Keith St. Lawrence

Using perfusion MRI to measure the dynamic changes in neural activation associated with tonic muscular pain.

&NA; Knowledge regarding neural pain processing is primarily the result of studies involving models of brief cutaneous pain; however, clinical pain generally originates in deep tissue and is prolonged. This study measured the dynamic neural activation associated with a muscular pain model incorporating both acute and tonic states. Hypertonic saline (5% NaCl) was infused into the brachioradialis muscle of eleven healthy volunteers for 15 min after an initial bolus of 0.5 mL. Ten controls followed the same protocol with normal saline (0.9% NaCl). Magnetic resonance images of cerebral blood flow (CBF) were acquired using an arterial spin labelling method. The imaging volume extended from the thalamus to the primary somatosensory cortices, but did not include the brainstem and cerebellum. Using a numerical scale from 0 to 10, ratings of pain intensity peaked at 5.9 ± 0.6 and remained near 5 for the remainder of the trial. Controls experienced minimal pain, reporting a peak value of 1.8 ± 0.4. Significant CBF increases in rostral and caudal anterior insula bilaterally, anterior mid‐cingulate cortex (aMCC), bilateral thalamus, and contralateral posterior insula were observed. The time courses of CBF revealed significant differences in the activation pattern during tonic pain. In particular, a more rapid return to baseline in aMCC versus insula was interpreted as a preferential decrease in the affective component of pain. This conclusion was supported by the strong correlation between pain intensity ratings and CBF in the contralateral insula (R2 = 0.911, p < 0.01), which is a region believed to be responsible for pain intensity processing.

Calibration of diffuse correlation spectroscopy with a time-resolved near-infrared technique to yield absolute cerebral blood flow measurements

A primary focus of neurointensive care is the prevention of secondary brain injury, mainly caused by ischemia. A noninvasive bedside technique for continuous monitoring of cerebral blood flow (CBF) could improve patient management by detecting ischemia before brain injury occurs. A promising technique for this purpose is diffuse correlation spectroscopy (DCS) since it can continuously monitor relative perfusion changes in deep tissue. In this study, DCS was combined with a time-resolved near-infrared technique (TR-NIR) that can directly measure CBF using indocyanine green as a flow tracer. With this combination, the TR-NIR technique can be used to convert DCS data into absolute CBF measurements. The agreement between the two techniques was assessed by concurrent measurements of CBF changes in piglets. A strong correlation between CBF changes measured by TR-NIR and changes in the scaled diffusion coefficient measured by DCS was observed (R2 = 0.93) with a slope of 1.05 ± 0.06 and an intercept of 6.4 ± 4.3% (mean ± standard error).

Quantification issues in arterial spin labeling perfusion magnetic resonance imaging.

Arterial spin labeling (ASL) perfusion magnetic resonance imaging has gained wide acceptance for its value in clinical and neuroscience applications during recent years. Its capability for noninvasive and absolute perfusion quantification is a key characteristic that makes ASL attractive for many clinical applications. In the present review, we discuss the main parameters or factors that affect the reliability and accuracy of ASL perfusion measurements. Our secondary goal was to outline potential solutions that may improve the reliability and accuracy of ASL in clinical settings. It was found that, through theoretical analyses, flow quantification is most sensitive to tagging efficiency and estimation of the equilibrium magnetization of blood signal (M0b). Variations of blood T1 have a greater effect on perfusion quantification than variations of tissue T1. Arterial transit time becomes an influential factor when it is longer than the postlabeling delay time. The T2s of blood and tissue impose minimal effects on perfusion calculation at field strengths equal to or lower than 3.0 T. Subsequently, we proposed various approaches for in vivo estimation or calibration of the above parameters, such as the use of phase-contrast magnetic resonance imaging for calibration of the labeling efficiency as well as the use of inversion recovery TrueFISP (true fast imaging with steady-state precession) sequence for blood T1 mapping. We also list representative clinical cases in which implicit assumptions for ASL perfusion quantification may be violated, such as the venous outflow effect in children with sickle cell disease. Finally, an optimal imaging protocol including in vivo measurements of several critical parameters was recommended for clinical ASL studies.

