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Blood oxygenation level-dependent (BOLD) or arterial spin labeling (ASL) MRI with hypercapnic stimuli allow for measuring cerebrovascular reactivity (CVR). Hypercapnic stimuli are also employed in calibrated BOLD functional MRI for quantifying neuronally-evoked changes in cerebral oxygen metabolism (CMRO2). It is often assumed that hypercapnic stimuli (with or without hyperoxia) are iso-metabolic; increasing arterial CO2 or O2 does not affect CMRO2. We evaluated the null hypothesis that two common hypercapnic stimuli, ‘CO2 in air’ and carbogen, are iso-metabolic. TRUST and ASL MRI were used to measure the cerebral venous oxygenation and cerebral blood flow (CBF), from which the oxygen extraction fraction (OEF) and CMRO2 were calculated for room-air, ‘CO2 in air’ and carbogen. As expected, CBF significantly increased (9.9% ± 9.3% and 12.1% ± 8.8% for ‘CO2 in air’ and carbogen, respectively). CMRO2 decreased for ‘CO2 in air’ (−13.4% ± 13.0%, p 2 during carbogen did not significantly change. Our findings indicate that ‘CO2 in air’ is not iso-metabolic, while carbogen appears to elicit a mixed effect; the CMRO2 reduction during hypercapnia is mitigated when including hyperoxia. These findings can be important for interpreting measurements using hypercapnic or hypercapnic-hyperoxic (carbogen) stimuli.

Ultra-high field functional magnetic resonance imaging (fMRI) offers the spatial resolution to measure neuronal activity at the scale of cortical layers. However, cortical depth dependent vascularization differences, such as a higher prevalence of macro-vascular compartments near the pial surface, have a confounding effect on depth-resolved blood-oxygen-level dependent (BOLD) fMRI signals. In the current study, we use hypercapnic and hyperoxic breathing conditions to quantify the influence of all venous vascular and micro-vascular compartments on laminar BOLD fMRI, as measured with gradient-echo (GE) and spin-echo (SE) scan sequences, respectively. We find that all venous vascular and micro-vascular compartments are capable of comparable theoretical maximum signal intensities, as represented by the M-value parameter. However, the capacity for vessel dilation, as reflected by the cerebrovascular reactivity (CVR), is approximately two and a half times larger for all venous vascular compartments combined compared to the micro-vasculature at superficial layers. Finally, there is roughly a 35% difference in estimates of CBV changes between all venous vascular and micro-vascular compartments, although this relative difference was approximately uniform across cortical depth. Thus, our results suggest that fMRI BOLD signal differences across cortical depth are likely caused by differences in dilation properties between macro- and micro-vascular compartments.

Background: Patients with psychotic disorders often show prominent cognitive impairment. Glutamate seems to play a prominent role, but its role in deep gray matter (DGM) regions is unclear. Aims: To evaluate glutamate levels within deep gray matter structures in patients with a psychotic disorder in relation to cognitive functioning, using advanced spectroscopic acquisition, reconstruction, and post-processing techniques. Methods: A 7-Tesla magnetic resonance imaging scanner combined with a lipid suppression coil and subject-specific water suppression pulses was used to acquire high-resolution magnetic resonance spectroscopic imaging data. Tissue fraction correction and registration to a standard brain were performed for group comparison in specifically delineated DGM regions. The brief assessment of cognition in schizophrenia was used to evaluate cognitive status. Results: Average glutamate levels across DGM structures (i.e. caudate, pallidum, putamen, and thalamus) in mostly medicated patients with a psychotic disorder ( n = 16, age = 33, 4 females) were lower compared to healthy controls ( n = 23, age = 24, 7 females; p = 0.005, d = 1.06). Stratified analyses showed lower glutamate levels in the caudate ( p = 0.046, d = 0.76) and putamen p = 0.013, d = 0.94). These findings were largely explained by age differences between groups. DGM glutamate levels were positively correlated with psychomotor speed ( r(30) = 0.49, p = 0.028), but not with other cognitive domains. Conclusions: We find reduced glutamate levels across DGM structures including the caudate and putamen in patients with a psychotic disorder that are linked to psychomotor speed. Despite limitations concerning age differences, these results underscore the potential role of detailed in vivo glutamate assessments to understand cognitive deficits in psychotic disorders.

