey matter (GM) cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen consumption (CMRO2) and effective oxygen diffusivity of the capillary network (DC). We also quantified physical and cognitive function in PwMS and controls. There was no significant difference in GM volume between 22 PwMS and 20 healthy controls (p=0.302). Significant differences in CBF (PwMS vs. controls: 44.91 +/- 6.10 vs. 48.90 +/- 5.87 ml/100g/min, p=0.010), CMRO2 (117.69 +/- 17.31 vs. 136.49 +/- 14.48 μmol/100g/min p<0.001) and DC (2.70 +/- 0.51 vs. 3.18 +/- 0.41 μmol/100g/mmHg/min, p=0.002) were observed in the PwMS. No significant between-group differences were observed for OEF (PwMS vs. controls: 0.38 +/- 0.09 vs. 0.39 +/- 0.02, p=0.358). Regional analysis showed widespread reductions in CMRO2 and DC for PwMS compared to healthy volunteers. There was a significant correlation between physiological measures and T2 lesion volume, but no association with current clinical disability. Our findings demonstrate concurrent reductions in oxygen supply and consumption in the absence of an alteration in oxygen extraction that may be indicative of a reduced demand for oxygen (O2), an impaired transfer of O2 from capillaries to mitochondria, and/or a reduced ability to utilise O2 that is available at the mitochondria. With no between-group differences in GM volume, our results suggest that changes in brain physiology may precede MRI-detectable GM loss and thus may be one of the pathological drivers of neurodegeneration and disease progression.

Download Full-text

Quantitative Oxygen Extraction Fraction from 7-Tesla MRI Phase: Reproducibility and Application in Multiple Sclerosis

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.187 ◽

2014 ◽

Vol 35 (1) ◽

pp. 131-139 ◽

Cited By ~ 18

Author(s):

Audrey P Fan ◽

Sindhuja T Govindarajan ◽

R Philip Kinkel ◽

Nancy K Madigan ◽

A Scott Nielsen ◽

...

Keyword(s):

Multiple Sclerosis ◽

Three Dimensional ◽

Structural Mri ◽

Brain Regions ◽

Oxygen Extraction Fraction ◽

Oxygen Extraction ◽

7 Tesla ◽

Information Processing Speed ◽

Prefrontal Cortical ◽

Extraction Fraction

Quantitative oxygen extraction fraction (OEF) in cortical veins was studied in patients with multiple sclerosis (MS) and healthy subjects via magnetic resonance imaging (MRI) phase images at 7 Tesla (7 T). Flow-compensated, three-dimensional gradient-echo scans were acquired for absolute OEF quantification in 23 patients with MS and 14 age-matched controls. In patients, we collected T2∗-weighted images for characterization of white matter, deep gray matter, and cortical lesions, and also assessed cognitive function. Variability of OEF across readers and scan sessions was evaluated in a subset of volunteers. OEF was averaged from 2 to 3 pial veins in the sensorimotor, parietal, and prefrontal cortical regions for each subject (total of ∼10 vessels). We observed good reproducibility of mean OEF, with intraobserver coefficient of variation (COV)=2.1%, interobserver COV=5.2%, and scan—rescan COV=5.9%. Patients exhibited a 3.4% reduction in cortical OEF relative to controls ( P=0.0025), which was not different across brain regions. Although oxygenation did not relate with measures of structural tissue damage, mean OEF correlated with a global measure of information processing speed. These findings suggest that cortical OEF from 7-T MRI phase is a reproducible metabolic biomarker that may be sensitive to different pathologic processes than structural MRI in patients with MS.

