Bayesian inference of hemodynamic changes in functional arterial spin labeling data

How far is arterial spin labeling MRI from a clinical reality? Insights from arterial spin labeling comparative studies in Alzheimer's disease and other neurological disorders.

The most widely-used functional magnetic resonance imaging (fMRI) technique is based on the blood oxygenation level dependent (BOLD) effect, which requires at least partial uncoupling between cerebral blood flow (CBF) and oxygen consumption changes during increased mental activity. To compare BOLD and CBF effects during tasking, BOLD and flow-sensitive alternating inversion recovery (FAIR) images were acquired during visual stimulation with red goggles at a frequency of 8 Hz in an interleaved fashion. With the FAIR technique, absolute and relative CBF changes were determined. Relative oxygen consumption changes can be estimated using the BOLD and relative CBF changes. In gray matter areas in the visual cortex, absolute and relative CBF changes in humans during photic stimulation were 31 +/- 11 SD ml/100 g tissue/min and 43 +/- 16 SD % (n = 12), respectively, while the relative oxygen consumption change was close to zero. These findings agree extremely well with previous results using positron emission tomography. The BOLD signal change is not linearly correlated with the relative CBF increase across subjects and negatively correlates with the oxygen consumption change. Caution should be exercised when interpreting the BOLD percent change as a quantitative index of the CBF change, especially in inter-subject comparisons.

Functional magnetic resonance imaging (fMRI) is a unique window to the brain, enabling scientists to follow changes in brain activity in response to hormones, ageing, environment, drugs of abuse and other stimuli. There are two features that make fMRI unique when compared with other imaging modalities used in behavioural neuroscience. First, it can be entirely noninvasive: each animal can serve as its own control over the natural course of its life, vital for following neuroadaptation and other developmental processes critical to understanding behaviour. Second, fMRI has the spatial and temporal resolution to observe patterns of neuronal activity across the entire brain in less than a minute. Although fMRI does not have the cellular spatial resolution of immunostaining, nor the millisecond temporal resolution of electrophysiology, synchronised changes in neuronal activity across multiple brain areas seen with functional MRI can be viewed as functional neuroanatomical circuits coordinating the thoughts, memories and emotions for particular behaviours. Thus, fMRI affords a systems approach to the study of the brain, complementing and building from other neurobiological techniques to understand how behaviour is organised across multiple brain regions. In this review, we present a general background to fMRI and the different imaging modalities that can be used in fMRI studies. Included are examples of the application of fMRI in behavioural neuroscience research, along with discussion of the advantages and disadvantages of this technology.

Functional MR imaging was performed in sixteen healthy human subjects measuring both regional cerebral blood flow (CBF) and blood oxygen level dependent (BOLD) signal when visual and auditory stimuli were presented to subjects in the presence or absence of anesthesia. During anesthesia, 0.25 mean alveolar concentration (MAC) sevoflurane was administrated. We found that low-dose sevoflurane decreased the task-induced changes in both BOLD and CBF. Within the visual and auditory regions of interest inspected, both baseline CBF and the task-induced changes in CBF decreased significantly during anesthesia. Low-dose sevoflurane significantly altered the task-induced CBF-BOLD coupling; for a unit change of CBF, a larger change in BOLD was observed in the anesthesia condition than in the anesthesia-free condition. Low-dose sevoflurane was also found to have significant impact on the spatial nonuniformity of the task-induced coupling. The alteration of task-induced CBF-BOLD coupling by low-dose sevoflurane introduces ambiguity to the direct interpretation of functional MRI (fMRI) data based on only one of the indirect measures-CBF or BOLD. Our observations also indicate that the manipulation of the brain with an anesthetic agent complicates the model-based quantitative interpretation of fMRI data, in which the relative task-induced changes in oxidative metabolism are calculated by means of a calibrated model given the relative changes in the indirect vascular measures, usually CBF and BOLD.

Cerebrovascular reactivity measured with arterial spin labeling and blood oxygen level dependent techniques

Reproducibility of BOLD, perfusion, and CMRO2 measurements with calibrated-BOLD fMRI

Resting-state brain activity has been widely investigated using blood oxygenation level dependent (BOLD) contrast techniques. However, BOLD signal changes reflect a combination of the effects of cerebral blood flow (CBF), cerebral blood volume (CBV), as well as the cerebral metabolic rate of oxygen (CMRO2). In this study, resting-state brain activation was detected and compared using the following techniques: (a) BOLD, using a gradient-echo echo planar imaging (GE-EPI) sequence; (b) CBV-weighted signal, acquired using gradient and spin echo (GRASE) based vascular space occupancy (VASO); and (c) CBF, using pseudo-continuous arterial spin labeling (pCASL). Reliable brain networks were detected using VASO and ASL, including sensorimotor, auditory, primary visual, higher visual, default mode, salience and left/right executive control networks. Differences between the resting-state activation detected with ASL, VASO and BOLD could potentially be due to the different temporal signal-to-noise ratio (tSNR) and the short post-labeling delay (PLD) in ASL, along with differences in the spin-echo readout of VASO. It is also possible that the dynamics of spontaneous fluctuations in BOLD, CBV and CBF could differ due to biological reasons, according to their location within the brain.