Ultra-high field functional Magnetic Resonance Imaging (fMRI) offers the spatial resolution to measure neural activity at the scale of cortical layers. Most fMRI studies make use of the Blood-Oxygen-Level Dependent (BOLD) signal, arising from a complex interaction of changes in cerebral blood flow (CBF) and volume (CBV), and venous oxygenation. However, along with cyto- and myeloarchitectural changes across cortical depth, laminar fMRI is confronted with additional confounds related to vascularization differences that exist across cortical depth. In the current study, we quantify how the non-uniform distribution of macro- and micro-vascular compartments, as measured with Gradient-Echo (GE) and Spin-Echo (SE) scan sequences, respectively, affect laminar BOLD fMRI responses following evoked hypercapnic and hyperoxic breathing conditions. We find that both macro- and micro-vascular compartments are capable of comparable theoretical maximum signal intensities, as represented by the M-scaling parameter. However, the capacity for vessel dilation, as reflected by the cerebrovascular reactivity (CVR), is approximately three times larger for the macro-compared to the micro-vasculature at superficial layers. Finally, there is roughly a 35% difference in CBV estimates between the macro- and micro-vascular compartments, although this relative difference is approximately uniform across cortical depth.

Patients with psychotic disorders often show prominent cognitive impairment. Glutamate seems to play a prominent role, but knowledge on its role in deep gray matter regions is limited and previous studies have yielded heterogeneous results. The aim was to evaluate glutamate levels within deep gray matter structures in patients with a psychotic disorder in relation to cognitive functioning, using advanced spectroscopic acquisition, reconstruction and post-processing techniques. A 7 tesla MRI scanner combined with a unique lipid suppression coil and subject specific water signal suppression pulses were used to acquire high-resolution magnetic resonance spectroscopic imaging data. Anatomical scans were used to perform tissue fraction correction and registration to a standard brain for group comparison in specifically delineated brain regions. The brief assessment of cognition in schizophrenia was used to evaluate cognitive status. Average glutamate levels across deep gray matter structures (i.e. caudate, pallidum, putamen, and thalamus) in patients with a psychotic disorder (n=16, 4 females) were lower compared to healthy controls (n=23, 7 females). Stratified analyses showed lower glutamate levels in the caudate and putamen but not in the pallidum or thalamus. Average glutamate levels across deep gray matter structures were positively correlated with cognition, particularly to psychomotor speed. We find reduced glutamate levels across deep brain structures such as the caudate and putamen in patients with a psychotic disorder that are linked to psychomotor speed. Our results underscore the potential role of detailed in vivo glutamate assessments to understand cognitive deficits in patients with psychotic disorders.

Objective Moyamoya vasculopathy is a rare, often bilateral disease characterized by progressive stenosis and occlusion of the distal internal carotid artery, leading to a progressive deterioration of cerebrovascular reactivity (CVR) and increased risk of transient ischemic attacks (TIAs), infarction and hemorrhage. Surgical revascularization is a widely accepted symptomatic treatment, often performed bilaterally in one or two stages. To possibly further optimize treatment strategy, we investigated the effect of unilateral revascularization surgery on the CVR of, and TIA frequency originating from, the contralateral hemisphere. Methods From our database of 143 moyamoya vasculopathy patients we selected those with bilateral disease, who underwent hemodynamic imaging ([15O]H2O positron emission tomography (PET)-CT with acetazolamide challenge) before and 14 months (median) after unilateral revascularization. We evaluated CVR in three regions per hemisphere, and averaged these per hemisphere for statistical comparison. Conservatively treated patients were showed as a comparison group. To examine TIA frequency, we selected patients who presented with TIAs that (also) originated from the contralateral – not to be operated – hemisphere. We scored changes in CVR and TIA frequency of the ipsilateral and contralateral hemisphere over time. Results Seven surgical and seven conservative patients were included for CVR comparison. Of the 20 scored contralateral regions in the surgical group, 15 showed improved CVR after unilateral revascularization, while 5 remained stable. The averaged scores improved significantly for both hemispheres. In conservatively treated patients, however, only 3 of the 20 scored regions improved in the least-affected (contralateral) hemispheres, and 9 deteriorated. From the 6 patients with contralateral TIAs at presentation, 4 had a decreased TIA frequency originating from the contralateral hemisphere after unilateral surgery, while 2 patients remained stable. Conclusion Both CVR and TIA frequency in the contralateral hemisphere can improve after unilateral revascularization surgery in bilateral MMV.