Download Full-text

Familial multiple sclerosis: volumetric assessment in clinically symptomatic and asymptomatic individuals

Multiple Sclerosis Journal ◽

10.1177/135245859900500202 ◽

1999 ◽

Vol 5 (2) ◽

pp. 74-77 ◽

Cited By ~ 7

Author(s):

Jennifer C Fulton ◽

Robert I Grossman ◽

Lois J Mannon ◽

Jayaram Udupa ◽

Dennis L Kolson

Keyword(s):

Multiple Sclerosis ◽

Monozygotic Twins ◽

Subsequent Development ◽

Monozygotic Twin ◽

Lesion Volume ◽

Sibling Pairs ◽

Clinically Normal ◽

Volumetric Assessment ◽

Significant Difference ◽

Normal Offspring

A genetic basis for clustering of multiple sclerosis (MS) cases, based on studies of MS families, has been proposed for decades. Few reports provide detailed neurological as well as neuroradiological findings on these patients. We report total T2-weighted intracranial lesion volumes on members of three familial MS cohorts: a mother and father with conjugal MS with one affected son and a neurologically normal son and daughter, one pair of monozygotic twin sisters with MS, and a female sibling pair with MS. We hypothesized that asymptomatic siblings in a family with two affected parents and another affected child might demonstrate clinically silent T2-weighted lesions; and that monozygotic twins with MS are more likely to express similar T2-weighted lesion volumes than non-twin sibling pairs. We found clinically silent lesions in unaffected children of the symptomatic parent couple, with a significant difference in total T2 lesion volume between these unaffected siblings and their parents, as well as their affected brother. In our other sibling pairs, T2 lesion volumes were similar between the twins and significantly different in the non-twin pair, despite similar levels of clinical functioning as determined by EDSS scoring. These results suggest that foci of demyelination might be expected in clinically normal offspring of parents with MS, possibly reflecting a genetic predisposition to subsequent development of MS.

Download Full-text

The effect of cross-talk on MRI lesion numbers and volumes in multiple sclerosis using conventional and turbo spin-echo

Multiple Sclerosis Journal ◽

10.1177/135245859800400602 ◽

1998 ◽

Vol 4 (6) ◽

pp. 471-474 ◽

Cited By ~ 3

Author(s):

Massimo Filippi ◽

Tarek A Yousry ◽

Maria A Rocca ◽

Clodoaldo Pereira ◽

Hatem Alkadhi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cross Talk ◽

Spin Echo ◽

Brain Magnetic Resonance Imaging ◽

Acquisition Time ◽

Lesion Volume ◽

Turbo Spin Echo ◽

Turbo Spin ◽

Acquisition Scheme ◽

Significant Difference

We measured and compared lesion numbers and volumes present on brain magnetic resonance imaging (MRI) scans of patients with multiple sclerosis (MS) acquired with contiguous (scheme A) and interleaved (scheme B) slice acquisition, to evaluate whether there was a gain in sensitivity using the second pattern of acquisition and whether this counterbalanced the doubled acquisition time. Conventional spin-echo (CSE) sequences were performed for eight patient and turbo spin-echo (TSE) sequences for ten. Acquisition scheme B detected 3.8% more lesions than acquisition scheme A (the increase was 3. 1% for CSE and 4.5% for TSE). These differences were not statistically significant. No significant difference in lesion numbers was found when different lesion locations were also considered. Lesion volumes were significantly higher when scheme B was used (P= 0.024). This was due to higher lesion volumes on TSE images (P= 0.006), especially on even-numbered slices (P= 0.008). Inter-slice cross-talk has a negligible effect on lesion numbers and volume estimates in MS for CSE sequence, whilst it cannot be neglected when TSE sequences are used to measure MS lesion volume.

Download Full-text

Iron Rims in Patients With Multiple Sclerosis as Neurodegenerative Marker? A 7-Tesla Magnetic Resonance Study

Frontiers in Neurology ◽

10.3389/fneur.2021.632749 ◽

2021 ◽

Vol 12 ◽

Author(s):

A. Dal-Bianco ◽

R. Schranzer ◽

G. Grabner ◽

M. Lanzinger ◽

S. Kolbrink ◽

...