Technical aspects and utility of fMRI using BOLD and ASL

To detect symptomatic hemispheres during the postoperative course of subarachnoid haemorrhage (SAH) using arterial spin labelling (ASL). Eighteen patients with aneurysmal SAH were included; four exhibited symptomatic vasospasm postoperatively. All patients underwent ASL on days 9-10 (single time-point ASL). Nine patients underwent serial measurements of ASL (serial ASL) on days 1-2, 9-10 and 13-21, and seven patients also underwent imaging on days 4-7. CBF in the posterior part of the MCA territory was measured, and the ipsilateral/contralateral ratio of CBF was calculated. Differences between symptomatic hemispheres and others underwent ROC analysis. Single time-point ASL revealed that CBF(day9-10) and CBF(i/c_day9-10) were significantly lower in symptomatic hemispheres than in asymptomatic hemispheres (P < 0.001). Serial ASL was significantly decreased on CBF(day4-7) compared with CBF(day1-2) and on CBF(day9-10) compared with CBF(day4-7), and significantly increased on CBF(day13-21) compared with CBF(day9-10). ROC analysis of single time-point ASL revealed that AUC for CBF(day9-10) was 0.95, significantly higher than CBF(i/c_day9-10) (P < 0.001). ROC analysis of serial ASL showed that AUC for CBF(day9-10) was 0.93 and significantly higher than CBF(day9-10/day1-2) and CBF(i/c_day9-10) (P < 0.001). Single time-point ASL revealed significant CBF reduction in symptomatic hemispheres compared with asymptomatic hemispheres. Serial ASL showed time-dependent CBF changes after SAH. • MR arterial spin labelling (ASL) can non-invasively assess cerebral blood flow (CBF) • ASL revealed significant CBF reduction in symptomatic hemispheres compared with asymptomatic hemispheres • Serial ASL measurements enable observation of time-dependent CBF changes after SAH • ASL is non- invasive and suitable for serial repeated examinations.

The idea that regional cerebral blood flow (CBF) could reflect neuronal ­activity began with experiments of Roy and Sherrington in 1890.1 This concept is the basis for all hemodynamic-based brain imaging techniques being used today. The focal increase in CBF can be considered to relate directly to neuronal activity because the glucose metabolism and CBF changes are coupled closely.2 Thus, the measurement of CBF change induced by stimulation has been used for mapping brain functions. Because cerebral metabolic rate of glucose (CMRglu) and CBF changes are coupled, it is assumed that cerebral metabolic rate of oxygen (CMRO2) and CBF changes also are coupled. However, based on positron emission tomographic measurements of CBF and CMRO2 in humans during somatosensory and visual stimulation, Fox and colleagues reported that an increase in CBF surpassed an increase in CMRO2.3,4 Consequently, a mismatch between CBF and CMRO2 changes results in an increase in the capillary and venous oxygenation level, opening a new physiological parameter (in addition to CBF change) for brain mapping. In 1990, based on rat brain studies during global stimulation at 7 Tesla (T), Ogawa and colleagues at AT&T Bell Laboratories reported that functional brain mapping is possible by using the venous blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) contrast.5–7 The BOLD contrast relies on changes in deoxyhemoglobin (dHb), which acts as an endogenous paramagnetic contrast agent.5,8, Therefore, changes in the local dHb concentration in the brain lead to alterations in the signal intensity of magnetic resonance images.5–7,9

Arterial Spin Labelling (ASL) imaging derives a perfusion image by tracing the accumulation of magnetically labeled blood water in the brain. As the image generated has an intrinsically low signal to noise ratio (SNR), multiple measurements are routinely acquired and averaged, at a penalty of increased scan duration and opportunity for motion artefact. However, this strategy alone might be ineffective in clinical settings where the time available for acquisition is limited and patient motion are increased. This study investigates the use of an Independent Component Analysis (ICA) approach for denoising ASL data, and its potential for automation.72 ASL datasets (pseudo-continuous ASL; 5 different post-labeling delays: 400, 800, 1200, 1600, 2000 m s; total volumes = 60) were collected from thirty consecutive acute stroke patients. The effects of ICA-based denoising (manual and automated) where compared to two different denoising approaches, aCompCor, a Principal Component-based method, and Enhancement of Automated Blood Flow Estimates (ENABLE), an algorithm based on the removal of corrupted volumes. Multiple metrics were used to assess the changes in the quality of the data following denoising, including changes in cerebral blood flow (CBF) and arterial transit time (ATT), SNR, and repeatability. Additionally, the relationship between SNR and number of repetitions acquired was estimated before and after denoising the data.The use of an ICA-based denoising approach resulted in significantly higher mean CBF and ATT values (p < 0.001), lower CBF and ATT variance (p < 0.001), increased SNR (p < 0.001), and improved repeatability (p < 0.05) when compared to the raw data. The performance of manual and automated ICA-based denoising was comparable. These results went beyond the effects of aCompCor or ENABLE. Following ICA-based denoising, the SNR was higher using only 50% of the ASL-dataset collected than when using the whole raw data.The results show that ICA can be used to separate signal from noise in ASL data, improving the quality of the data collected. In fact, this study suggests that the acquisition time could be reduced by 50% without penalty to data quality, something that merits further study. Independent component classification and regression can be carried out either manually, following simple criteria, or automatically.