Comparison of time-resolved and continuous-wave near-infrared techniques for measuring cerebral blood flow in piglets.

A primary focus of neurointensive care is monitoring the injured brain to detect harmful events that can impair cerebral blood flow (CBF), resulting in further injury. Since current noninvasive methods used in the clinic can only assess blood flow indirectly, the goal of this research is to develop an optical technique for measuring absolute CBF. A time-resolved near-infrared (TR-NIR) apparatus is built and CBF is determined by a bolus-tracking method using indocyanine green as an intravascular flow tracer. As a first step in the validation of this technique, CBF is measured in newborn piglets to avoid signal contamination from extracerebral tissue. Measurements are acquired under three conditions: normocapnia, hypercapnia, and following carotid occlusion. For comparison, CBF is concurrently measured by a previously developed continuous-wave NIR method. A strong correlation between CBF measurements from the two techniques is revealed with a slope of 0.79±0.06, an intercept of -2.2±2.5 ml∕100 g∕min, and an R2 of 0.810±0.088. Results demonstrate that TR-NIR can measure CBF with reasonable accuracy and is sensitive to flow changes. The discrepancy between the two methods at higher CBF could be caused by differences in depth sensitivities between continuous-wave and time-resolved measurements.

Quantification of renal perfusion: Comparison of arterial spin labeling and dynamic contrast‐enhanced MRI

To provide the first comparison of absolute renal perfusion obtained by arterial spin labeling (ASL) and separable compartment modeling of dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI). Moreover, we provide the first application of the dual bolus approach to quantitative DCE‐MRI perfusion measurements in the kidney.

Quantitative measurement of cerebral blood flow in a juvenile porcine model by depth-resolved near-infrared spectroscopy

Nearly half a million children and young adults are affected by traumatic brain injury each year in the United States. Although adequate cerebral blood flow (CBF) is essential to recovery, complications that disrupt blood flow to the brain and exacerbate neurological injury often go undetected because no adequate bedside measure of CBF exists. In this study we validate a depth-resolved, near-infrared spectroscopy (NIRS) technique that provides quantitative CBF measurement despite significant signal contamination from skull and scalp tissue. The respiration rates of eight anesthetized pigs (weight: 16.2+/-0.5 kg, age: 1 to 2 months old) are modulated to achieve a range of CBF levels. Concomitant CBF measurements are performed with NIRS and CT perfusion. A significant correlation between CBF measurements from the two techniques is demonstrated (r(2)=0.714, slope=0.92, p<0.001), and the bias between the two techniques is -2.83 mL min(-1)100 g(-1) (CI(0.95): -19.63 mL min(-1)100 g(-1)-13.9 mL min(-1)100 g(-1)). This study demonstrates that accurate measurements of CBF can be achieved with depth-resolved NIRS despite significant signal contamination from scalp and skull. The ability to measure CBF at the bedside provides a means of detecting, and thereby preventing, secondary ischemia during neurointensive care.

A multi-centre evaluation of eleven clinically feasible brain PET/MRI attenuation correction techniques using a large cohort of patients.