Keyword(s):

Multiple Sclerosis ◽

7 Tesla ◽

Neuropsychological Performance ◽

Lesion Volume ◽

Information Processing Speed ◽

Tissue Destruction ◽

Subcortical Structures ◽

Neurofilament Light Chain ◽

Lateral Ventricles ◽

Significant Difference

Introduction: Multiple sclerosis (MS) is a demyelinating and neurodegenerative disease of the central nervous system, characterized by inflammatory-driven demyelination. Symptoms in MS manifest as both physical and neuropsychological deficits. With time, inflammation is accompanied by neurodegeneration, indicated by brain volume loss on an MRI. Here, we combined clinical, imaging, and serum biomarkers in patients with iron rim lesions (IRLs), which lead to severe tissue destruction and thus contribute to the accumulation of clinical disability.Objectives: Subcortical atrophy and ventricular enlargement using an automatic segmentation pipeline for 7 Tesla (T) MRI, serum neurofilament light chain (sNfL) levels, and neuropsychological performance in patients with MS with IRLs and non-IRLs were assessed.Methods: In total 29 patients with MS [15 women, 24 relapsing-remitting multiple sclerosis (RRMS), and five secondary-progressive multiple sclerosis (SPMS)] aged 38 (22–69) years with an Expanded Disability Status Score of 2 (0–8) and a disease duration of 11 (5–40) years underwent neurological and neuropsychological examinations. Volumes of lesions, subcortical structures, and lateral ventricles on 7-T MRI (SWI, FLAIR, and MP2RAGE, 3D Segmentation Software) and sNfL concentrations using the Simoa SR-X Analyzer in IRL and non-IRL patients were assessed.Results: (1) Iron rim lesions patients had a higher FLAIR lesion count (p = 0.047). Patients with higher MP2Rage lesion volume exhibited more IRLs (p <0.014) and showed poorer performance in the information processing speed tested within 1 year using the Symbol Digit Modalities Test (SDMT) (p <0.047). (2) Within 3 years, patients showed atrophy of the thalamus (p = 0.021) and putamen (p = 0.043) and enlargement of the lateral ventricles (p = 0.012). At baseline and after 3 years, thalamic volumes were lower in IRLs than in non-IRL patients (p = 0.045). (3) At baseline, IRL patients had higher sNfL concentrations (p = 0.028). Higher sNfL concentrations were associated with poorer SDMT (p = 0.004), regardless of IRL presence. (4) IRL and non-IRL patients showed no significant difference in the neuropsychological performance within 1 year.Conclusions: Compared with non-IRL patients, IRL patients had higher FLAIR lesion counts, smaller thalamic volumes, and higher sNfL concentrations. Our pilot study combines IRL and sNfL, two biomarkers considered indicative for neurodegenerative processes. Our preliminary data underscore the reported destructive nature of IRLs.

Download Full-text

On the determination of the dorso-ventral polarity in Xenopus laevis embryos

Development ◽

10.1242/dev.33.4.879 ◽

1975 ◽

Vol 33 (4) ◽

pp. 879-895

Author(s):

Ulf Landström ◽

Søren Løvtrup

Keyword(s):

Oxygen Consumption ◽

Xenopus Laevis ◽

Oxygen Supply ◽

Substantial Reduction ◽

Total Consumption ◽

Time Treatment ◽

Oxygen Effects ◽

Significant Difference ◽

Xenopus Laevis Embryos

1. When embryos, or dorsal or ventral half-embryos, of Xenopus laevis are subjected to unilateral restriction of oxygen supply, the posterior end will always appear at the aerobic side, while the development of the anterior end, oriented towards the anaerobic side, will be partly suppressed. The shorter the time treatment lasts, the more normal the development will be. 2. When the restriction of oxygen effects an inversion of the dorso-ventral polarity, development is retarded, otherwise not. 3. Measurements of oxygen consumption show a substantial reduction in the experimental embryos, as compared with normal ones. The change in oxygen consumption in inverted embryos is delayed relative to non-inverted ones, but there is no significant difference in the total consumption of oxygen. 4. Our results support the idea that the dorso-ventral polarity is associated with a gradient in oxygen consumption, and various kinds of evidence suggest that oxygen consumption is, in part, required for the formation of Ruffini's flask-cells, responsible for the initiation of invagination. 5. It is suggested that the basic mechanisms involved in the determination of the normal, and the inverted, dorso-ventral polarity are fundamentally different, the latter being in fact an induction of a new polarity.