Introduction Magnetic resonance spectroscopic imaging (MRSI) has the potential to add a layer of understanding of the neurobiological mechanisms underlying brain diseases, disease progression, and treatment efficacy. Limitations related to metabolite fitting of low signal‐to‐noise ratios data, signal variations due to partial‐volume effects, acquisition and extracranial lipid artifacts, along with clinically relevant aspects such as scan time constraints, are among the challenges associated with in vivo MRSI. Methods The aim of this work was to address some of these factors and to develop an acquisition, reconstruction, and postprocessing pipeline to derive lipid‐suppressed metabolite values of central brain structures based on free‐induction decay measurements made using a 7 T MR scanner. Anatomical images were used to perform high‐resolution (1 mm3) partial‐volume correction to account for gray matter, white matter (WM), and cerebral‐spinal fluid signal contributions. Implementation of automatic quality control thresholds and normalization of metabolic maps from 23 subjects to the Montreal Neurological Institute (MNI) standard atlas facilitated the creation of high‐resolution average metabolite maps of several clinically relevant metabolites in central brain regions, while accounting for macromolecular distributions. Partial‐volume correction improved the delineation of deep brain nuclei. We report average metabolite values including glutamate + glutamine (Glx), glycerophosphocholine, choline and phosphocholine (tCho), (phospo)creatine, myo‐inositol and glycine (mI‐Gly), glutathione, N‐acetyl‐aspartyl glutamate(and glutamine), and N‐acetyl‐aspartate in the basal ganglia, central WM (thalamic radiation, corpus callosum) as well as insular cortex and intracalcarine sulcus. Conclusion MNI‐registered average metabolite maps facilitate group‐based analysis, thus offering the possibility to mitigate uncertainty in variable MRSI data., We use a 7 T MRI scanner along with a combination of advanced acquisition, reconstruction, and postprocessing techniques to derive metabolic distribution in deep brain structures.

Structural and calibrated magnetic resonance imaging data were acquired on 44 collegiate football players prior to the season ( PRE), following the first four weeks in-season ( PTC) and one month after the last game ( POST). Exposure data collected from g-Force accelerometers mounted to the helmet of each player were used to split participants into HIGH ( N = 22) and LOW ( N = 22) exposure groups, based on the frequency of impacts sustained by each athlete. Significant decreases in grey-matter volume specific to the HIGH group were documented at POST ( P = 0.009), compared to baseline. Changes in resting cerebral blood flow (CBF0), corrected for partial volume effects, were observed within the HIGH group, throughout the season ( P 2|0) mid-season were also documented in the HIGH group, with respect to both PRE- and POST values. No physiological changes were observed in the LOW group. Therefore, cerebral metabolic demand may be elevated in players with greater exposure to head impacts. These results provide novel insight into the effects of sub-concussive collisions on brain structure and cerebrovascular physiology and emphasize the importance of multi-modal imaging for a complete characterization of cerebral health.

Existing cerebrovascular reactivity (CVR) techniques assess flow reactivity in either the largest cerebral vessels or at the level of the parenchyma. We examined the ability of 2D phase contrast MRI at 7 T to measure CVR in small cerebral perforating arteries. Blood flow velocity in perforators was measured in 10 healthy volunteers (mean age 26 years) using a 7 T MR scanner, using phase contrast acquisitions in the semioval center (CSO), the basal ganglia (BG) and the middle cerebral artery (MCA). Changes in flow velocity in response to a hypercapnic breathing challenge were assessed, and expressed as the percentual increase of flow velocity as a function of the increase in end tidal partial pressure of CO2. The hypercapnic challenge increased (fit ± standard error) flow velocity by 0.7 ± 0.3%/mmHg in the CSO (P, Graphical abstract Image 1, Highlights • We show that 2D phase contrast at 7T MRI is capable of measuring reactivity in small cerebral perforating arteries. • Reactivity to hypercapnia was measured in perforating arteries of the semi-oval center and the basal ganglia. • Both blood flow velocity and the number of detected perforating arteries increased during hypercapnia. • The proposed method bridges the gap between current reactivity measurements in parenchyma and large arteries.