Aim: To accurately quantify the radioactivity concentration measured by PET, emission data need to be corrected for photon attenuation; however, the MRI signal cannot easily be converted into attenuation values, making attenuation correction (AC) in PET/MRI challenging. In order to further improve the current vendor‐implemented MR‐AC methods for absolute quantification, a number of prototype methods have been proposed in the literature. These can be categorized into three types: template/atlas‐based, segmentation‐based, and reconstruction‐based. These proposed methods in general demonstrated improvements compared to vendor‐implemented AC, and many studies report deviations in PET uptake after AC of only a few percent from a gold standard CT‐AC. Using a unified quantitative evaluation with identical metrics, subject cohort, and common CT‐based reference, the aims of this study were to evaluate a selection of novel methods proposed in the literature, and identify the ones suitable for clinical use. Methods: In total, 11 AC methods were evaluated: two vendor‐implemented (MR‐ACDIXON and MR‐ACUTE), five based on template/atlas information (MR‐ACSEGBONE (Koesters et al., 2016), MR‐ACONTARIO (Anazodo et al., 2014), MR‐ACBOSTON (Izquierdo‐Garcia et al., 2014), MR‐ACUCL (Burgos et al., 2014), and MR‐ACMAXPROB (Merida et al., 2015)), one based on simultaneous reconstruction of attenuation and emission (MR‐ACMLAA (Benoit et al., 2015)), and three based on image‐segmentation (MR‐ACMUNICH (Cabello et al., 2015), MR‐ACCAR‐RiDR (Juttukonda et al., 2015), and MR‐ACRESOLUTE (Ladefoged et al., 2015)). We selected 359 subjects who were scanned using one of the following radiotracers: [18F]FDG (210), [11C]PiB (51), and [18F]florbetapir (98). The comparison to AC with a gold standard CT was performed both globally and regionally, with a special focus on robustness and outlier analysis. Results: The average performance in PET tracer uptake was within ±5% of CT for all of the proposed methods, with the average±SD global percentage bias in PET FDG uptake for each method being: MR‐ACDIXON (−11.3±3.5)%, MR‐ACUTE (−5.7±2.0)%, MR‐ACONTARIO (−4.3±3.6)%, MR‐ACMUNICH (3.7±2.1)%, MR‐ACMLAA (−1.9±2.6)%, MR‐ACSEGBONE (−1.7±3.6)%, MR‐ACUCL (0.8±1.2)%, MR‐ACCAR‐RiDR (−0.4±1.9)%, MR‐ACMAXPROB (−0.4±1.6)%, MR‐ACBOSTON (−0.3±1.8)%, and MR‐ACRESOLUTE (0.3±1.7)%, ordered by average bias. The overall best performing methods (MR‐ACBOSTON, MR‐ACMAXPROB, MR‐ACRESOLUTE and MR‐ACUCL, ordered alphabetically) showed regional average errors within ±3% of PET with CT‐AC in all regions of the brain with FDG, and the same four methods, as well as MR‐ACCAR‐RiDR, showed that for 95% of the patients, 95% of brain voxels had an uptake that deviated by less than 15% from the reference. Comparable performance was obtained with PiB and florbetapir. Conclusions: All of the proposed novel methods have an average global performance within likely acceptable limits (±5% of CT‐based reference), and the main difference among the methods was found in the robustness, outlier analysis, and clinical feasibility. Overall, the best performing methods were MR‐ACBOSTON, MR‐ACMAXPROB, MR‐ACRESOLUTE and MR‐ACUCL, ordered alphabetically. These methods all minimized the number of outliers, standard deviation, and average global and local error. The methods MR‐ACMUNICH and MR‐ACCAR‐RiDR were both within acceptable quantitative limits, so these methods should be considered if processing time is a factor. The method MR‐ACSEGBONE also demonstrates promising results, and performs well within the likely acceptable quantitative limits. For clinical routine scans where processing time can be a key factor, this vendor‐provided solution currently outperforms most methods. With the performance of the methods presented here, it may be concluded that the challenge of improving the accuracy of MR‐AC in adult brains with normal anatomy has been solved to a quantitatively acceptable degree, which is smaller than the quantification reproducibility in PET imaging.

