Alex A. Bhogal

Investigating the non-linearity of the BOLD cerebrovascular reactivity response to targeted hypo/hypercapnia at 7 T

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 (7T) 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.

Age-related changes in brain hemodynamics; A calibrated MRI study.

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.

Examining the regional and cerebral depth-dependent BOLD cerebrovascular reactivity response at 7 T

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±1.6mmHg above baseline end-tidal CO2. White matter CVR was generally reduced compared to that of the gray matter (peak white matter CVR was ~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 ~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.

Calibrated MRI to evaluate cerebral hemodynamics in patients with an internal carotid artery occlusion.

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.

The BOLD cerebrovascular reactivity response to progressive hypercapnia in young and elderly.

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.

1H-MRS processing parameters affect metabolite quantification : The urgent need for uniform and transparent standardization

Proton magnetic resonance spectroscopy (1H–MRS) can be used to quantify in vivo metabolite levels, such as lactate, γ‐aminobutyric acid (GABA) and glutamate (Glu). However, there are considerable analysis choices which can alter the accuracy or precision of 1H–MRS metabolite quantification. It is currently unknown to what extent variations in the analysis pipeline used to quantify 1H–MRS data affect outcomes. The purpose of this study was to evaluate whether the quantification of identical 1H–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 Pearsons 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 1H–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 1H–MRS studies, and that basis sets used for processing should be made available to the scientific community.

A novel perspective to calibrate temporal delays in cerebrovascular reactivity using hypercapnic and hyperoxic respiratory challenges

Abstract 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; Bonferroni corrected), grey matter regions showed homogenous hemodynamic latencies (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. HighlightsHypercapnic stimulus can introduce errors in vascular reactivity measurements.Non‐vasoactive hyperoxia can serve as an endogenous tracer for baseline CBV.Combining hypercapnic and hyperoxic delays can highlight blood flow redistribution.Calibrated delays provide insights about differences in CVR across tissue depth.

Quantitative T1 mapping under precisely controlled graded hyperoxia at 7T

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.

Temporal B0 field variation effects on MRSI of the human prostate at 7 T and feasibility of correction using an internal field probe

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

Blood Oxygenation Level–dependent/Functional Magnetic Resonance Imaging: Underpinnings, Practice, and Perspectives

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.