Download Full-text

Coming off cannabis: a cognitive and magnetic resonance imaging study in patients with multiple sclerosis

Brain ◽

10.1093/brain/awz213 ◽

2019 ◽

Vol 142 (9) ◽

pp. 2800-2812 ◽

Cited By ~ 7

Author(s):

Anthony Feinstein ◽

Cecilia Meza ◽

Cristiana Stefan ◽

Richard W. Staines

Keyword(s):

Multiple Sclerosis ◽

Executive Function ◽

Functional Mri ◽

Processing Speed ◽

Visual Memory ◽

Cognitive Change ◽

Group Differences ◽

Lesion Volume ◽

Memory Processing ◽

Cognitive Improvement

AbstractCognitive dysfunction affects 40–80% of patients with multiple sclerosis. Smoking cannabis may add to these deficits. It is unclear whether coming off cannabis results in cognitive improvement. To address this question, 40 patients with multiple sclerosis who started using cannabis after the onset of multiple sclerosis and who used it for at least 4 days a week over many years were divided by odd-even number selection into two groups: cannabis continuation and cannabis withdrawal. Assessments took place at baseline and after 28 days and included serial versions of the Brief Repeatable Neuropsychological Battery for multiple sclerosis containing tests of verbal and visual memory, processing speed and executive function; structural and functional MRI, the latter entailing a compatible version of the Symbol Digit Modalities Test; urine for cannabinoid metabolites to detect compliance with abstinence. Only those participants deemed globally impaired at baseline (failure on at least two cognitive domains) were enrolled. The results revealed that the two groups were well matched demographically and neurologically. One subject was removed from the withdrawal group because of failed abstinence. Urine analysis revealed the cannabinoid consumed was predominantly tetrahydrocannabinol (THC). There were no baseline between group cognitive differences, but by Day 28 the withdrawal group performed significantly better on every cognitive index (P < 0.0001 for all). Significant within group differences were present for every test over time, but only in the abstinent group (P < 0.0001 for all tests). There were no between group baseline or Day 28 differences in structural MRI indices (global atrophy, total T1 and T2 lesion volume). At index assessment the two groups had a similar performance on the functional MRI-compatible Symbol Digit Modalities Test and there were no group differences in brain activation. However, by Day 28, the withdrawal group completed more trials correctly (P < 0.012) and had a faster reaction time (P < 0.002), associated with significantly increased activation in brain regions known to be associated with performance of the test (bilateral inferior frontal gyri, caudate and declive/cerebellum, P < 0.001 for all regions). These results reveal that patients with multiple sclerosis who are frequent, long-term cannabis users can show significant improvements in memory, processing speed and executive function after 28 days of drug abstinence. The absence of similar improvements in a matched multiple sclerosis group that remained on cannabis shows that beneficial cognitive change after stopping cannabis is not solely attributable to the effects of practice.

Download Full-text

Intestinal and Cerebral Oxygenation during Severe Isovolemic Hemodilution and Subsequent Hyperoxic Ventilation in a Pig Model

Anesthesiology ◽

10.1097/00000542-200209000-00021 ◽

2002 ◽

Vol 97 (3) ◽

pp. 660-670 ◽

Cited By ~ 80

Author(s):

Jasper van Bommel ◽

Adrianus Trouwborst ◽

Lothar Schwarte ◽

Martin Siegemund ◽

Can Ince ◽

...

Keyword(s):