Detecting changes in human cerebral blood flow after acute exercise using arterial spin labeling: Implications for fMRI

Application of BOLD Magnetic Resonance Imaging for Evaluating Regional Volumetric Foot Tissue Oxygenation: A Feasibility Study in Healthy Volunteers

Baseline GABA concentration and fMRI response

Methodological advancements of functional Magnetic Resonance Imaging (fMRI) in recent years allow researchers to approach the mesoscopic spatial regime of cortical layers and cortical columns. In principle, this could revolutionize the ability to tackle cortical information processing within micro-circuits and across brain systems. One of the major limitations of conventional gradient-echo BOLD fMRI, however, is that it probes neuronal activity changes only indirectly via evoked cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMRO2) changes. Since, the resulting gradient-echo BOLD signal is mostly sensitive to ascending veins in the tissue and to pial veins, the achievable spatial specificity to neuronal activation is limited. Furthermore, the non-linear interaction of CBF, CBV and CMRO2 at high resolutions can hamper quantitative interpretations of the BOLD signal across cortical layer and columns with different baseline physiology. Measuring CBF, CBV or CMRO2 directly on a laminar and columnar level can overcome these limitations. This presentation will introduce laminar non-BOLD fMRI methods, summarize resent advancements, and provide an overview of how to use these methods to improve the neuroscientific interpretability in application studies. First, I will review the physiology of the cortical blood supply in the sub-millimeter regime and the corresponding practical challenges in high-resolution fMRI. Then, I will review the most-widely used non-BOLD fMRI methods to measure high-resolution CBF, CBV and CMRO2 responses and discuss them with respect to their sequence parameter space, sensitivity, specificity and applicability. Specific focus will be on the methods of arterial spin labeling (ASL), vascular space occupancy (VASO) and calibrated fMRI. Finally, I will conclude that non-BOLD methods at submillimeter resolution have an inherently low signal-to-noise ratio (SNR) are thus still challenging. However, their spatial specificity is improved, they are quantifiable, and, hence, the obtained results are physiologically interpretable. Therefore, they can potentially be superior alternatives to conventional GE-BOLD never the less. This conclusion will be discussed in the light of recent neuroscientific application studies that pinpoint laminar and columnar microcircuits in visual cortex, sensorimotor cortex, and prefrontal cortex. References 1. Polimeni, J.R., Fischl, B., Greve, D.N., and Wald, L.L. (2010). Laminar analysis of 7T BOLD using an imposed spatial activation pattern in human V1. Neuroimage 52, 1334–1346. 2. Kay, K., Jamison, K., Vizioli, L., Zhang, R., Margalit, E., and Ugurbil, K. (2018). A critical assessment of data quality and venous effects in ultra-high-resolution fMRI. BioRxiv 1–45. 3. Kim, S.-G., and Ogawa, S. (2012). Biophysical and physiological origins of blood oxygenation level-dependent fMRI signals. J. Cereb. Blood Flow Metab. 32, 1188–1206. 4. Goense, J.B.M., Whittingstall, K., and Logothetis, N.K. (2012). Neural and BOLD responses across the brain. Wiley Interdiscip. Rev. Cogn. Sci. 3, 75–86. 5. Huber, L., Uludaǧ, K., and Möller, H.E. (2017). Non-BOLD contrast for laminar fMRI in humans: CBF, CBV, and CMRO2. Neuroimage ahead of print. 6. Huber, Finn, Handwerker ... Bandettini (2018). Unique functional digit representation in human motor cortex across columns and layers. In 48th Society for Neuroscience, p. 675.03. 7. Finn, Huber, Jangraw, and Bandettini (2018). Layer-dependent activity in human prefrontal cortex during working memory. BioRxiv 425249. 8. Huber, Handwerker, Jangraw ... Bandettini (2017). High-resolution CBV-fMRI allows mapping of laminar activity and connectivity of cortical cortical input and output in human M1.