PURPOSE: To detect neuronal activity-evoked pH changes by amide proton transfer-chemical exchange saturation transfer (APT-CEST) MRI at 7 T. METHODS: Three healthy subjects participated in the study. A low-power 3-dimensional APT-CEST sequence was optimized through the Bloch-McConnell equations. pH sensitivity of the sequence was estimated both in phantoms and in vivo. The feasibility of pH-functional MRI was tested in Bloch-McConnell-simulated data using the optimized sequence. In healthy subjects, the visual stimuli were used to evoke transient pH changes in the visual cortex, and a 3-dimensional APT-CEST volume was acquired at the pH-sensitive frequency offset of 3.5 ppm every 12.6 s. RESULTS: In theory, a three-component general linear model was capable of separating the effects of blood oxygenation level-dependent contrast and pH. The Bloch-McConnell equations indicated that a change in pH of 0.03 should be measurable at the experimentally determined temporal signal-to-noise ratio of 108. However, only a blood oxygenation level-dependent effect in the visual cortex could be discerned during the visual stimuli experiments performed in the healthy subjects. CONCLUSIONS: The results of this study suggest that if indeed there are any transient brain pH changes in response to visual stimuli, those are under 0.03 units pH change, which is extremely difficult to detect using the existent techniques. Magn Reson Med, 2017. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Patients with psychotic disorders often show prominent cognitive impairment. Glutamate seems to play a prominent role, but knowledge on its role in deep gray matter regions is limited and previous studies have yielded heterogeneous results. The aim was to evaluate glutamate levels within deep gray matter structures in patients with a psychotic disorder in relation to cognitive functioning, using advanced spectroscopic acquisition, reconstruction and post-processing techniques. A 7 tesla MRI scanner combined with a unique lipid suppression coil and subject specific water signal suppression pulses were used to acquire high-resolution magnetic resonance spectroscopic imaging data. Anatomical scans were used to perform tissue fraction correction and registration to a standard brain for group comparison in specifically delineated brain regions. The brief assessment of cognition in schizophrenia was used to evaluate cognitive status. Average glutamate levels across deep gray matter structures (i.e. caudate, pallidum, putamen, and thalamus) in patients with a psychotic disorder (n=16, 4 females) were lower compared to healthy controls (n=23, 7 females). Stratified analyses showed lower glutamate levels in the caudate and putamen but not in the pallidum or thalamus. Average glutamate levels across deep gray matter structures were positively correlated with cognition, particularly to psychomotor speed. We find reduced glutamate levels across deep brain structures such as the caudate and putamen in patients with a psychotic disorder that are linked to psychomotor speed. Our results underscore the potential role of detailed in vivo glutamate assessments to understand cognitive deficits in patients with psychotic disorders.

Background and purpose: The BOLD signal amplitude as a response to a hypercapnia stimulus is commonly used to assess cerebrovascular reserve. Despite recent advances, the implementation remains cumbersome and alternative ways to assess hemodynamic impairment are desirable. Resting-state BOLD signal fluctuations (rsBOLD) have been proposed however data on its sensitivity and dependence on baseline venous cerebral blood volume (vCBV) is limited. The primary aim of this study was to compare the effect sizes of resting-state and hypercapnia induced BOLD signal changes in the detection of hemodynamic impairment. The second aim of the study was to assess the dependence of BOLD signal variability on vCBV. Materials and methods: Fifteen patients with internal carotid artery occlusive disease and 15 matched healthy controls were included in this study. The BOLD signal was derived from a dual-echo gradient-echo echo-planar sequence during hypercapnia (HC) and hyperoxia (HO) gas modulations. BOLD (fractional) amplitude of low frequency fluctuations ((f)ALFF) was compared to HC-BOLD, BOLD response delays derived from time delay analysis and ΔBOLD in response to progressively increasing HC. Effect sizes (i.e. the standard mean difference between patients and controls) were calculated. HO-BOLD was used to estimate vCBV, and its contribution to the variability in rsBOLD signal was evaluated. Results: The effect sizes of ALFF and fALFF (0.61 and 0.72) were lower than the effect sizes related to hypercapnia-based hemodynamic assessment analysis; 1.62, 1.56 and 0.90 for HC-BOLD, BOLD response delays and ΔBOLD in response to progressively increasing HC. A moderate relation was found between (f)ALFF and HC-BOLD in controls (R2 of 0.61 and 0.42), but this relation decreased in patients (R2 of 0.33 and 0.15). (f)ALFF did not differ between patients and controls whereas HC-BOLD did (p < 0.005). The ΔBOLD response to progressively increasing HC was significantly different in between patients and controls for ΔEtCO2 values ≥ 2 mmHg (at +2 mmHg F(1, 18) = 5.85, p = 0.026). Up to 31% and 53% of the variance in the ALFF and HC-BOLD spatial distribution could be explained by HO-BOLD. Conclusion: ALFF and fALFF demonstrated a moderate effect size to detect hemodynamic impairment whereas the effect size was large for methods employing a hypercapnia-based vascular stress stimulus. Based on our analysis of BOLD signal change as a response to a progressively increasing hypercapnia stimulus we can argue that a hypercapnia stimulus of at least 2 mmHg above baseline EtCO2 is necessary to evaluate hemodynamic impairment. We also demonstrated that a substantial amount of information imbedded in the rsBOLD and HC-BOLD was explained by HO-BOLD. HO-BOLD can serve as a proxy for vCBV and this thus indicates that one should be careful when adopting these techniques in disease cases with compromised CBV.