Oxygen Consumption ◽

Oxygen Delivery ◽

Oxygen Supply ◽

Cerebral Oxygenation ◽

Oxygen Extraction ◽

Control Group ◽

Isovolemic Hemodilution ◽

Systemic Oxygen ◽

Fraction Of Inspired Oxygen ◽

Hyperoxic Ventilation

Background During severe isovolemic hemodilution, determination of critical hematocrit levels for the microvascular oxygenation of different organs might provide more insight into the effect of the redistribution of blood flow and oxygen delivery on the oxygenation of different organs. The effect of an increased amount of dissolved oxygen on tissue oxygenation during severely decreased hematocrit levels is not clear. Methods Fifteen anesthetized pigs were randomized between an experimental group (n = 10), in which severe isovolemic hemodilution was performed with 6% hydroxyethylstarch (1:1), and a time-matched control group (n = 5). Systemic, intestinal, and cerebral hemodynamic and oxygenation parameters were monitored. Microvascular oxygen partial pressure (muPo(2) ) was measured in the cerebral cortex and the intestinal serosa and mucosa, using the oxygen-dependent quenching of Pd-porphyrin phosphorescence. In the final phase of the experiment, fraction of inspired oxygen was increased to 1.0. Results Hemodilution decreased hematocrit from 25.3 +/- 3.0 to 7.6 +/- 1.2% (mean +/- SD). Systemic and intestinal oxygen delivery fell with the onset of hemodilution; intestinal oxygen consumption deceased at a hematocrit of 9.9%, whereas the systemic oxygen consumption decreased at a hematocrit of 7.6%. During hemodilution, the intestinal and cerebral oxygen extraction ratios increased from baseline with 130 and 52%, respectively. Based on the intersection of the two best-fit regression lines, determined by a least sum of squares technique, similar critical hematocrit levels were found for systemic oxygen consumption and the cerebral and intestinal mucosa muPo(2); the intestinal serosa muPo(2) decreased at an earlier stage (P < 0.05). Hyperoxic ventilation improved the muPo(2) values but not systemic or intestinal oxygen consumption. Conclusions During isovolemic hemodilution, the diminished oxygen supply was redistributed in favor of organs with a lower capacity to increase oxygen extraction. It is hypothesized that redirection of the oxygen supply within the intestines resulted in the preservation of oxygen consumption and mucosal muPo(2) compared with serosal muPo(2).

Download Full-text

Brain oxygen extraction fraction mapping in patients with multiple sclerosis

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211048031 ◽

2021 ◽

pp. 0271678X2110480

Author(s):

Junghun Cho ◽

Thanh D Nguyen ◽

Weiyuan Huang ◽

Elizabeth M Sweeney ◽

Xianfu Luo ◽

...

Keyword(s):

Multiple Sclerosis ◽

Oxygen Extraction Fraction ◽

Oxygen Extraction ◽

Linear Mixed Effect Model ◽

Oxygen Utilization ◽

Mixed Effect ◽

Whole Brain ◽

Brain Oxygen ◽

Normal Appearing White Matter ◽

Extraction Fraction

We aimed to demonstrate the feasibility of whole brain oxygen extraction fraction (OEF) mapping for measuring lesion specific and regional OEF abnormalities in multiple sclerosis (MS) patients. In 22 MS patients and 11 healthy controls (HC), OEF and neural tissue susceptibility ([Formula: see text]) maps were computed from MRI multi-echo gradient echo data. In MS patients, 80 chronic active lesions with hyperintense rim on quantitative susceptibility mapping were identified, and the mean OEF and [Formula: see text] within the rim and core were compared using linear mixed-effect model analysis. The rim showed higher OEF and [Formula: see text] than the core: relative to their adjacent normal appearing white matter, OEF contrast = −6.6 ± 7.0% vs. −9.8 ± 7.8% (p < 0.001) and [Formula: see text] contrast = 33.9 ± 20.3 ppb vs. 25.7 ± 20.5 ppb (p = 0.017). Between MS and HC, OEF and [Formula: see text]were compared using a linear regression model in subject-based regions of interest. In the whole brain, compared to HC, MS had lower OEF, 30.4 ± 3.3% vs. 21.4 ± 4.4% (p < 0.001), and higher [Formula: see text], −23.7 ± 7.0 ppb vs. −11.3 ± 7.7 ppb (p = 0.018). Our feasibility study suggests that OEF may serve as a useful quantitative marker of tissue oxygen utilization in MS.

Download Full-text

A frequency-domain machine learning method for dual-calibrated fMRI mapping of oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO2)

10.1101/660357 ◽

2019 ◽

Author(s):

Michael Germuska ◽

Hannah Chandler ◽

Thomas Okell ◽

Fabrizio Fasano ◽

Valentina Tomassini ◽

...