Quantifying the cerebral metabolic rate of oxygen by combining diffuse correlation spectroscopy and time-resolved near-infrared spectroscopy

Abstract. Preterm infants are highly susceptible to ischemic brain injury; consequently, continuous bedside monitoring to detect ischemia before irreversible damage occurs would improve patient outcome. In addition to monitoring cerebral blood flow (CBF), assessing the cerebral metabolic rate of oxygen (CMRO2) would be beneficial considering that metabolic thresholds can be used to evaluate tissue viability. The purpose of this study was to demonstrate that changes in absolute CMRO2 could be measured by combining diffuse correlation spectroscopy (DCS) with time-resolved near-infrared spectroscopy (TR-NIRS). Absolute CBF was determined using bolus-tracking TR-NIRS to calibrate the DCS measurements. Cerebral venous blood oxygenation (SvO2) was determined by multiwavelength TR-NIRS measurements, the accuracy of which was assessed by directly measuring the oxygenation of sagittal sinus blood. In eight newborn piglets, CMRO2 was manipulated by varying the anesthetics and by injecting sodium cyanide. No significant differences were found between the two sets of SvO2 measurements obtained by TR-NIRS or sagittal sinus blood samples and the corresponding CMRO2 measurements. Bland–Altman analysis showed a mean CMRO2 difference of 0.0268±0.8340  mL O2/100  g/min between the two techniques over a range from 0.3 to 4 mL O2/100  g/min.

Measurement of cerebral oxidative metabolism with near-infrared spectroscopy: a validation study

Predicting the onset of secondary energy failure after a hypoxic–ischemic insult in newborns is critical for providing effective treatment. Measuring reductions in the cerebral metabolic rate of oxygen (CMRO2) may be one method for early detection, as hypoxia–ischemia is believed to impair oxidative metabolism. We have developed a near-infrared spectroscopy (NIRS) technique based on the Fick Principle for measuring CMRO2. This technique combines cerebral blood flow (CBF) measurements obtained using the tracer indocyanine green with measurements of the cerebral deoxy-hemoglobin (Hb) concentration. In this study, NIRS measurements of CMRO2 were compared with CMRO2 determined from the product of CBF and the cerebral arteriovenous difference in oxygen measured from blood samples. The blood samples were collected from a peripheral artery and the sagittal sinus. Eight piglets were subjected to five cerebral metabolic states created by varying the plane of anesthesia. No significant difference was found between CMRO2 measurements obtained with the two techniques at any anesthetic level (P > 0.5). Furthermore, there was a strong correlation when concomitant CMRO2 values from the two techniques were compared (R2 = 0.88, P< 0.001). This work showed that CMRO2 can be determined accurately by combining NIRS measurements of CBF and Hb. Since NIRS is safe and measurements can be obtained at the bedside, it is believed that this technique could assist in the early diagnosis of cerebral energy dysfunction after hypoxia–ischemia.

A two-stage approach for measuring vascular water exchange and arterial transit time by diffusion-weighted perfusion MRI.

Changes in the exchange rate of water across the blood‐brain barrier, denoted kw, may indicate blood‐brain barrier dysfunction before the leakage of large‐molecule contrast agents is observable. A previously proposed approach for measuring kw is to use diffusion‐weighted arterial spin labeling to measure the vascular and tissue fractions of labeled water, because the vascular‐to‐tissue ratio is related to kw. However, the accuracy of diffusion‐weighted arterial spin labeling is affected by arterial blood contributions and the arterial transit time (τa). To address these issues, a two‐stage method is proposed that uses combinations of diffusion‐weighted gradient strengths and post‐labeling delays to measure both τa and kw. The feasibility of this method was assessed by acquiring diffusion‐weighted arterial spin labeling data from seven healthy volunteers. Repeat measurements and Monte Carlo simulations were conducted to determine the precision and accuracy of the kw estimates. Average grey and white matter kw values were 110 ± 18 and 126 ± 18 min−1, respectively, which compare favorably to blood‐brain barrier permeability measurements obtained with positron emission tomography. The intrasubject coefficient of variation was 26% ± 23% in grey matter and 21% ± 17% in white matter, indicating that reproducible kw measurements can be obtained. Magn Reson Med, 2012.