INTRODUCTION: Blood oxygenation-level dependent (BOLD) magnetic resonance imaging signal changes in response to stimuli have been used to evaluate age-related changes in neuronal activity. Contradictory results from these types of experiments have been attributed to differences in cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2 ). To clarify the effects of these physiological parameters, we investigated the effect of age on baseline CBF and CMRO2 . MATERIALS AND METHODS: Twenty young (mean ± sd age, 28 ± 3 years), and 45 older subjects (66 ± 4 years) were investigated. A dual-echo pseudocontinuous arterial spin labeling (ASL) sequence was performed during normocapnic, hypercapnic, and hyperoxic breathing challenges. Whole brain and regional gray matter values of CBF, ASL cerebrovascular reactivity (CVR), BOLD CVR, oxygen extraction fraction (OEF), and CMRO2 were calculated. RESULTS: Whole brain CBF was 49 ± 14 and 40 ± 9 ml/100 g/min in young and older subjects respectively (P

Changes in cerebral blood flow (CBF) in response to hypercapnia induced changes in vascular tone, known as cerebrovascular reactivity (CVR), can be measured using the Blood Oxygenation Level Dependent (BOLD) MR contrast. We examine regional differences in the BOLD-CVR response to a progressively increasing hypercapnic stimulus as well as regional BOLD characteristics for the return to baseline normocapnia. CVR across 9 subjects was highest in the cerebral lobes and deep gray matter. Peak CVR in these regions was measured at 3.6 +/- 1.6 mm Hg above baseline end-tidal CO2. White matter CVR was generally reduced compared to that of the gray matter (peak white matter CVR was similar to 48% lower). A positive relationship between the end-tidal CO2 value at which peak CVR was measured and white matter depth is observed. Furthermore, the time required for the BOLD signal to return to baseline after cessation of the hypercapnic stimulus, was also related to white matter depth; the return, expressed as a time constant, was similar to 25% longer in white matter. To explain the observed differences in regional CVR response, a model is proposed that takes into account the local architecture of the cerebrovascular, which can result in changes in regional blood flow distribution as a function of end-tidal CO2. (C) 2015 Elsevier Inc. All rights reserved.

The purpose of this study was to assess whether calibrated magnetic resonance imaging (MRI) can identify regional variances in cerebral hemodynamics caused by vascular disease. For this, arterial spin labeling (ASL)/blood oxygen level-dependent (BOLD) MRI was performed in 11 patients (65±7 years) and 14 controls (66±4 years). Cerebral blood flow (CBF), ASL cerebrovascular reactivity (CVR), BOLD CVR, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) were evaluated. The CBF was 34±5 and 36±11 mL/100 g per minute in the ipsilateral middle cerebral artery (MCA) territory of the patients and the controls. Arterial spin labeling CVR was 44±20 and 53±10% per 10 mm Hg ΔEtCO2 in patients and controls. The BOLD CVR was lower in the patients compared with the controls (1.3±0.8 versus 2.2±0.4% per 10 mm Hg ΔEtCO2, P < 0.01). The OEF was 41±8% and 38±6%, and the CMRO2 was 116±39 and 111±40 μmol/100 g per minute in the patients and the controls. The BOLD CVR was lower in the ipsilateral than in the contralateral MCA territory of the patients (1.2±0.6 versus 1.6±0.5% per 10 mmHg ΔEtCO2, P < 0.01). Analysis was hampered in three patients due to delayed arrival time. Thus, regional hemodynamic impairment was identified with calibrated MRI. Delayed arrival artifacts limited the interpretation of the images in some patients.