Keyword(s):

Machine Learning ◽

Blood Flow ◽

Oxygen Consumption ◽

Oxygen Metabolism ◽

Oxygen Extraction Fraction ◽

Oxygen Extraction ◽

Single Subject ◽

Extraction Fraction ◽

Wide Range ◽

Calibrated Fmri

AbstractMagnetic resonance imaging (MRI) offers the possibility to non-invasively map the brain’s metabolic oxygen consumption (CMRO2), which is essential for understanding and monitoring neural function in both health and disease. However, in depth study of oxygen metabolism with MRI has so far been hindered by the lack of robust methods. One MRI method of mapping CMRO2 is based on the simultaneous acquisition of cerebral blood flow (CBF) and blood oxygen level dependent (BOLD) weighted images during respiratory modulation of both oxygen and carbon dioxide. Although this dual-calibrated methodology has shown promise in the research setting, current analysis methods are unstable in the presence of noise and/or are computationally demanding. In this paper, we present a machine learning implementation for the multi-parametric assessment of dual-calibrated fMRI data. The proposed method aims to address the issues of stability, accuracy, and computational overhead, removing significant barriers to the investigation of oxygen metabolism with MRI. The method utilizes a time-frequency transformation of the acquired perfusion and BOLD-weighted data, from which appropriate feature vectors are selected for training of machine learning regressors. The implemented machine learning methods are chosen for their robustness to noise and their ability to map complex non-linear relationships (such as those that exist between BOLD signal weighting and blood oxygenation). An extremely randomized trees (ET) regressor is used to estimate resting blood flow and a multi-layer perceptron (MLP) is used to estimate CMRO2 and the oxygen extraction fraction (OEF). Synthetic data with additive noise are used to train the regressors, with data simulated to cover a wide range of physiologically plausible parameters. The performance of the implemented analysis method is compared to published methods both in simulation and with in-vivo data (n=30). The proposed method is demonstrated to significantly reduce computation time, error, and proportional bias in both CMRO2 and OEF estimates. The introduction of the proposed analysis pipeline has the potential to not only increase the detectability of metabolic difference between groups of subjects, but may also allow for single subject examinations within a clinical context.

Download Full-text

Comparing the Safety and Efficacy of Ziferon and Betaferon in Patients With Remitting- Relapsing Multiple Sclerosis

Pharmaceutical and Biomedical Research ◽

10.18502/pbr.v5i4.2393 ◽

2020 ◽

Author(s):

Mohammad Reza Gheini ◽

Mohammad Ali Sahraian ◽

Amir Reza Azimi ◽

Naser Mmoghadasi ◽

Mahmud Abdoli ◽

...

Keyword(s):

Multiple Sclerosis ◽

Relapse Rate ◽

Safety Profile ◽

Lesion Volume ◽

Cumulative Number ◽

Efficacy And Safety ◽

T2 Lesions ◽

Number Of Patients ◽

Significant Difference ◽

Magnetic Resonance Imaging Mri

Background: The present study aimed to compare the clinical efficacy and safety profile of Ziferon and Betaferon. Objectives: In total, 41 consecutive patients with relapsing forms of Multiple Sclerosis (MS) were selected from the MS outpatient clinic affiliated to Tehran University of Medical Sciences. The patients were randomly assigned into two groups. Methods: Each group either received Ziferon 250 mcg Subcutaneously (SC) in alternate days or Betaferon 250 mcg SC on alternate days. Clinical and para-clinical outcomes, such as mean relapse rate/year score, mean Expanded Disability Status Scale (EDSS)/year score, the cumulative number, and the volume of gadolinium-enhancing lesions, in addition to the cumulative number of new T2 lesions and safety profile were evaluated for each group during the years of treatment. Results: There were no significant differences in Magnetic Resonance Imaging (MRI) outcomes (change in total lesion volume, new lesion per T2-weighted scan, and gadoliniumenhancing lesions per T1-weighted scan from baseline; P=0.236, P=0.56, & P=0.496, respectively was observed). There was no significant difference in the relapse rate between Ziferon and Betaferon treated groups (P=0.56). There were no unexpected safety events. The number of patients who discontinued the study due to adverse events occurrence was similar between the two groups. Conclusion: Evidence demonstrates the non-inferiority and bio-similarity of Ziferon (interferon beta-1b) to Betaferon in terms of efficacy and safety profile.

Download Full-text