Redistribution of blood flow across different brain regions, arising from the vasoactive nature of hypercapnia, can introduce errors when examining cerebrovascular reactivity (CVR) response delays. In this study, we propose a novel analysis method to characterize hemodynamic delays in the blood oxygen level dependent (BOLD) response to hypercapnia, and hyperoxia, as a way to provide insight into transient differences in vascular reactivity between cortical regions, and across tissue depths. A pseudo-continuous arterial spin labeling sequence was used to acquire BOLD and cerebral blood flow simultaneously in 19 healthy adults (12 F; 20 ± 2 years) during boxcar CO2 and O2 gas inhalation paradigms. Despite showing distinct differences in hypercapnia-induced response delay times (P 0.05) once calibrated for bolus arrival time derived using non-vasoactive hyperoxic gas challenges. Longer hypercapnic temporal delays were observed as the depth of the white matter tissue increased, although no significant differences in response lag were found during hyperoxia across tissue depth, or between grey and white matter. Furthermore, calibration of hypercapnic delays using hyperoxia revealed that deeper white matter layers may be more prone to dynamic redistribution of blood flow, which introduces response lag times ranging between 1 and 3 s in healthy subjects. These findings suggest that the combination of hypercapnic and hyperoxic gas-inhalation MRI can be used to distinguish between differences in CVR that arise as a result of delayed stimulus arrival time (due to the local architecture of the cerebrovasculature), or preferential blood flow distribution. Calibrated response delays to hypercapnia provide important insights into cerebrovascular physiology, and may be used to correct response delays associated with vascular impairment.

Purpose To detect neuronal activity–evoked pH changes by amide proton transfer–chemical exchange saturation transfer (APT‐CEST) MRI at 7 T. Methods Three healthy subjects participated in the study. A low‐power 3‐dimensional APT‐CEST sequence was optimized through the Bloch‐McConnell equations. pH sensitivity of the sequence was estimated both in phantoms and in vivo. The feasibility of pH–functional MRI was tested in Bloch‐McConnell‐simulated data using the optimized sequence. In healthy subjects, the visual stimuli were used to evoke transient pH changes in the visual cortex, and a 3‐dimensional APT‐CEST volume was acquired at the pH‐sensitive frequency offset of 3.5 ppm every 12.6 s. Results In theory, a three‐component general linear model was capable of separating the effects of blood oxygenation level–dependent contrast and pH. The Bloch‐McConnell equations indicated that a change in pH of 0.03 should be measurable at the experimentally determined temporal signal‐to‐noise ratio of 108. However, only a blood oxygenation level–dependent effect in the visual cortex could be discerned during the visual stimuli experiments performed in the healthy subjects. Conclusions The results of this study suggest that if indeed there are any transient brain pH changes in response to visual stimuli, those are under 0.03 units pH change, which is extremely difficult to detect using the existent techniques. Magn Reson Med 80:126–136, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Item does not contain fulltext Proton magnetic resonance spectroscopy ((1) H-MRS) can be used to quantify in vivo metabolite levels, such as lactate, gamma-aminobutyric acid (GABA) and glutamate (Glu). However, there are considerable analysis choices which can alter the accuracy or precision of (1) H-MRS metabolite quantification. It is currently unknown to what extent variations in the analysis pipeline used to quantify (1) H-MRS data affect outcomes. The purpose of this study was to evaluate whether the quantification of identical (1) H-MRS scans across independent and experienced research groups would yield comparable results. We investigated the influence of model parameters and spectral quantification software on fitted metabolite concentration values. Sixty spectra in 30 individuals (repeated measures) were acquired using a 7-T MRI scanner. Data were processed by four independent research groups with the freedom to choose their own individualized and optimal parameter settings using LCModel software. Data were processed a second time in one group using an independent software package (NMRWizard) for an additional comparison with a different post-processing platform. Correlations across research groups of the ratio between the highest and, arguably, the most relevant resonances for neurotransmission [N-acetyl aspartate (NAA), N-acetyl aspartyl glutamate (NAAG) and Glu] over the total creatine [creatine (Cr) + phosphocreatine (PCr)] concentration, using Pearson's product-moment correlation coefficient (r), were calculated. Mean inter-group correlations using LCModel software were 0.87, 0.88 and 0.77 for NAA/Cr + PCr, NAA + NAAG/Cr + PCr and Glu/Cr + PCr, respectively. The mean correlations when comparing NMRWizard results with LCModel fitting results at University Medical Center Utrecht (UMCU) were 0.87, 0.89 and 0.71 for NAA/Cr + PCr, NAA + NAAG/Cr + PCr and Glu/Cr + PCr, respectively. Metabolite quantification using identical (1) H-MRS data was influenced by processing parameters, basis sets and software choice. Locally preferred processing choices affected metabolite quantification, even when using identical software. Our results reinforce the notion that standard practices should be established to regularize outcomes of (1) H-MRS studies, and that basis sets used for processing should be made available to the scientific community.

Increasing the concentration of oxygen dissolved in water is known to increase the recovery rate (R1 = 1/T1) of longitudinal magnetization (T1 relaxation). Direct T1 changes in response to precise hyperoxic gas challenges have not yet been quantified and the actual effect of increasing arterial oxygen concentration on the T1 of brain parenchyma remains unclear. The aim of this work was to use quantitative T1 mapping to measure tissue T1 changes in response to precisely targeted hyperoxic respiratory challenges ranging from baseline end-tidal oxygen (PetO2) to approximately 500 mmHg. We did not observe measureable T1 changes in either gray matter or white matter parenchymal tissue. The T1 of peripheral cerebrospinal fluid located within the sulci, however, was reduced as a function of PetO2. No significant T1 changes were observed in the ventricular cerebrospinal fluid under hyperoxia. Our results indicate that care should be taken to distinguish actual T1 changes from those which may be related to partial volume effects with cerebrospinal fluid, or regions with increased fluid content such as edema when examining hyperoxia-induced changes in T1 using methods based on T1-weighted imaging.

Spectral degradations as a result of temporal field variations are observed in MRSI of the human prostate. Moving organs generate substantial temporal and spatial field fluctuations as a result of susceptibility mismatch with the surrounding tissue (i.e. periodic breathing, cardiac motion or random bowel motion). Nine patients with prostate cancer were scanned with an endorectal coil (ERC) on a 7-T MR scanner. Temporal B0 field variations were observed with fast dynamic B0 mapping in these patients. Simulations of dynamic B0 corrections were performed using zero- to second-order shim terms. In addition, the temporal B0 variations were applied to simulated MR spectra causing, on average, 15% underestimation of the choline/citrate ratio. Linewidth distortions and frequency shifts (up to 30 and 8 Hz, respectively) were observed. To demonstrate the concept of observing local field fluctuations in real time during MRSI data acquisition, a field probe (FP) tuned and matched for the 19 F frequency was incorporated into the housing of the ERC. The data acquired with the FP were compared with the B0 field map data and used to correct the MRSI datasets retrospectively. The dynamic B0 mapping data showed variations of up to 30 Hz (0.1 ppm) over 72 s at 7 T. The simulated zero-order corrections, calculated as the root mean square, reduced the standard deviation (SD) of the dynamic variations by an average of 41%. When using second-order corrections, the reduction in the SD was, on average, 56%. The FP data showed the same variation range as the dynamic B0 data and the variation patterns corresponded. After retrospective correction, the MRSI data showed artifact reduction and improved spectral resolution. B0 variations can degrade the MRSI substantially. The simple incorporation of an FP into an ERC can improve prostate cancer MRSI without prior knowledge of the origin of the dynamic field distortions. Copyright © 2014 John Wiley & Sons, Ltd.

Cerebrovascular reactivity (CVR) is a mechanism responsible for maintaining stable perfusion pressure within the brain via smooth muscle mediated modulations of vascular tone. The amplitude of cerebral blood flow (CBF) change in response to a stimulus has been evaluated using Blood Oxygen Level Dependent (BOLD) MRI, however the relationship between the stimulus and the measured signal remains unclear. CVR measured invasively in animal models and using blood-velocity based measurements in humans has demonstrated a sigmoidal relationship between cerebral blood flow and CO2 partial pressure. Using an ultra-high magnetic field strength (7 T) MRI scanner and a computer controlled gas delivery system, we examined the regional and voxel-wise CVR response in relation to a targeted progressively increasing hypo- to hypercapnic stimulus. The aim of this study was to assess the non-linearity/sigmoidal behavior of the CVR response at varying arterial CO2 (PaCO2) levels. We find that a sigmoidal model provides a better description of the BOLD signal response to increasing PaCO2 than a linear model. A distinct whole-brain and gray matter BOLD-CVR signal plateau was observed in both voxel-wise and regional analysis. Furthermore, we demonstrate that a progressively increasing stimulus in combination with a sigmoidal response model can be used to obtain CVR values and provides additional physiologically relevant information (such as linear and non-linear response domains, and maximum response amplitudes) that may be more difficult to obtain from blocked CVR experiments. Considering these results, we propose an alternative way in which to define CVR based on the derivative of the BOLD-CVR response curve, which can potentially be used to differentiate between healthy and diseased vascular states.

Loss-of-function mutations in glutaminase (GLS), the enzyme converting glutamine into glutamate, and the counteracting enzyme glutamine synthetase (GS) cause disturbed glutamate homeostasis and severe neonatal encephalopathy. We report a de novo Ser482Cys gain-of-function variant in GLS encoding GLS associated with profound developmental delay and infantile cataract. Functional analysis demonstrated that this variant causes hyperactivity and compensatory downregulation of GLS expression combined with upregulation of the counteracting enzyme GS, supporting pathogenicity. Ser482Cys-GLS likely improves the electrostatic environment of the GLS catalytic site, thereby intrinsically inducing hyperactivity. Alignment of +/−12.000 GLS protein sequences from >1000 genera revealed extreme conservation of Ser482 to the same degree as catalytic residues. Together with the hyperactivity, this indicates that Ser482 is evolutionarily preserved to achieve optimal—but submaximal—GLS activity. In line with GLS hyperactivity, increased glutamate and decreased glutamine concentrations were measured in urine and fibroblasts. In the brain (both grey and white matter), glutamate was also extremely high and glutamine was almost undetectable, demonstrated with magnetic resonance spectroscopic imaging at clinical field strength and subsequently supported at ultra-high field strength. Considering the neurotoxicity of glutamate when present in excess, the strikingly high glutamate concentrations measured in the brain provide an explanation for the developmental delay. Cataract, a known consequence of oxidative stress, was evoked in zebrafish expressing the hypermorphic Ser482Cys-GLS and could be alleviated by inhibition of GLS. The capacity to detoxify reactive oxygen species was reduced upon Ser482Cys-GLS expression, providing an explanation for cataract formation. In conclusion, we describe an inborn error of glutamate metabolism caused by a GLS hyperactivity variant, illustrating the importance of balanced GLS activity.

Dynamic magnetic field shimming is gaining interest for field sensitive MRI acquisitions. Using slice based or real-time shim updating, significant improvements in static field (B0) uniformity can be obtained. While the ability to rapidly switch shim fields can improve overall B0 homogeneity, it induces eddy current fields that must be characterized and compensated for. Methods used to achieve this have thus far been based on linear projection spin echo sequences or field probe assemblies. Here, a novel image-based method is presented to measure and characterize eddy current fields without the need for field probes or projection based measurements. This technique can be extended to characterize very high order spherical harmonic fields, making it a useful tool to calibrate next-generation shim systems implementing dynamic field steering with greater than third order shim terms. Results are used to calibrate a Dynamic Shim Updating unit for pre-emphasis and eddy current compensation. Three-dimensional datasets are acquired at multiple MR facilities containing complete spatiotemporal field information to compensate eddy current field self- and cross-terms for up to third order. Furthermore, simulation studies are performed to investigate the effect of scan resolution and phantom size with respect to accurate eddy current field characterization. © 2014 Wiley Periodicals, Inc. Concepts Magn Reson Part A 42A: 245–260, 2013.

Imaging studies using blood oxygenation level-dependent (BOLD) functional magnetic resonance (fMR) imaging have provided significant insight into the functional workings of the human brain. BOLD fMR imaging-based techniques have matured to include clinically viable imaging techniques that may one day render invasive diagnostic procedures unnecessary. This article explains how BOLD fMR imaging was developed. The characteristics of the BOLD signal are explained and the concepts of specificity and sensitivity are addressed with respect to pulse sequence and field strength. An overview of recent clinical applications is provided and future directions and perspectives are discussed.

Blood Oxygenation Level Dependent (BOLD) imaging in combination with vasoactive stimuli can be used to probe cerebrovascular reactivity (CVR). Characterizing the healthy, age-related changes in the BOLD-CVR response can provide a reference point from which to distinguish abnormal CVR from the otherwise normal effects of ageing. Using a computer controlled gas delivery system, we examine differences in BOLD-CVR response to progressive hypercapnia between 16 young (28±3years, 9 female) and 30 elderly subjects (66±4years, 13 female). Furthermore, we incorporate baseline T2* information to broaden our interpretation of the BOLD-CVR response. Significant age-related differences were observed. Grey matter CVR at 7mmHg above resting PetCO2 was lower amongst elderly (0.19±0.06%ΔBOLD/mmHg) as compared to young subjects (0.26±0.07%ΔBOLD/mmHg). White matter CVR at 7mmHg above baseline PetCO2 showed no significant difference between young (0.04±0.02%ΔBOLD/mmHg) and elderly subjects (0.05±0.03%ΔBOLD/mmHg). We saw no significant differences in the BOLD signal response to progressive hypercapnia between male and female subjects in either grey or white matter. The observed differences in the healthy BOLD-CVR response could be explained by age-related changes in vascular mechanical properties.